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Find video protocols related to scientific articles indexed in Pubmed.
Metastatic consequences of immune escape from NK cell cytotoxicity by human breast cancer stem cells.
Cancer Res.
PUBLISHED: 08-27-2014
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Breast cancer stem-like cells (BCSC) are crucial for metastasis but the underlying mechanisms remain elusive. Here, we report that tumor-infiltrating natural killer (NK) cells failed to limit metastasis and were not associated with improved therapeutic outcome of BCSC-rich breast cancer. Primary BCSCs were resistant to cytotoxicity mediated by autologous/allogeneic NK cells due to reduced expression of MICA and MICB, two ligands for the stimulatory NK cell receptor NKG2D. Furthermore, the downregulation of MICA/MICB in BCSCs was mediated by aberrantly expressed oncogenic miR20a, which promoted the resistance of BCSC to NK cell cytotoxicity and resultant lung metastasis. The breast cancer cell differentiation-inducing agent, all-trans retinoic acid, restored the miR20a-MICA/MICB axis and sensitized BCSC to NK cell-mediated killing, thereby reducing immune escape-associated BCSC metastasis. Together, our findings reveal a novel mechanism for immune escape of human BCSC and identify the miR20a-MICA/MICB signaling axis as a therapeutic target to limit metastatic breast cancer. Cancer Res; 74(20); 5746-57. ©2014 AACR.
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Clinical diagnostic dilemma of intracranial germinoma manifesting as wide skull base extension.
J Craniofac Surg
PUBLISHED: 08-23-2014
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The aims of this study were to present an uncommon intracranial germinoma manifesting as skull base extension and analyze its clinical characteristics to give valuable insight into such uncommon radiologic variant.
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CLIC4, ERp29, and Smac/DIABLO derived from metastatic cancer stem-like cells stratify prognostic risks of colorectal cancer.
Clin. Cancer Res.
PUBLISHED: 06-10-2014
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Cancer stem-like cells have been well accepted to be involved in recurrence and metastasis of cancers, but the prognostic potential of biomarkers integrating with metastasis and cancer stem-like cells for colorectal cancer is unclear.
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ALDH1A1 expression correlates with clinicopathologic features and poor prognosis of breast cancer patients: a systematic review and meta-analysis.
BMC Cancer
PUBLISHED: 06-06-2014
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Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) has been identified as a putative cancer stem cell (CSC) marker in breast cancer. However, the clinicopathological and prognostic significance of this protein in breast cancer patients remains controversial.
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Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway.
J. Pathol.
PUBLISHED: 02-20-2014
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Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation.
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Primate-specific miR-663 functions as a tumor suppressor by targeting PIK3CD and predicts the prognosis of human glioblastoma.
Clin. Cancer Res.
PUBLISHED: 02-12-2014
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To determine the prognostic significance of miR-663 in glioblastoma, its effect in tumor progression, and the underlying mechanism.
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Increased pro-angiogenic factors, infiltrating neutrophils and CD163(+) macrophages in bronchoalveolar lavage fluid from lung cancer patients.
Int. Immunopharmacol.
PUBLISHED: 02-05-2014
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Infiltration of inflammatory cells and production of pro-angiogenic factors are important in lung cancer immunity. The distributions of those cells and their contributions to the production of pro-angiogenic factors and the activation phenotype of macrophages in bronchoalveolar lavage fluid (BALF) from lung cancer patients remain unclear. We analyzed the presence of distinct inflammatory cells and the macrophage activation phenotype together with the levels of vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8) within BALF from 54 smoking lung cancer patients including 36 squamous cell carcinoma (SCC), 9 adenocarcinoma (AC), and 9 small cell lung cancer (SCLC) in comparison with those from 13 non-smoking and 7 smoking patients with nonspecific chronic inflammation and 8 non-smoking normal controls. We found a significantly lower percentage of total macrophages and a much higher percentage of neutrophils among all inflammatory cells in BALF from lung cancer and non-specific chronic inflammation patients. BALF from AC patients had a significantly higher percentage of lymphocytes. CD163(+)) macrophages predominantly existed in BALF from SCLC patients. BALF of lung cancer patients had markedly higher levels of IL-8 and VEGF. Interestingly, IL-8 level was positively correlated to the numbers of neutrophils and lymphocytes. VEGF level was inversely correlated to the number of lymphocytes but positively to cancer cells in SCC cases, whereas no correlation existed between CD163(+)) macrophages and the levels of IL-8 and VEGF. Our results suggest that the detection of infiltrating inflammatory cells and pro-angiogenic factors in BALF will be helpful for diagnosis of cancerous inflammation in lungs.
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Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 01-21-2014
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Resistance to antiestrogens is one of the major challenges in breast cancer treatment. Although phosphorylation of estrogen receptor ? (ER?) is an important factor in endocrine resistance, the contributions of specific kinases in endocrine resistance are still not fully understood. Here, we report that an important innate immune response kinase, the I?B kinase-related TANK-binding kinase 1 (TBK1), is a crucial determinant of resistance to tamoxifen therapies. We show that TBK1 increases ER? transcriptional activity through phosphorylation modification of ER? at the Ser-305 site. Ectopic TBK1 expression impairs the responsiveness of breast cancer cells to tamoxifen. By studying the specimens from patients with breast cancer, we find a strong positive correlation of TBK1 with ER?, ER? Ser-305, and cyclin D1. Notably, patients with tumors highly expressing TBK1 respond poorly to tamoxifen treatment and show high potential for relapse. Therefore, our findings suggest that TBK1 contributes to tamoxifen resistance in breast cancer via phosphorylation modification of ER?.
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Resistance to apoptosis should not be taken as a hallmark of cancer.
Chin J Cancer
PUBLISHED: 01-15-2014
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In the research community, resistance to apoptosis is often considered a hallmark of cancer. However, pathologists who diagnose cancer via microscope often see the opposite. Indeed, increased apoptosis and mitosis are usually observed simultaneously in cancerous lesions. Studies have shown that increased apoptosis is associated with cancer aggressiveness and poor clinical outcome. Furthermore, overexpression of Bcl-2, an antiapoptotic protein, is linked with better survival of cancer patients. Conversely, Bax, CD95, Caspase-3, and other apoptosis-inducing proteins have been found to promote carcinogenesis. This notion of the role of apoptosis in cancer is not new; cancer cells were found to be short-lived 88 years ago. Given these observations, resistance to apoptosis should not be considered a hallmark of cancer.
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Overexpression of the transcription factor MEF2D in hepatocellular carcinoma sustains malignant character by suppressing G2-M transition genes.
Cancer Res.
PUBLISHED: 01-03-2014
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The underlying molecular pathogenesis in hepatocellular carcinoma remains poorly understood. The transcription factor MEF2D promotes survival in various cell types and it seems to function as an oncogene in leukemia. However, its potential contributions to solid cancers have not been explored. In this study, we investigated MEF2D expression and function in hepatocellular carcinoma, finding that MEF2D elevation in hepatocellular carcinoma clinical specimens was associated with poor prognosis. MEF2D-positive primary hepatocellular carcinoma cells displayed a faster proliferation rate compared with MEF2D-negative cells, and silencing or promoting MEF2D expression in these settings limited or accelerated cell proliferation, respectively. Notably, MEF2D-silencing abolished hepatocellular carcinoma tumorigenicity in mouse xenograft models. Mechanistic investigations revealed that MEF2D-silencing triggered G2-M arrest in a manner associated with direct downregulation of the cell-cycle regulatory genes RPRM, GADD45A, GADD45B, and CDKN1A. Furthermore, we identified MEF2D as an authentic target of miR-122, the reduced expression of which in hepatocellular carcinoma may be responsible for MEF2D upregulation. Together, our results identify MEF2D as a candidate oncogene in hepatocellular carcinoma and a potential target for hepatocellular carcinoma therapy.
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Metastatic cancer stem cells: from the concept to therapeutics.
Am J Stem Cells
PUBLISHED: 01-01-2014
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Metastatic cancer stem cells (MCSCs) refer to a subpopulation of cancer cells with both stem cell properties and invasion capabilities that contribute to cancer metastasis. MCSCs have capability of self-renewal, potentials of multiple differentiation and development and/or reconstruction of cancer tissues. As compared with stationary cancer stem cells, MCSCs are capable of invasion to normal tissues such as vasculatures, resistance to chemo- and/or radio-therapies, escape from immune surveillance, survival in circulation and formation of metastasis. MCSCs are derived from invasive cancer stem cells (iCSCs) due to the plasticity of cancer stem cells, which is one of the characteristics of cancer cell heterogeneity. Both stages of iCSCs and MSCSs are the potential therapeutic targets for cancer metastasis in the future strategies of personalized cancer therapy.
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Disruption of the ER-?36-EGFR/HER2 positive regulatory loops restores tamoxifen sensitivity in tamoxifen resistance breast cancer cells.
PLoS ONE
PUBLISHED: 01-01-2014
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Tamoxifen provided a successful treatment for ER-positive breast cancer for many years. However, most breast tumors develop tamoxifen resistance and are eventually refractory to tamoxifen therapy. The molecular mechanisms underlying development of tamoxifen resistance have not been well established. Recently, we reported that breast cancer cells with high levels of ER-?36, a variant of ER-?, were resistant to tamoxifen and knockdown of ER-?36 expression in tamoxifen resistant cells with the shRNA method restored tamoxifen sensitivity, indicating that gained ER-?36 expression is one of the underlying mechanisms of tamoxifen resistance. Here, we found that tamoxifen induced expression of ER-?36-EGFR/HER2 positive regulatory loops and tamoxifen resistant MCF7 cells (MCF7/TAM) expressed enhanced levels of the loops. Disruption of the ER-?36-EGFR/HER2 positive regulatory loops with the dual tyrosine kinase inhibitor Lapatinib or ER-?36 down-regulator Broussoflavonol B in tamoxifen resistant MCF7 cells restored tamoxifen sensitivity. In addition, we also found both Lapatinib and Broussoflavonol B increased the growth inhibitory activity of tamoxifen in tumorsphere cells derived from MCF7/TAM cells. Our results thus demonstrated that elevated expression of the ER-?36-EGFR/HER2 loops is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy. Our results thus provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting the ER-?36-EGFR/HER2 loops.
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Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma.
Int J Clin Exp Pathol
PUBLISHED: 01-01-2014
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Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC.
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Is CD133 expression a prognostic biomarker of non-small-cell lung cancer? A systematic review and meta-analysis.
PLoS ONE
PUBLISHED: 01-01-2014
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The clinical and prognostic significance of CD133 in non-small-cell lung cancer (NSCLC) remains controversial. To clarify a precise determinant of the clinical significance of CD133, we conducted a systematic review and meta-analysis to evaluate the association of CD133 with prognosis and clinicopathological features of NSCLC patients.
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A facile strategy to decorate Cu?S? nanocrystals on polyaniline nanowires and their synergetic catalytic properties.
Sci Rep
PUBLISHED: 09-04-2013
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Here, we demonstrated a novel method to decorate Cu?S? nanocrystals on polyaniline (PANI) nanowires using the dopant of mercaptoacetic acid (MAA) in the PANI matrix as the sulfur source under a hydrothermal reaction. TEM images showed that Cu?S? nanocrystals with a size in the range of 5-20?nm were uniformly formed on the surface of PANI nanowires. Significantly, the as-prepared PANI/Cu?S? composite nanowires have been proven to be novel peroxidase mimics toward the oxidation of the peroxidase substrate 3,3,5,5-tetramethylbenzidine (TMB) in the presence of H?O?. Due to the synergetic effects between polyaniline nanowires and Cu?S? nanocrystals, the obtained PANI/Cu?S? composite nanowires exhibit superior catalytic activity over the independent components. This work not only presents a simple and versatile method to decorate semiconductor nanocrystals on the surface of conducting polymer nanostructures, but also provides fundamental guidelines for further investigations into the synergetic effect between conducting polymers and other materials.
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ALDH1A1 defines invasive cancer stem-like cells and predicts poor prognosis in patients with esophageal squamous cell carcinoma.
Mod. Pathol.
PUBLISHED: 07-11-2013
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Invasion and metastasis are the major cause of deaths in patients with esophageal cancer. In this study, we isolated cancer stem-like cells from an esophageal squamous cell carcinoma cell line EC109 based on aldehyde dehydrogenase 1A1 (ALDH1A1), and found that ALDH1A1(high) cells possessed the capacities of self-renewal, differentiation and tumor initiation, indications of stem cell properties. To support their stemness, ALDH1A1(high) cells exhibited increased potential of invasion and metastasis as compared with ALDH1A1(low) cells. ALDH1A1(high) esophageal squamous cell carcinoma cells expressed increased levels of mRNA for vimentin, matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9), but decreased the level of E-cadherin mRNA, suggesting that epithelial-mesenchymal transition and secretary MMPs may be attributed to the high invasive and metastatic capabilities of ALDH1A1(high) cells. Furthermore, we examined esophageal squamous cell carcinoma specimens from 165 patients and found that ALDH1A1(high) cells were associated with esophageal squamous dysplasia and the grades, differentiation and invasion depth, lymph node metastasis and UICC stage of esophageal squamous cell carcinoma, as well as poor prognosis of patients. Our results provide the strong evidence that ALDH1A1(high) cancer stem-like cells contribute to the invasion, metastasis and poor outcome of human esophageal squamous cell carcinoma.Modern Pathology advance online publication, 8 November 2013; doi:10.1038/modpathol.2013.189.
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Strategies for isolating and enriching cancer stem cells: well begun is half done.
Stem Cells Dev.
PUBLISHED: 05-09-2013
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Cancer stem cells (CSCs) constitute a subpopulation of cancer cells that have the potential for self-renewal, multipotent differentiation, and tumorigenicity. Studies on CSC biology and CSC-targeted therapies depend on CSC isolation and/or enrichment methodologies. Scientists have conducted extensive research in this field since John Dicks group successfully isolated CSCs based on the expression of the CD34 and CD38 surface markers. Progress in CSC research has been greatly facilitated by the enrichment and isolation of these cells. In this review, we summarize the current strategies used in our and other laboratories for CSC isolation and enrichment, including methods based on stem cell surface markers, intracellular enzyme activity, the concentration of reactive oxygen species, the mitochondrial membrane potential, promoter-driven fluorescent protein expression, autofluorescence, suspension/adherent culture, cell division, the identification of side population cells, resistance to cytotoxic compounds or hypoxia, invasiveness/adhesion, immunoselection, and physical property. Although many challenges remain to be overcome, it is reasonable to believe that more reliable, efficient, and convenient methods will be developed in the near future.
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?-Catenin/POU5F1/SOX2 transcription factor complex mediates IGF-I receptor signaling and predicts poor prognosis in lung adenocarcinoma.
Cancer Res.
PUBLISHED: 03-28-2013
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Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3?/?-catenin cascade. POU5F1 could form a novel complex with ?-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with ?-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR-mediated POU5F1 expression to form a complex with ?-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, ?-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma.
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The telomere/telomerase binding factor PinX1 is a new target to improve the radiotherapy effect of oesophageal squamous cell carcinomas.
J. Pathol.
PUBLISHED: 02-22-2013
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Chemoradiotherapy (CRT) is a standard treatment for oesophageal squamous cell carcinoma (ESCC) in its advanced stages. The telomerase/telomere interacting protein PinX1 contributes to telomere maintenance, tumourigenicity, and influences the DNA damage agent-induced apoptotic response in telomerase-positive cancer cells. However, the clinical and biological significance of PinX1 in human ESCCs remains unclear. We examined the expression dynamics of PinX1 by immunohistochemistry in a learning cohort (n?=?98) and a validation cohort (n?=?59) of ESCC patients treated with definite chemoradiotherapy (CRT). A series of in vivo and in vitro assays were performed to elucidate the effect of PinX1 on ESCC cells CRT response and underlying mechanisms. Knockdown of PinX1 did not affect ESCC cells chemosensitivities to 5-fluorouracil and cisplatin, but substantially increased ESCC cells therapeutic efficacy of radiation both in vitro and in vivo. Ectopic overexpression of PinX1 dramatically enhanced ESCC cells resistance to radiotherapy. Furthermore, we demonstrated that PinX1 resistance to radiotherapy (RT) was attributed to PinX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe (MC). High expression of Pinx1 correlated positively with ESCCs resistance to CRT, and was a strong and independent predictor for short disease-specific survival (DSS) of ESCC patients. Our data suggest that PinX1 could serve as a novel predictor for a CRT response to ESCC patients, and the pathway of PinX1-mediated telomere stability might represent a new target to improve the RT effect of ESCC.
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Functional characterization of a PEI-CyD-FA-coated adenovirus as delivery vector for gene therapy.
Curr. Med. Chem.
PUBLISHED: 02-05-2013
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The recombinant adenovirus is evolving as a promising gene delivery vector for gene therapy due to its efficiency in transducing different genes into most types of cells. However, the host-immune response elicited by primary inoculation of an adenovirus can cause rapid clearance of the vector, impairing the efficacy of the adenovirus and hence obstructing its clinical application. We have previously synthesized a biodegradable co-polymer consisting of a low molecular weight PEI (MW 600 Da), cross-linked with ?-cyclodextrin, and conjugated with folic acid (PEI-CyD-FA, named H1). Here we report that coating the adenovirus vector (Adv) with H1 (H1/rAdv) could significantly improve both the efficacy and biosafety of Adv. Enhanced transfection efficiency as well as prolonged duration of gene expression were clearly demonstrated either by intratumoral or systemic injection of a single dose of H1/rAdv in immunocompetent mice. Importantly, repeated injections of H1/rAdv did not reduce the transfection efficiency in immunocompetent mice. Furthermore, H1 transformed the surface charge of the adenovirus capsomers from negative to positive in physiological solution, suggesting that H1 coated the capsid protein of the adenovirus. This could shelter the epitopes of capsid proteins of the adenovirus, resulting in a reduced host-immune response and enhanced transfection efficiency. Taken together, these findings suggest that H1/rAdv is an effective gene delivery system superior to the adenovirus alone and that it could be considered as a preferred vehicle for gene therapy.
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Type II, but not type I, cGMP-dependent protein kinase reverses bFGF-induced proliferation and migration of U251 human glioma cells.
Mol Med Rep
PUBLISHED: 01-29-2013
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Previous data have shown that the type II cGMP?dependent protein kinase (PKG II) inhibits the EGF?induced MAPK signaling pathway. In order to thoroughly investigate PKG, it is necessary to elucidate the function of another type of PKG, PKG I. The aim of this study was to investigate the possible inhibitory effect of PKG II and PKG I activity on the basic fibroblast growth factor (bFGF)?induced proliferation and migration of U251 human glioma cells and the possible underlying mechanisms. U251 cells were infected with adenoviral constructs encoding cDNA of PKG I (Ad?PKG I) or PKG II (Ad?PKG II) to increase the expression levels of PKG I or PKG II and then treated with 8?Br?cGMP and 8?pCPT?cGMP, respectively, to activate the enzyme. An MTT assay was used to detect the proliferation of the U251 cells. The migration of the U251 cells was analyzed using a Transwell migration assay. Western blot analysis was used to detect the phosphorylation/activation of the fibroblast growth factor receptor (FGFR), MEK and ERK and the nuclear distribution of p-ERK. The results showed that bFGF treatment increased the proliferation and migration of U251 cells, accompanied by increased phosphorylation of FGFR, MEK and ERK. Furthermore, the nuclear distribution of p-ERK increased following bFGF treatment. Increasing the activity of PKG II through infection with Ad-PKG II and stimulation with 8-pCPT-cGMP significantly attenuated the aforementioned effects of the bFGF treatment, while increased PKG I activity did not inhibit the effects of bFGF treatment. These data suggest that increased PKG II activity attenuates bFGF?induced proliferation and migration by inhibiting the MAPK/ERK signaling pathway, whereas PKG I does not.
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Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model.
J. Mol. Med.
PUBLISHED: 01-06-2013
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It has been demonstrated that numerous microRNAs (miRNAs) have potent tumor-suppressing effects on a variety of cancers, implicating a possible application of miRNA in tumor therapy. Oncolytic adenovirus is a suitable vector to deliver tumor suppressor genes for treatment of cancers. However, it remains unknown whether co-expression of tumor suppressor genes and miRNAs can contribute to a more potent antitumor capacity within an oncolytic adenovirus delivery system. In this study, we found that expression of miRNA-34a was reduced in hepatocellular carcinoma (HCC), and the reduced expression of miRNA-34a was associated with worse outcome of HCC patients. Thus, we developed an oncolytic adenoviral vector, AdCN205, to co-express miRNA-34a and IL-24 driven by an adenovirus endogenous E3 promoter in HCC cells. High levels of miRNA-34a and IL-24 expression were detected in AdCN205-IL-24-miR-34a-infected HCC cells. AdCN205-IL-24-miR-34a significantly induced dramatic antitumor activity, as compared with that induced by AdCN205-IL-24 or AdCN205-miR-34a alone. Transfer of miRNA-34a into HCC cells inhibited the expression of its target genes, Bcl-2 and SIRT1. Treatment of established xenograft HCC tumors with AdCN205-IL-24-miR-34a in a mouse model resulted in complete tumor regression without recurrence. Taken together, our data provide a promising and reasonable delivery strategy of double-aimed cancer therapy, in which miRNAs and tumor-suppressing genes are used simultaneously.
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POU5F1 Enhances the Invasiveness of Cancer Stem-Like Cells in Lung Adenocarcinoma by Upregulation of MMP-2 Expression.
PLoS ONE
PUBLISHED: 01-01-2013
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Lung cancer is the leading cause of cancer-related human deaths. Exploration of the mechanisms underlying the metastasis of cancer stem-like cells (CSLCs) will open new avenues in lung cancer diagnosis and therapy. Here, we demonstrated that CSLCs-derived from lung adenocarcinoma (LAC) cells displayed highly invasive and migratory capabilities via expressing high levels of POU5F1 and MMP-2. We found that POU5F1 directly regulated MMP-2 transcription via interaction with the promoter of MMP-2. POU5F1 knockdown in LACSLCs reduced MMP-2 protein abundance, leading to inhibition of the cell invasion, migration and tumorigenesis potentials of LAC cells. Clinically, aberrantly high expressions of POU5F1 and MMP-2 were inversely correlated with the survival of LAC patients, and the double-positive POU5F1 and MMP-2 showed the worst prediction for the patients poor survival. These results indicate that POU5F1 can bind to the MMP-2 promoter for the degradation of surrounding extracellular matrix, and therefore promote invasive and migratory capabilities of LACSLCs. Moreover, our data implicate that the pathological detection of the double-positive expressions for POU5F1 and MMP-2 will be useful as diagnostic and prognostic biomarkers in LAC to advance anti-metastasis therapy.
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Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1.
PLoS ONE
PUBLISHED: 01-01-2013
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DNA methylation is an important epigenetic modification and is frequently altered in cancer. Convert of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation (TET) family enzymes plays important biological functions in embryonic stem cells, development, aging and disease. Recent reports showed that level of 5 hmC was altered in various types of cancers. However, the change of 5 hmC level in hepatocellular carcinoma (HCC) and association with clinical outcome were not well defined. Here, we reported that level of 5 hmC was decreased in HCC tissues, as compared with non-tumor tissues. Clincopathological analysis showed the decreased level of 5 hmC in HCC was associated with tumor size, AFP level and poor overall survival. We also found that the decreased level of 5 hmC in non-tumor tissues was associated with tumor recurrence in the first year after surgical resection. In an animal model with carcinogen DEN-induced HCC, we found that the level of 5 hmC was gradually decreased in the livers during the period of induction. There was further reduction of 5 hmC in tumor tissues when tumors were developed. In contrast, level of 5 mC was increased in HCC tissues and the increased 5 mC level was associated with capsular invasion, vascular thrombosis, tumor recurrence and overall survival. Furthermore, our data showed that expression of TET1, but not TET2 and TET3, was downregulated in HCC. Taken together, our data indicated 5 hmC may be served as a prognostic marker for HCC and the decreased expression of TET1 is likely one of the mechanisms underlying 5 hmC loss in HCC.
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A novel zebrafish xenotransplantation model for study of glioma stem cell invasion.
PLoS ONE
PUBLISHED: 01-01-2013
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Invasion and metastasis of solid tumors are the major causes of death in cancer patients. Cancer stem cells (CSCs) constitute a small fraction of tumor cell population, but play a critical role in tumor invasion and metastasis. The xenograft of tumor cells in immunodeficient mice is one of commonly used in vivo models to study the invasion and metastasis of cancer cells. However, this model is time-consuming and labor intensive. Zebrafish (Danio rerio) and their transparent embryos are emerging as a promising xenograft tumor model system for studies of tumor invasion. In this study, we established a tumor invasion model by using zebrafish embryo xenografted with human glioblastoma cell line U87 and its derived cancer stem cells (CSCs). We found that CSCs-enriched from U87 cells spreaded via the vessels within zebrafish embryos and such cells displayed an extremely high level of invasiveness which was associated with the up-regulated MMP-9 by CSCs. The invasion of glioma CSCs (GSCs) in zebrafish embryos was markedly inhibited by an MMP-9 inhibitor. Thus, our zebrafish embryo model is considered a cost-effective approach tostudies of the mechanisms underlying the invasion of CSCs and suitable for high-throughput screening of novel anti-tumor invasion/metastasis agents.
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MiR-637 maintains the balance between adipocytes and osteoblasts by directly targeting Osterix.
Mol. Biol. Cell
PUBLISHED: 08-31-2011
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Bone development is dynamically regulated by homeostasis, in which a balance between adipocytes and osteoblasts is maintained. Disruption of this differentiation balance leads to various bone-related metabolic diseases, including osteoporosis. In the present study, a primate-specific microRNA (miR-637) was found to be involved in the differentiation of human mesenchymal stem cells (hMSCs). Our preliminary data indicated that miR-637 suppressed the growth of hMSCs and induced S-phase arrest. Expression of miR-637 was increased during adipocyte differentiation (AD), whereas it was decreased during osteoblast differentiation (OS), which suggests miR-637 could act as a mediator of adipoosteogenic differentiation. Osterix (Osx), a significant transcription factor of osteoblasts, was shown to be a direct target of miR-637, which significantly enhanced AD and suppressed OS in hMSCs through direct suppression of Osx expression. Furthermore, miR-637 also significantly enhanced de novo adipogenesis in nude mice. In conclusion, our data indicated that the expression of miR-637 was indispensable for maintaining the balance of adipocytes and osteoblasts. Disruption of miR-637 expression patterns leads to irreversible damage to the balance of differentiation in bone marrow.
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Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial-mesenchymaltransition.
Gut
PUBLISHED: 08-03-2011
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The authors have previously isolated a putative oncogene, eukaryotic initiation factor 5A2 (EIF5A2) from 3q26. In this study, EIF5A2 was characterised for its role in colorectal carcinoma (CRC) aggressiveness and underlying molecular mechanisms.
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Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells.
Int. Immunopharmacol.
PUBLISHED: 07-15-2011
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Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy.
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Overexpression of eIF5A-2 is an adverse prognostic marker of survival in stage I non-small cell lung cancer patients.
Int. J. Cancer
PUBLISHED: 07-05-2011
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We have previously isolated an oncogene EIF5A2 (eukaryotic initiation factor 5A2) from a frequently amplified region at 3q of a primary ovarian cancer cell line, and demonstrated its impact on prognosis in human ovarian cancer. Amplification of chromosome 3q has also been detected frequently in non-small cell lung cancer (NSCLC), however, abnormalities of EIF5A2 and its clinicopathologic significance in NSCLC havent been studied. In our study, the methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of EIF5A2 in 248 surgically resected NSCLCs (learning cohort) and another validation cohort of 120 stage I NSCLC patients. Overexpression and amplification of EIF5A2 was detected informatively in 48.7% and 13.7% of NSCLCs in learning cohort, 33.3% and 6.0% of NSCLCs in validation cohort. Overexpression of eIF5A-2 was found to correlate with gene amplification, increased cell proliferation and advanced T stage. In learning cohort, eIF5A-2 expression was evaluated as a strong prognostic factor on disease-specific survival, but in subgroup analyses, it only retained its stratified significance in stage I set (Hazards ratio = 2.799, p = 0.001). In validation cohort, the impact of eIF5A-2 expression on survival in stage I NSCLC patients was also observed (Hazard ratio = 2.097, p = 0.014). Our findings suggested that overexpression of eIF5A-2 correlates with local invasion of NSCLC, and might serve as an adverse prognostic marker of survival for stage I NSCLC patients.
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The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2.
Gut
PUBLISHED: 06-14-2011
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Recent profile studies of microRNA (miRNA) expression have documented a deregulation of miRNA (miR-124) in hepatocellular carcinoma (HCC).
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Consice review: Contribution of cancer stem cells to neovascularization.
Stem Cells
PUBLISHED: 05-11-2011
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Cancer stem cells (CSCs), a special subpopulation of tumor cells, are considered as tumor initiating cells. More recently, these cells have also been identified as initiators of tumor neovascularization. A better understanding of the contribution of CSCs to neovascularization should elucidate the mechanisms of cancer initiation and progression as well as establish new concepts for cancer diagnosis and treatment. In this review, we discuss the evidence for the roles of CSCs in tumor vascularization, including production of proangiogenic factors, transdifferentiation into vascular mural cells such as endothelial and smooth muscle-like cells, and formation of nonendothelium-lined vasculogenic mimicry. In addition, the potential therapeutic significance of targeting CSCs is envisaged.
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Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells.
Int. J. Cancer
PUBLISHED: 04-25-2011
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Energy metabolism is the foundation of survival for all organisms, and mitochondria are the most important energy-supplying organelles in eukaryotic cells. However, the mitochondrial and energy/metabolism-related properties of cancer stem cells (CSCs), the stem cell-like subpopulation in tumor masses, remain unknown. In our study, we compared the masses of mitochondria and mitochondrial DNA (mtDNA), the mitochondrial membrane potential (??m), oxygen/glucose consumption, and the concentration of reactive oxygen species (ROS) and ATP between lung CSCs (LCSCs) and non-LCSCs. In addition, the change in features during differentiation was examined. Some mitochondrial and energy metabolism-related properties, such as perinuclear mitochondrial distribution, a lower quantity of mtDNA, higher ??m, lower oxygen/glucose consumption, and lower intracellular concentrations of ROS and ATP, can be used as indicators of LCSCs.
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Effective melanoma immunotherapy with interleukin-2 delivered by a novel polymeric nanoparticle.
Mol. Cancer Ther.
PUBLISHED: 04-25-2011
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Interleukin-2 (IL-2) has been shown to possess antitumor activity in numerous preclinical and clinical studies. However, the short half-life of recombinant IL-2 protein in serum requires repeated high-dose injections, resulting in severe side effects. Although adenovirus-mediated IL-2 gene therapy has shown antitumor efficacy, the host antibody response to adenoviral particles and potential biosafety concerns still obstruct its clinical applications. Here we report a novel nanopolymer for IL-2 delivery, consisting of low molecular weight polyethylenimine (600 Da) linked by ?-cyclodextrin and conjugated with folate (named H1). H1 was mixed with IL-2 plasmid to form H1/pIL-2 polyplexes of around 100 nm in diameter. Peritumoral injection of these polyplexes suppressed the tumor growth and prolonged the survival of C57/BL6 mice bearing B16-F1 melanoma grafts. Importantly, the antitumor effects of H1/pIL-2 (50 ?g DNA) were similar to those of recombinant adenoviruses expressing IL-2 (rAdv-IL-2; 2 × 10(8) pfu). Furthermore, we showed that H1/pIL-2 stimulated the activation and proliferation of CD8+, CD4+ T cell, and natural killer cells in peripheral blood and increased the infiltration of CD8+, CD4+ Tcells, and natural killer cells into the tumor environment. In conclusion, these results show that H1/pIL-2 is an effective and safe melanoma therapeutic with an efficacy comparable to that of rAdv-IL-2. This treatment represents an alternative gene therapy strategy for melanoma.
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HOXB7 as a prognostic factor and mediator of colorectal cancer progression.
Clin. Cancer Res.
PUBLISHED: 04-07-2011
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This study was to investigate the clinicopathologic significance and potential role of HOXB7 in the development and progression of colorectal cancer (CRC).
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Contribution of cancer stem cells to tumor vasculogenic mimicry.
Protein Cell
PUBLISHED: 03-13-2011
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Vasculogenic mimicry (VM), a newly-defined pattern of tumor blood supply, provides a special passage without endothelial cells and is conspicuously different from angiogenesis and vasculogenesis. The biological features of the tumor cells that form VM remain unknown. Cancer stem cells (CSCs) are believed to be tumor-initiating cells, capable of self-renewal and multipotent differentiation, which resemble normal stem cells in phenotype and function. Recently CSCs have been shown to contribute to VM formation as well as angiogenesis. These findings challenge the previous understanding of the cellular basis of VM formation. In this review, we present evidence for participation of CSCs in VM formation. We also discuss the potential mechanisms and possible interaction of CSCs with various elements in tumor microenvironment niche. Based on the importance of VM in tumor progression, it constitutes a novel therapeutic target for cancer.
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Gastric cancer stem-like cells possess higher capability of invasion and metastasis in association with a mesenchymal transition phenotype.
Cancer Lett.
PUBLISHED: 03-02-2011
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Cancer stem cells have been isolated from various types of cancer including leukemia and solid tumors. However, the methods for isolating gastric cancer stem-like cells (GCSCs) have not been well established. As a consequence, the biological behavior and the significance of these cells to cancer progression remains to be clarified. In this study, we isolated and characterized GCSCs from a gastric cancer cell line SGC7901 and found their enhanced capabilities of invasion in vitro and metastasis in vivo. We further studied the expression of molecules related to epithelial-mesenchymal and invasion in GCSCs and found there were decreased E-cadherin, but increased vimentin and matrix metalloproteinase 2 (MMP-2), in these cells. Our results suggest that decreased E-cadherin and increased MMP-2 may be associated with the capacity of GCSCs to metastasize.
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Endogenous axon guiding chemorepulsant semaphorin-3F inhibits the growth and metastasis of colorectal carcinoma.
Clin. Cancer Res.
PUBLISHED: 02-24-2011
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To elucidate the role of Semaphorin-3F (SEMA3F), originally described as an axon guiding chemorepulsant implicated in nerve development, in the progression of colorectal carcinoma.
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FMNL2 is a positive regulator of cell motility and metastasis in colorectal carcinoma.
J. Pathol.
PUBLISHED: 01-26-2011
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FMNL2 is a member of diaphanous-related formins which act as effectors of Rho family GTPases and control the actin-dependent processes such as cell motility or invasion. We previously found that FMNL2 overexpression in metastatic cell lines and tissues of colorectal carcinoma is associated with more aggressive tumour behaviour. Here we used gain-of-function and loss-of-function approaches to investigate the effects of FMNL2 on colorectal carcinoma in vitro and in vivo. Forced expression of FMNL2 caused a significant increase in tumour cell proliferation, motility, invasion in vitro, and metastasis in vivo, whereas FMNL2 depletion showed opposite effects. We examined gene expression profiles following knockdown of FMNL2 in SW480/M5 cells. Expression of 323 genes was up-regulated by more than two-fold, whereas 222 genes were down-regulated by more than two-fold in FMNL2-depleting SW480/M5 cells. Gene ontology analysis showed that most of genes belong to functional categories such as cell cycle, cytoskeleton, transcription factor, and G-protein modulator. Pathway analysis revealed that cytoskeletal regulation by the Rho GTPase pathway, the Wnt pathway, the G-protein pathway, and the P53 pathway were affected by FMNL2. Many of these genes are in functional networks associated with cell proliferation, metastasis, Wnt or the Rho signalling pathway involved in the regulation of FMNL2. The expression of five differentially expressed genes including CXXC4, CD200, VAV1, CSF1, and EPHA2 was validated by real-time PCR and western blot analysis. Thus, FMNL2 is a positive regulator of cell motility, invasion, and metastasis of colorectal carcinoma.
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The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell-mediated VEGF production and tumour angiogenesis via PI3K/AKT signalling.
J. Pathol.
PUBLISHED: 01-19-2011
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Chemokines and their receptors are actively involved in inflammation, immune responses, and cancer development. Here we report the detection of CD133(+) glioma stem-like cells (GSCs) co-expressing a chemokine receptor CXCR4 in human primary glioma tissues. These GSCs were located in areas adjacent to tumour vascular capillaries, suggesting an association between GSCs and tumour angiogenesis. To test this hypothesis, we isolated CD133(+) GSCs from surgical specimens of human primary gliomas and glioma cell lines. As compared to CD133(-) cells, CD133(+) GSCs expressed significantly higher levels of CXCR4 mRNA and protein, and migrated more efficiently in response to the CXCR4 ligand CXCL12. In addition, CXCL12 induced vascular endothelial growth factor (VEGF) production by CD133(+) GSCs via activation of the PI3K/AKT signalling pathway. Furthermore, knocking down of CXCR4 using RNA interference or inhibition of CXCR4 function by an antagonist AMD3100 not only reduced VEGF production by CD133(+) GSCs in vitro, but also attenuated the growth and angiogenesis of tumour xenografts in vivo formed by CD133(+) GSCs in SCID mice. These results indicate that CXCL12 and its receptor CXCR4 promote GSC-initiated glioma growth and angiogenesis by stimulating VEGF production.
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miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling.
J. Biol. Chem.
PUBLISHED: 09-07-2010
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The emerging concept of generating cancer stem cells from epithelial-mesenchymal transition has attracted great interest; however, the factors and molecular mechanisms that govern this putative tumor-initiating process remain largely elusive. We report here that miR-200a not only regulates epithelial-mesenchymal transition but also stem-like transition in nasopharyngeal carcinoma cells. We first showed that stable knockdown of miR-200a promotes the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype. More importantly, it also induced several stem cell-like traits, including CD133(+) side population, sphere formation capacity, in vivo tumorigenicity in nude mice, and stem cell marker expression. Consistently, stable overexpression of miR-200a switched mesenchyme-like C666-1 cells to the epithelial state, accompanied by a significant reduction of stem-like cell features. Furthermore, in vitro differentiation of the C666-1 tumor sphere resulted in diminished stem-like cell population and miR-200a induction. To investigate the molecular mechanism, we demonstrated that miR-200a controls epithelial-mesenchymal transition by targeting ZEB2, although it regulates the stem-like transition differentially and specifically by ?-catenin signaling. Our findings reveal for the first time the function of miR-200a in shifting nasopharyngeal carcinoma cell states via a reversible process coined as epithelial-mesenchymal to stem-like transition through differential and specific mechanisms.
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P70S6K 1 regulation of angiogenesis through VEGF and HIF-1alpha expression.
Biochem. Biophys. Res. Commun.
PUBLISHED: 06-16-2010
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The 70kDa ribosomal S6 kinase 1 (p70S6K1), a downstream target of phosphoinositide 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK), is an important regulator of cell cycle progression, and cell proliferation. Recent studies indicated an important role of p70S6K1 in PTEN-negative and AKT-overexpressing tumors. However, the mechanism of p70S6K1 in tumor angiogenesis remains to be elucidated. In this study, we specifically inhibited p70S6K1 activity in ovarian cancer cells using vector-based small interfering RNA (siRNA) against p70S6K1. We found that knockdown of p70S6K1 significantly decreased VEGF protein expression and VEGF transcriptional activation through the HIF-1alpha binding site at its enhancer region. The expression of p70S6K1 siRNA specifically inhibited HIF-1alpha, but not HIF-1beta protein expression. We also found that p70S6K1 down-regulation inhibited ovarian tumor growth and angiogenesis, and decreased cell proliferation and levels of VEGF and HIF-1alpha expression in tumor tissues. Our results suggest that p70S6K1 is required for tumor growth and angiogenesis through HIF-1alpha and VEGF expression, providing a molecular mechanism of human ovarian cancer mediated by p70S6K1 signaling.
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Human malignant glioma cells expressing functional formylpeptide receptor recruit endothelial progenitor cells for neovascularization.
Int. Immunopharmacol.
PUBLISHED: 04-19-2010
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Endothelial progenitor cells (EPCs) are involved in tumor neovascularization with undefined mechanisms. In this study, we explored the role of formylpeptide receptor, a G protein-coupled receptor, expressed by human malignant glioma cells in neovascularization of malignant glioma. EPCs were isolated from human umbilical cord blood and their migratory capability and tubulogenesis induced by the supernatant of U87 glioblastoma (GBM) cell line were examined. We also assessed the recruitment and incorporation of EPCs into orthotopic intracranial tumors formed by implanted U87 GBM cells. The supernatant of control U87 cells induced high levels of migration and tubule-formation in vitro by EPCs. In contrast, the chemotactic and tubule-stimulating activities on EPCs in the supernatant of U87 cells with FPR knocking down by small interference (si) RNA were significantly attenuated. In addition, the number of EPCs recruited and incorporated into intracranial glioma xenografts was significantly higher in tumors formed by control U87 cells than tumors formed by U87 cells containing FPR-siRNA. Our results suggest that expression of functional FPR in glioma cells plays an important role in regulating vasculogenesis by EPCs, which constitute a novel target for anti-angiogenic therapy in gliomas.
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Contribution of myeloid-derived suppressor cells to tumor-induced immune suppression, angiogenesis, invasion and metastasis.
J Genet Genomics
PUBLISHED: 03-25-2010
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Growing evidence suggests that myeloid-derived suppressor cells (MDSCs), which have been named "immature myeloid cells" or "myeloid suppressor cells" (MSCs), play a critical role during the progression of cancer in tumor-bearing mice and cancer patients. As their name implies, these cells are derived from bone marrow and have a tremendous potential to suppress immune responses. Recent studies indicated that these cells also have a crucial role in tumor progression. MDSCs can directly incorporate into tumor endothelium. They secret many pro-angiogenic factors as well. In addition, they play an essential role in cancer invasion and metastasis through inducing the production of matrix metalloproteinases (MMPs), chemoattractants and creating a pre-metastatic environment. Increasing evidence supports the idea that cancer stem cells (CSCs) are responsible for tumorigenesis, resistance to therapies, invasion and metastasis. Here, we hypothesize that CSCs may "hijack" MDSCs for use as alternative niche cells, leading to the maintenance of stemness and enhanced chemo- and radio-therapy resistance. The countermeasure that directly targets to MDSCs may be useful for against angiogenesis and preventing cancer from invasion and metastasis. Therefore, the study of MDSCs is important to understand tumor progression and to enhance the therapeutic efficacy against cancer.
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Electrochemical recognition for sugars on the chitosan-poly(diallyldimethylammonium chloride)-nano-Prussian blue/nano-Au/4-mercaptophenylboronic acid modified glassy carbon electrode.
Bioprocess Biosyst Eng
PUBLISHED: 03-18-2010
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A new amperometric biosensor for the detection of sugars was prepared. A glassy carbon electrode was modified with Prussian blue (PB) nanoparticles protected by chitosan (CS) and poly(diallyldimethylammonium chloride) (PDDA), and then gold nanoparticles were assembled onto the electrode followed by the assembly of 4-mercaptophenylboronic acid (MPBA) onto the surface of gold nanoparticles through a sulfur-Au bond to fabricate a self-assembled biosensor. The PB nanoparticles protected by CS and PDDA were characterized using transmission electron microscopy and UV-vis absorption spectroscopy. The characterization of the self-assembled electrode was investigated by cyclic voltammetry and electrochemical impedance spectroscopy. The pKa values of the MPBA monolayer before and after combining with sugars were determined. The fabricated electrode exhibited excellent performances for determining D(+)-glucose, D(+)-mannose, and D(-)-fructose on the basis of the change in i(p) of the Fe(CN)6(3-/4-) ion in the presence of sugars.
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miR-200a-mediated downregulation of ZEB2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion.
Biochem. Biophys. Res. Commun.
PUBLISHED: 11-10-2009
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Nasopharyngeal carcinoma (NPC), a highly metastatic and invasive malignant tumor originating from the nasopharynx, is widely prevalent in Southeast Asia, the Middle East and North Africa. Although viral, dietary and genetic factors have been implicated in NPC, the molecular basis of its pathogenesis is not well defined. Based on a recent microRNA (miRNA) microarray study showing miR-200 downregulation in NPC, we further investigated the role of miR-200a in NPC carcinogenesis. We found that the endogenous miR-200a expression level increases with the degree of differentiation in a panel of NPC cell lines, namely undifferentiated C666-1, high-differentiated CNE-1, and low-differentiated CNE-2 and HNE1 cells. By a series of gain-of-function and loss-of-function studies, we showed that over-expression of miR-200a inhibits C666-1 cell growth, migration and invasion, whereas its knock-down stimulates these processes in CNE-1 cells. In addition, we further identified ZEB2 and CTNNB1 as the functional downstream targets of miR-200a. Interestingly, knock-down of ZEB2 solely impeded NPC cell migration and invasion, whereas CTNNB1 suppression only inhibited NPC cell growth, suggesting that the inhibitory effects of miR-200a on NPC cell growth, migration and invasion are mediated by distinct targets and pathways. Our results reveal the important role of miR-200a as a regulatory factor of NPC carcinogenesis and a potential candidate for miRNA-based therapy against NPC.
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Intraparenchymal myofibromatosis of the brain in an adult: report of an unusual case.
Neuropathology
PUBLISHED: 10-21-2009
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An unusual case of intraparenchymal myofibromatosis of the brain occurring in a 29-year-old woman is described. Preoperative CT and MRI examinations revealed two well-circumscribed nodular masses localized in the wall of the left lateral ventricle and right temporal lobe, respectively. Both masses were completely resected, and the patient remains disease-free 2 years post-surgery. Histopathologically, the lesions were characterized by stratification. From outer to inner, there was a reactive glial component, lamellated well-differentiated muscle-like cells, densely compact collagen fibers and cellular tumor with nodular and hemangiopericytoma-like patterns, respectively. The myofibroblastic nature of this tumor was verified by immunohistochemical staining and ultrastructural analysis. Intraparenchymal myofibromatosis may be confused with, and should be distinguished from, meningioma, myopericytoma, solitary fibrous tumor, leiomyoma and inflammatory myofibroblastic tumor for accurate diagnosis and optimal treatment.
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Enrichment of cancer stem cells based on heterogeneity of invasiveness.
Stem Cell Rev
PUBLISHED: 09-23-2009
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Cancer stem cells (CSCs) have multiple potentials in carcinogenesis and tumor progression. However, it is rather difficult to enrich and amplify CSCs either from tumor cell lines or even primary tumor tissues. Therefore, establishing new methodologies for isolation and enrichment based on the functional properties of CSCs is of great importance for studies on CSCs. According to the findings that CSCs possess more infiltrative capability as compared with their differentiated descendants, we propose a novel strategy based on heterogeneity of cancer cell invasiveness for isolation and enrichment of CSCs from committed cancer cell population. In addition, we hypothesize that existence of CSCs might be the real root of tumor invasion and metastasis.
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Incorporation of endothelial progenitor cells into the neovasculature of malignant glioma xenograft.
J. Neurooncol.
PUBLISHED: 09-17-2009
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Endothelial progenitor cells (EPCs) are important initiators of vasculogenesis in the process of tumor neovascularization. However, it is unclear how circulating EPCs contribute to the formation of tumor microvessels. In this study, we isolated CD34(+)/CD133(+) cells from human umbilical cord blood (HUCB) and obtained EPCs with the capacities of forming colonies, uptaking acetylated low-density lipoprotein (ac-LDL), binding lectins and expressing vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2, KDR), CD31 and von Willebrand factor (vWF). These EPCs were actively proliferative and migratory, and could formed capillary-like tubules in response to VEGF. When injected into mice bearing subcutaneously implanted human malignant glioma, EPCs specifically accumulated at the sites of tumors and differentiated into mature endothelial cells (ECs), which accounted for 18% ECs of the tumor microvessels. The incorporation of circulating EPCs into tumor vessel walls significantly affected the morphology and structure of the vasculature. Our results suggest that circulating EPCs constitute important components of tumor microvessel network and contribute to tumor microvascular architecture phenotype heterogeneity.
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Impaired opening of the upper esophageal sphincter in patients with medullary infarctions.
Dysphagia
PUBLISHED: 06-06-2009
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The aim of this study was to report on nine dysphagic patients with medullary infarction and to evaluate swallowing characteristics based on the location of the lesions.We retrospectively reviewed the medical records of these nine patients. The medullary lesions were midlateral (three patients), dorsolateral (one patient), inferodorsolateral (four patients), and paramedian (one patient). The levels of the lesions were upper (four patients), middle (two patients), upper and middle (two patients), and middle and lower medulla (one patient). Dysphagia after medullary infarction was more common in patients with upper or middle medullary level and dorsolateral medullary level lesions. The common findings on videofluoroscopic swallowing studies in patients with lateral medullary infarctions were impaired upper esophageal sphincter opening, aspiration from pyriform sinuses residue caused by pharyngeal weakness, and multiple swallowing to clear boluses from the pharynx to the esophagus. In patients with medullary infarctions, the lesion levels and loci and their related clinical findings can be useful in predicting dysphagia and aspiration. Because severe dysphagia with serious complication is very common in patients with medullary infarctions, active diagnostic and therapeutic approaches are needed.
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Downregulating FPR restrains xenograft tumors by impairing the angiogenic potential and invasive capability of malignant glioma cells.
Biochem. Biophys. Res. Commun.
PUBLISHED: 02-11-2009
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G-protein-coupled formylpeptide receptor (FPR) has recently been found to be functionally expressed in gliomas and are probably involved in their malignant biological behavior. In an attempt to explore the therapeutic significance of FPRs, we used wild-type human glioblastoma cells (U87), the corresponding FPR short-interfering RNA transfected (siRNA U87) cells, and mock-transfected U87 cells (mock U87) to establish xenografts in mice brains. Compared to wild-type and mock transfected cells, siRNA U87 cells formed smaller and more well-differentiated xenografts with fewer mitotic figures and more glial filaments within their cytoplasm. The density of microvessels, which presented as a nearly normal morphous, was also decreased significantly in FPR knockdown cells. Moreover, fewer invasive foci could be observed in the xenografts derived from siRNA U87 cells, which also showed a poor migratory capacity in vitro. We suggest that decreased VEGF and MMP-2/-9 expression might be a possible mechanism for the decreasing angiogenic potential and invasive capability of U87 cells after FPR knockdown. Functional FPR might be essential for sustaining the growth and aggressive phenotype of gliomas, and could therefore be a potential therapeutic target.
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A novel approach to the identification and enrichment of cancer stem cells from a cultured human glioma cell line.
Cancer Lett.
PUBLISHED: 01-24-2009
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Enrichment of cancer stem cells for studies of carcinogenesis remains a difficult issue. We hypothesized that the unique features of cancer stem cells (CSCs) may allow formation of their colonies in vitro with distinct morphology. We therefore investigated the possibility to use morphological diversity of colonies to identify and enrich CSCs from cultured malignant human glioma cells. We found that a small proportion of the cells from a human glioma cell line U251 formed tight and round-shaped colonies in culture. Most cells in such colonies were capable of self-renewal, generating tumor spheres and differentiating into lineages with markers for neurons, astrocytes and oligodendrocytes. In addition, several neural stem cell-related genes were highly expressed by tumor cells in those tight colonies. Our results thus demonstrate a novel approach to the identification and enrichment of CSCs based on unique morphology of their colonies formed in vitro.
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Inhibition of U-87 human glioblastoma cell proliferation and formyl peptide receptor function by oligomer procyanidins (F2) isolated from grape seeds.
Chem. Biol. Interact.
PUBLISHED: 01-10-2009
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Gliomas are the most common and lethal tumor type in the brain. The present study investigated the effect of oligomer procyanidins (F2) (F2, degree of polymerization 2-15), a natural fraction isolated from grape seeds on the biological behavior of glioblastoma cells. We found that F2 significantly inhibited the glioblastoma growth, with little cytotoxicity on normal cells, induced G2/M arrest and decreased mitochondrial membrane potential in U-87 cells. It also induced a non-apoptotic cell death phenotype resembling paraptosis in U-87 cells. In addition, it was found for the first time that F2 in non-cytotoxic concentrations selectively inhibited U-87 cell chemotaxis mediated by a G-protein coupled receptor formyl peptide receptor FPR, which is implicated in tumor cell invasion and metastasis. Further experiments indicated that F2 inhibited fMLF-induced U-87 cell calcium mobilization and MAP kinases ERK1/2 phosphorylation. Moreover, F2 attenuated the glioblastoma FPR expression, a new molecular target for glioma therapeutics, which has been shown to play important roles in glioma cells chemotaxis, proliferation and angiogenesis in addition to its promotion to tumor progression, but did not affect FPR mRNA expression in U-87 cells. Taken together, our results suggest that F2 may be a promising candidate for the development of novel anti-tumor therapeutics.
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The effect of C-reactive protein on functional outcome in ischemic stroke patients.
Int. J. Neurosci.
PUBLISHED: 01-01-2009
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This study was performed to evaluate the effect of C-reactive protein (CRP) measured within 24 hr after stroke onset on functional outcome in ischemic stroke patients. The medical records of 28 first-ever hemiplegic ischemic stroke patients with the lesions on the middle cerebral arterial territory were reviewed. Subjects were classified into experimental group (serum CRP >or= 0.5 mg/dL) and control group (serum CRP<0.5 mg/dL) based on the level of serum CRP measured within 24 hr after stroke onset. Serum CRP measured within 24 hr after stroke onset was significantly correlated with functional scales in ischemic stroke patients.
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Protective effects of enalapril, an angiotensin-converting enzyme inhibitor, on multiple organ damage following scald injury in rats.
Biotechnol. Appl. Biochem.
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The aim of this study is to investigate the effects of enalapril, an angiotensin-converting enzyme inhibitor, on multiple organ damage after scald injury. Healthy adult rats (half male and half female; 8-12 weeks old) were randomly assigned to the following treatments: sham operation, scald injury, and intraperitoneal enalapril (1, 2, and 4 mg/kg body weight) treatment after scalding. At 1, 12, and 24 H postscald, left ventricular and aortic hemodynamics were measured using a multichannel physiological recorder. Functional and pathological changes of the heart, liver, and kidney were examined by biochemical and histological methods. Compared with sham controls, untreated scalded animals showed decreased hemodynamic parameters and increased myocardial angiotensin II, serum creatine kinase heart isoenzyme, and serum cardiac troponin I and histopathological inflammation in the myocardium 12 H postscald. These hemodynamic, functional, and pathological changes were attenuated by 1 mg/kg enalapril. Enalapril reversed scald-induced elevations in aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and blood creatinine 12 H postscald, and ameliorated focal necrosis in the liver and erythrocyte cast formation in renal tubules. However, higher doses of enalapril yielded less or no improvement in organ dysfunction. Enalapril at 1 mg/kg attenuates scald-induced multiple organ damage in rats.
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TGF-?1 enhances tumor-induced angiogenesis via JNK pathway and macrophage infiltration in an improved zebrafish embryo/xenograft glioma model.
Int. Immunopharmacol.
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Angiogenesis plays a crucial role at the early stage of tumorigenesis and tumor progression. A suitable model will be useful not only for the clarification of the underlying molecular mechanisms, but also for high-throughput identification of novel anti-angiogenesis compounds. Here, we established a zebrafish model for the purpose to investigate angiogenesis and screen anti-angiogenic compounds. Glioma U87 cells expressing red fluorescent protein (RFP) were transplanted in fli:GFP transgenic zebrafish embryos where significant angiogenesis was observed. TGF-?1 enhanced glioma-induced angiogenesis, which was inhibited by JNK inhibitor SP600125 but not p38 MAPK inhibitor SB202190, ERK inhibitor PD98059, or PI3K inhibitor LY294002, indicating the important role of TGF-?1 and JNK pathways in this process. Moreover, the glioma-induced angiogenesis was associated with macrophage infiltration that was further enhanced by TGF-?1. Therefore, our zebrafish model provides a powerful in vivo tool for the investigation of tumor-induced angiogenesis, and a cost-effective system for high-throughput screening of anti-angiogenic compounds.
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Chimeric 5/35 adenovirus-mediated Dickkopf-1 overexpression suppressed tumorigenicity of CD44? gastric cancer cells via attenuating Wnt signaling.
J. Gastroenterol.
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Gastric cancer stem cells (CSCs), which require activation of Wnt signaling to maintain their self-renewal and tumorigenicity, are proposed to be critical targets for effective therapy of gastric carcinomas. Gene therapies that are delivered by adenovirus of serotype 5 (Ad5) or chimeric 5/35(Ad5/35) adenovirus have shown promise for treating various cancers. Here we aimed to develop a gene therapy strategy that targeted gastric CSCs (CD44? cells).
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Endogenous cGMP-dependent protein kinase reverses EGF-induced MAPK/ERK signal transduction through phosphorylation of VASP at Ser239.
Oncol Lett
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In our previous study, we demonstrated that type II cGMP-dependent protein kinase (PKG II) was expressed at lower levels in different human cancer cell lines and that exogenous PKG II inhibited epidermal growth factor (EGF)-induced MAPK/ERK signaling. In order to investigate its functions further in this signaling pathway, it is necessary to elucidate whether endogenous PKG has the same effect or not. This study aimed to investigate the possible inhibitory effect of endogenous PKG activity on EGF-induced MAPK/ERK signal transduction in human lung cancer cells and its mechanism. Human small cell lung carcinoma cells (SCLCs) were treated with the PKG-selective cGMP analog 8-pCPT-cGMP to activate endogenous PKG, EGF and cGMP followed by EGF, respectively. The results showed that increased endogenous PKG activity inhibited the EGF-induced phosphorylation of the epidermal growth factor receptor (EGFR) and the binding between Sos1 and Grb2. In addition, EGF-triggered Ras activation was reversed by increased endogenous PKG activity. While the EGF-induced phosphorylation of MEK and ERK were inhibited by increased endogenous PKG activity, there was a significant increase of phosphorylated vasodilator-stimulated phosphoprotein (p-VASP) at Ser239. Furthermore, we investigated whether endogenous PKG exerted its effects on EGF-induced MAPK/ERK signaling through phosphorylation of VASP at Ser239. Downregulation of the levels of p-VASP Ser239 by point mutation blocked the effects of endogenous PKG on EGF-induced MAPK/ERK signal transduction. The data shown here suggest that endogenous PKG reverses the EGF-induced MAPK/ERK signaling pathway by phosphorylating VASP at Ser239.
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Decreased expression of C-erbB-2 and CXCR4 in breast cancer after primary chemotherapy.
J Transl Med
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Biological molecular markers such as proto-oncogene erbB-2 (HER-2/neu, c-erbB-2), the CXC chemokine receptor 4 (CXCR4), estrogen receptor (ER), Proliferating Cell Nuclear Antigen (PCNA), DNA topoisomerase II (topo II), P-glycoprotein (P-gp) and glutathione S-transferase (GST) were observed for changes after administration of neochemotherapy and whether these protein expression changes were correlated with response to chemotherapy.
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Combined therapy with cytokine-induced killer cells and oncolytic adenovirus expressing IL-12 induce enhanced antitumor activity in liver tumor model.
PLoS ONE
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Both adoptive immunotherapy and gene therapy hold a great promise for treatment of malignancies. However, these strategies exhibit limited anti-tumor activity, when they are used alone. In this study, we explore whether combination of cytokine-induced killer (CIK) adoptive immunotherapy with oncolytic adenovirus-mediated transfer of human interleukin-12 (hIL-12) gene induce the enhanced antitumor potency. Our results showed that oncolytic adenovirus carrying hIL-12 (AdCN205-IL12) could produce high levels of hIL-12 in liver cancer cells, as compared with replication-defective adenovirus expressing hIL-12 (Ad-IL12). AdCN205-IL12 could specifically induce cytotoxocity to liver cancer cells. Combination of CIK cells with AdCN205-IL12 could induce higher antitumor activity to liver cancer cells in vitro than that induced by either CIK or AdCN205-IL12 alone, or combination of CIK and control vector AdCN205-GFP. Furthermore, treatment of the established liver tumors with the combined therapy of CIK cells and AdCN205-IL12 resulted in tumor regression and long-term survival. High level expression of hIL-12 in tumor tissues could increase traffic of CIK cells to tumor tissues and enhance their antitumor activities. Our study provides a novel strategy for the therapy of cancer by the combination of CIK adoptive immunotherapy with oncolytic adenovirus-mediated transfer of immune stimulatory molecule hIL-12.
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Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-?1 signaling pathway.
J. Immunol.
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The invasion of malignant glioma cells into the surrounding normal brain tissues is crucial for causing the poor outcome of this tumor type. Recent studies suggest that glioma stem-like cells (GSLCs) mediate tumor invasion. However, it is not clear whether microenvironment factors, such as tumor-associated microglia/macrophages (TAM/Ms), also play important roles in promoting GSLC invasion. In this study, we found that in primary human gliomas and orthotopical transplanted syngeneic glioma, the number of TAM/Ms at the invasive front was correlated with the presence of CD133(+) GSLCs, and these TAM/Ms produced high levels of TGF-?1. CD133(+) GSLCs isolated from murine transplanted gliomas exhibited higher invasive potential after being cocultured with TAM/Ms, and the invasiveness was inhibited by neutralization of TGF-?1. We also found that human glioma-derived CD133(+) GSLCs became more invasive upon treatment with TGF-?1. In addition, compared with CD133(-) committed tumor cells, CD133(+) GSLCs expressed higher levels of type II TGF-? receptor (TGFBR2) mRNA and protein, and downregulation of TGFBR2 with short hairpin RNA inhibited the invasiveness of GSLCs. Mechanism studies revealed that TGF-?1 released by TAM/Ms promoted the expression of MMP-9 by GSLCs, and TGFBR2 knockdown reduced the invasiveness of these cells in vivo. These results demonstrate that TAM/Ms enhance the invasiveness of CD133(+) GSLCs via the release of TGF-?1, which increases the production of MMP-9 by GSLCs. Therefore, the TGF-?1 signaling pathway is a potential therapeutic target for limiting the invasiveness of GSLCs.
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Nanog regulates self-renewal of cancer stem cells through the insulin-like growth factor pathway in human hepatocellular carcinoma.
Hepatology
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Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell-related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). Nanog(Pos) CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that Nanog(Pos) CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in Nanog(Pos) CSCs could decrease self-renewal accompanied with decreased expression of stem-cell-related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in Nanog(Neg) cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in Nanog(Pos) CSCs. Knock-down expression of Nanog in Nanog(Pos) CSCs inhibited the expression of IGF1R, and overexpression of Nanog in Nanog(Neg) cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal.
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Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells.
J. Biol. Chem.
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miR-124 is a brain-enriched microRNA that plays a crucial role in neural development and has been shown to be down-regulated in glioma and medulloblastoma, suggesting its possible involvement in brain tumor progression. Here, we show that miR-124 is down-regulated in a panel of different grades of glioma tissues and in all of the human glioma cell lines we examined. By integrated bioinformatics analysis and experimental confirmation, we identified SNAI2, which is often up-regulated in glioma, as a direct functional target of miR-124. Because SNAI2 has been shown to regulate stem cell functions, we examined the roles of miR-124 and SNAI2 in glioma cell stem-like traits. The results showed that overexpression of miR-124 and knockdown of SNAI2 reduced neurosphere formation, CD133(+) cell subpopulation, and stem cell marker (BMI1, Nanog, and Nestin) expression, and these effects could be rescued by re-expression of SNAI2. Furthermore, enhanced miR-124 expression significantly inhibited glioma cell invasion in vitro. Finally, stable overexpression of miR-124 and knockdown of SNAI2 inhibited the tumorigenicity and invasion of glioma cells in vivo. These findings reveal, for the first time, that the tumor suppressor activity of miR-124 could be partly due to its inhibitory effects on glioma stem-like traits and invasiveness through SNAI2.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.