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Find video protocols related to scientific articles indexed in Pubmed.
Decreased expression of Kallmann syndrome 1 sequence gene (KAL1) contributes to oral squamous cell carcinoma progression and significantly correlates with poorly differentiated grade.
J. Oral Pathol. Med.
PUBLISHED: 04-21-2014
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Kallmann syndrome 1 sequence gene (KAL1) protein is an extracellular matrix associated protein which plays vital roles in neurons development and cell migration. However, its biological functions and clinical implications have yet not been revealed in oral carcinogenesis. The objective of the study was to evaluate the role of KAL1 in oral cancer and determine clinical significance of KAL1 in oral squamous cell carcinomas (OSCCs).
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The potential of pH-responsive PEG-hyperbranched polyacylhydrazone micelles for cancer therapy.
Biomaterials
PUBLISHED: 01-15-2014
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pH-responsive hyperbranched polymers have attracted much attention due to their unique properties for tumor-targeted drug delivery. In this study, we describe a pH-responsive drug carrier, poly (ethylene glycol) (PEG)-hyperbranched polyacylhydrazone (HPAH), which can form nanoscale micelles to be used as anti cancer drug carriers with pH-controlled drug release. The molecular structure of PEG-HPAH was confirmed by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The drug-loaded micelles with a diameter of approximately 190 nm, were prepared using a dialysis method against PBS with a pH of 8.0. The drug-loaded micelles showed the desired pH-dependent drug release properties. The drug release levels were low at neutral and alkaline pH, but increased significantly with a decrease in the pH of the medium. Intracellular uptake results indicated that the PEG-HPAH-drug micelles could efficiently deliver chemotherapeutic drugs into the cells. In addition, it was found that the subcellular localization of the drug-loaded micelles was different from that of free drugs, in which the drug-loaded micelles were mainly in the cytoplasm. The docetaxel (DTX)-loaded PEG-HPAH micelles presented a high cytotoxic activity against tumor cells in vitro. When combined with the administration of glucose, the PEG-HPAH-DTX micelles exhibited a superior anti-tumor efficacy and a lower systemic toxicity in vivo. The biodistribution profile showed increased accumulated drug levels in tumor tissue and plasma in micelles treated group. The results indicate that the nanoscale PEG-HPAH-DTX micelles may serve as a selective tumor-targeting drug delivery system.
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miR-300 inhibits epithelial to mesenchymal transition and metastasis by targeting Twist in human epithelial cancer.
Mol. Cancer
PUBLISHED: 01-10-2014
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Epithelial-to-mesenchymal transition (EMT) is a key step of the progression of tumor cell metastasis. Recent work has demonstrated some miRNAs play critical roles in EMT. In this study, we focused on the roles of miR-300 in regulating EMT.
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Cyclic strain-induced cytoskeletal rearrangement of human periodontal ligament cells via the Rho signaling pathway.
PLoS ONE
PUBLISHED: 01-01-2014
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Although mechanical stimulations are known have a significant impact on cytoskeletal rearrangement, little is known regarding the behavioral alteration of human periodontal ligament cells (hPDLCs) under cyclic strain. The aim of this study was to elucidate the role of the Rho signaling pathway on cyclic strain-induced cytoskeletal rearrangement of hPDLCs.
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Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma.
Clin. Cancer Res.
PUBLISHED: 11-25-2013
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To determine Notch1 mutation status in oral squamous cell carcinoma (OSCC) from Chinese population and its potential clinical implications.
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The molecular mechanisms on glomangiopericytoma invasion.
Orphanet J Rare Dis
PUBLISHED: 09-15-2013
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To observed the imaging and pathological features of the glomangiopericytoma.
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TGM3, a candidate tumor suppressor gene, contributes to human head and neck cancer.
Mol. Cancer
PUBLISHED: 08-02-2013
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In our previous study using oligonucleotide microarrays, we revealed that transglutaminase 3 (TGM3) was remarkably down-regulated in head and neck cancer (HNC). However, the potential of TGM3 as a useful biomarker or molecular target for HNC is unclear.
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Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma.
Mol. Cell Proteomics
PUBLISHED: 07-31-2013
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Patients with advanced head and neck squamous cell carcinoma (HNSCC) have a poor prognosis with the currently available therapy, and tumor recurrence is frequently observed. The discovery of specific membrane-associated cancer stem cell (CSC) markers is crucial for the development of novel therapeutic strategies to target these CSCs. To address this issue, we established sphere cultures to enrich CSCs and used them for plasma membrane proteomics to identify specific membrane signatures of the HNSCC spheres. Of a dataset that included a total of 376 identified proteins, 200 were bona fide membrane proteins. Among them, 123 proteins were at least 1.5-fold up- or down-regulated in the spheres relative to the adherent cultures. These proteins included cell adhesion molecules, receptors, and transporter proteins. Some of them play key roles in wnt, integrin, and TGF? signaling pathways. When we compared our dataset with two published hESC membrane protein signatures, we found 18 proteins common to all three of the databases. CD166 and CD44 were two such proteins. Interestingly, the expression of CD166, rather than that of the well-established HNSCC CSC marker CD44, was significantly related to the malignant behavior of HNSCC. Relative to CD166(low) HNSCC cells, CD166(high) HNSCC cells had a greater sphere-formation ability in vitro and tumor formation ability in vivo. Patients whose tumors expressed high levels of CD166 had a significantly poorer clinical outcome than those whose tumors expressed low levels of CD166 (cohort 1: 96 cases, p = 0.040), whereas the level of CD44 expression had only a marginal influence on the clinical outcome of patients with HNSCC (p = 0.078). The level of CD166 expression in HNSCC tumors was also associated with the tumor recurrence rate (cohort 2: 104 cases, p = 0.016). This study demonstrates that CD166 is a valuable cell surface marker for the enrichment of HNSCC stem cells and that plasma membrane proteomics is a promising biological tool for investigating the membrane proteins of CSCs.
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20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.
Bioorg. Med. Chem.
PUBLISHED: 04-02-2013
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Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5?M) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.
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A new gamboge derivative Compound 2 inhibits cancer stem-like cells via suppressing EGFR tyrosine phosphorylation in head and neck squamous cell carcinoma.
J. Cell. Mol. Med.
PUBLISHED: 02-17-2013
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Cancer stem-like cells represent a population of tumour-initiating cells that lead to the relapse and metastasis of cancer. Conventional anti-cancer therapeutic drugs are usually ineffective in eliminating the cancer stem-like cells. Therefore, new drugs or therapeutic methods effectively targeting cancer stem-like cells are in urgent need to successfully cure cancer. Gamboge is a natural anti-cancer medicine whose pharmacological effects are different from those of conventional chemotherapeutical drugs and they can kill some kinds of cancer cells selectively. In this study, we identified a new gamboge derivative, Compound 2 (C2), which presents eminent suppression effects on cancer cells. Interestingly, when compared with cisplatin (CDDP), C2 effectively suppresses the growth of both cancer stem-like cells and non-cancer stem-like cells derived from head and neck squamous cell carcinoma (HNSCC), inhibiting the formation of tumour spheres and colony in vitro, resulting in the loss of expression of multiple cancer stem cell (CSC)-related molecules in HNSCC. Treating with C2 effectively inhibited the growth of HNSCC in BALB/C nude mice. Further investigation found that C2 notably inhibits the activation of epithelial growth factor receptor and the phosphorylation of its downstream protein kinase homo sapiens v-akt murine thymoma viral oncogene homolog (AKT) in HNSCC, resulting in down-regulation of multiple CSC-related molecules in HNSCC. Our study has demonstrated that C2 effectively inhibits the stem-like property of cancer stem-like cells in HNSCC and may be a hopeful targeting drug in cancer therapy.
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Promising noninvasive cellular phenotype in prostate cancer cells knockdown of matrix metalloproteinase 9.
ScientificWorldJournal
PUBLISHED: 02-06-2013
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Cell surface interaction of CD44 and MMP9 increases migration and invasion of PC3 cells. We show here that stable knockdown of MMP9 in PC3 cells switches CD44 isoform expression from CD44s to CD44v6 which is more glycosylated. These cells showed highly adhesive morphology with extensive cell spreading which is due to the formation of focal adhesions and well organized actin-stress fibers. MMP9 knockdown blocks invadopodia formation and matrix degradation activity as well. However, CD44 knockdown PC3 cells failed to develop focal adhesions and stress fibers; hence these cells make unstable adhesions. A part of the reason for these changes could be caused by silencing of CD44v6 as well. Immunostaining of prostate tissue microarray sections illustrated significantly lower levels of CD44v6 in adenocarcinoma than normal tissue. Our results suggest that interaction between CD44 and MMP9 is a potential mechanism of invadopodia formation. CD44v6 expression may be essential for the protection of non-invasive cellular phenotype. CD44v6 decrease may be a potential marker for prognosis and therapeutics.
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Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.
PLoS ONE
PUBLISHED: 01-31-2013
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The retinoic-acid-inducible gene (RIG)-like receptor (RLR) family proteins are major pathogen reorganization receptors (PRR) responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC). RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5-triphosphate RNA (3p-RNA) induces low levels of interferon and proinflammatory cytokines and promotes NF-?B- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNF? receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.
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Prognostic significance of p21, p27 and survivin protein expression in patients with oral squamous cell carcinoma.
Oncol Lett
PUBLISHED: 01-21-2013
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Oral squamous cell carcinoma (OSCC) accounts for >80% of head and neck malignancies. p21, p27 and survivin proteins are abnormally expressed in OSCC and have been previously reported to correlate with cell proliferation and apoptosis. However, the prognostic significance of p21, p27 and survivin remains controversial. The aim of the present study was to investigate the association of clinical parameters and prognosis with the levels of p21, p27 and survivin expression in patients with OSCC. The levels of the three biomarkers were evaluated by immunohistochemical staining in specimens from 110 patients with OSCC and each section was scored according to the percentage of positive tumor cells and staining intensity. Log-rank test and Cox proportional hazards regression were performed to assess the correlation between biomarkers and clinical events. The association between the immunoexpression of p21, p27 and survivin and clinical pathological variables were analyzed by the ?(2) test and a non-parametric analysis. The expression of p21 in patients with OSCC was found to correlate with the expression of p27 and survivin. The results of the current study revealed that the five-year survival rate was significantly lower in patients with high p21 expression. In addition, the expression of p27 also showed a negative correlation with the five-year survival rate of OSCC, but to a lesser extent. By contrast, the expression of survivin was not a prognostic factor for OSCC. A Kaplan-Meier analysis and Cox proportional hazards model showed that lymph node metastasis and p21 expression were independent prognostic factors of OSCC.
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A comparative study of the influence of three pure titanium plates with different micro- and nanotopographic surfaces on preosteoblast behaviors.
J Biomed Mater Res A
PUBLISHED: 01-02-2013
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There is a great demand for dental implants with the ability to accelerate periimplant bone regeneration. Modification of surface micro- and nanotopographies has been revealed to affect bone cell metabolism. In this study, we utilized dielectric barrier discharge (DBD) technology to modify commercially pure titanium (Ti-tr) surfaces and then investigated the cytocompability of DBD-modified Ti surface when compared with machined (Ti-m) and polished (Ti-p) Ti surfaces. These three kinds of Ti plates exhibited different surface energies and topographies at the micro- and nanoscale levels. The DBD-treated pure Ti surface significantly enhances cell adhesion, spread, and proliferation of MC3T3-E1 preosteoblast cells compared with the Ti-p and Ti-m surfaces, suggesting that Ti-tr has better cytocompatibility compared with the other two surfaces. Preosteoblast cells on Ti-m surface exhibited higher alkaline phosphatase activity than cells on Ti-tr and Ti-p surfaces 14 days after seeding. No significant difference in alkaline phosphatase activity was observed between cells grown on Ti-tr and Ti-p surfaces. Our study demonstrated that DBD modification significantly enhanced cell adhesion, spread, and proliferation of preosteoblasts with no negative effects on cell differentiation. Microtopography and nanotopography of the surfaces of different materials and chemical/energetic properties have a synergistic effect on cell attachment, proliferation, and differentiation.
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Pathological cyclic strain-induced apoptosis in human periodontal ligament cells through the RhoGDI?/caspase-3/PARP pathway.
PLoS ONE
PUBLISHED: 01-01-2013
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Human periodontal ligament (PDL) cells incur changes in morphology and express proteins in response to cyclic strain. However, it is not clear whether cyclic strain, especially excessive cyclic strain, induces PDL cell apoptosis and if so, what mechanism(s) are responsible. The aim of the present study was to elucidate the molecular mechanisms by which pathological levels of cyclic strain induce human PDL cell apoptosis.
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TRIM24 overexpression is common in locally advanced head and neck squamous cell carcinoma and correlates with aggressive malignant phenotypes.
PLoS ONE
PUBLISHED: 01-01-2013
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Tripartite motif-containing 24 (TRIM24), a member of the transcriptional intermediary factor 1 family, functions as a co-regulator that positively or negatively modulates the transcriptional activities of several nuclear receptors. The aim of this study was to investigate TRIM24 expression and its clinical significance in head and neck squamous cell carcinoma. The expression levels of TRIM24 variants were examined in head and neck squamous cell carcinoma (HNSCC) samples and cell lines by real-time PCR and WB. The expression levels of TRIM24 measured in 91 locally advanced HNSCC tumors were measured by immunohistochemistry and correlated with clinical and pathological parameters. The functional role of TRIM24 in HNSCC was further investigated by silencing its expression in HNSCC cell lines. TRIM24 variants were up-regulated in 56 HNSCC samples (P<.001) and 9 HNSCC cell lines (P<.05). TRIM24 protein was overexpressed in 6 of 8 HNSCC cell lines and in 2 of 3 HNSCC samples. Furthermore, 54.95% (50/91) of HNSCC samples exhibited remarkably elevated expression of TRIM24 by immunohistochemistry. Univariate analysis revealed that high TRIM24 expression was associated with worse overall survival (P?=?.020). In multivariate analysis, TRIM24 expression was identified as an independent predictor of overall survival (P?=?.030), after adjusting for other clinicopathological parameters. Upon TRIM24 silencing, the proliferation of HNSCC cells was notably inhibited due to the induction of apoptosis. These results suggest that aberrant TRIM24 expression may play an important role in the development of HNSCC and is a promising prognostic indicator for patients with locally advanced HNSCC.
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Up-regulation of enhancer of zeste homolog 2 is associated positively with cyclin D1 overexpression and poor clinical outcome in head and neck squamous cell carcinoma.
Cancer
PUBLISHED: 08-04-2011
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The authors previously observed that enhancer of zeste homolog 2 (EZH2) overexpression was associated significantly with the development of oral cancer. In the current study, they investigated whether EZH2 can function as a prognostic predictor for patients with head and neck squamous cell carcinoma (HNSCC).
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EZH2 promotes malignant phenotypes and is a predictor of oral cancer development in patients with oral leukoplakia.
Cancer Prev Res (Phila)
PUBLISHED: 06-22-2011
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Oral leukoplakia (OL) is the most common premalignancy in the oral cavity. A small proportion of OLs progresses to oral squamous cell carcinoma (OSCC). To assess OSCC risk of OLs, we investigated the role of the transcriptional repressor enhancer of zeste homolog 2 (EZH2) in oral tumorigenesis and its clinical implication as an OSCC risk predictor. Immunohistochemistry was used to measure EZH2 expression in OLs from 76 patients, including 37 who later developed OSCC and 39 who did not. EZH2 expression was associated with clinicopathologic parameters and clinical outcomes. To determine the biological role of EZH2 in OL, EZH2 level was reduced using EZH2 siRNAs in Leuk-1 cells, its impact on cell cycle, anchorage-dependent/independent growth, and invasion was assessed. We observed strong EZH2 expression in 34 (45%), moderate expression in 26 (34%), and weak/no expression in 16 (21%) of the OLs. The higher EZH2 levels were strongly associated with dysplasia (P < 0.001) and OSCC development (P < 0.0001). Multivariate analysis indicated that EZH2 expression was the only independent factor for OSCC development (P < 0.0001). At 5 years after diagnosis, 80% of patients whose OLs expressed strong EZH2 developed OSCC whereas only 24% patients with moderate and none with weak/no EZH2 expression did so (P < 0.0001). In Leuk-1 cells, EZH2 downregulation resulted in G(1) arrest; decreased invasion capability, decreased anchorage-independent growth; downregulation of cyclin D1 and upregulation of p15(INK4B). Our data suggest that EZH2 plays an important role in OL malignant transformation and may be a biomarker in predicting OSCC development in patients with OLs.
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CCND1 as a predictive biomarker of neoadjuvant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma.
PLoS ONE
PUBLISHED: 06-13-2011
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Cyclin D1 (CCND1) has been associated with chemotherapy resistance and poor prognosis. In this study, we tested the hypothesis that CCND1 expression determines response and clinical outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated with neoadjuvant chemotherapy followed by surgery and radiotherapy.
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A novel mutation of the PTCH1 gene activates the Shh/Gli signaling pathway in a Chinese family with nevoid basal cell carcinoma syndrome.
Biochem. Biophys. Res. Commun.
PUBLISHED: 04-06-2011
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Objective: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a predisposition to neoplasms and developmental abnormalities. Mutation of the PTCH1 gene, which is considered to be responsible for NBCCS, was investigated in a Chinese NBCCS family in this study. Methods: Genomic DNA was isolated from blood samples of all eight living individuals in this family. Mutation analysis of PTCH1 was done by amplified polymerase chain reaction and direct sequencing. Biophysical predictions of the altered protein were made using various bioinformatics tools. To determine the action of the mutated protein, the expression of Gli1 and Gli2 was investigated by immunohistochemistry. Results: A novel PTCH1 mutation at 897G?A in exon4 was identified in all four affected members. This mutation was not found in any unaffected members of this family or in 100 unrelated healthy Chinese people. The mutation causes amino acid replacement 237E?K in the first large extracellular loop of the PTCH1 protein which is required for Sonic Hedgehog (Shh) binding. This mutation changes the proteins biochemical properties and protein activity, resulting in subsequent activation of transcription factors, Gli1 and Gli2, in the Shh/Gli signaling pathway. Immunohistochemistry showed overexpression of Gli1 and Gli2 in the keratocystic odontogenic tumor (KCOT) tissues.
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HH/GLI signalling as a new therapeutic target for patients with oral squamous cell carcinoma.
Oral Oncol.
PUBLISHED: 03-13-2011
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Aberrant activation of HH/GLI has recently been reported in multiple cancer types, yet its role in oral squamous cell carcinoma (OSCC) has not been investigated. In this study, we aimed to determine the role of HH/GLI in OSCC. Expression of GLI1 and GLI2 was examined in OSCC samples from 136 patients by immunohistochemistry and correlated with clinicopathology parameters and clinical outcomes of the patients. Two HH/GLI specific small molecule inhibitors cyclopamine and GANT61, were used to test the potential role of HH/GLI in OSCC. We found that GLI2, one of the main transcriptional activators of HH/GLI signalling, was expressed in 60 (44%) of the 136 OSCC samples and the expression was significantly associated with poor clinical outcomes. Only 44% of the patients whose tumours expressed GLI2 survived at 5years after surgery compared to 77% of those whose tumours lacked the GLI2 expression (P<0.0001). Both cyclopamine and GANT61 effectively inhibited GLI expression, slowed cell growth, promoted G1 arrest, increased apoptosis and inhibited migration of OSCC cells. Our results demonstrate that activation of HH/GLI pathway plays an important role in OSCC progression. Together with the finding that expression of GLI2 is strongly associated with a poor clinic outcome of OSCC patients, the data suggest that a subset of OSCC patients may benefit from anti-HH/GLI therapies.
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Study of the differentially expressed genes in pleomorphic adenoma using cDNA microarrays.
Pathol. Oncol. Res.
PUBLISHED: 03-08-2011
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Recent studies have determined that gene expression profiling using microarray technology can be used to identify tumor-related molecules. The objective of this study was to screen the differentially expressed genes between pleomorphic adenoma (PA) and the normal tissue adjacent to PA using cDNA microarrays and to further validate the differentially expressed genes by real-time PCR. In this study, we selected five pairs of PA and the surrounding normal salivary gland tissues. The total RNA was isolated from tumor and normal tissues and purified to mRNA. The mRNA was reverse-transcribed to cDNA with the incorporation of fluorescent-labeled dUTP to prepare the hybridization probes. The mixed probes were hybridized to Whole Human Gene Expression Microarrays by Agilent. Tumor-related genes were screened by analyzing the fluorescence intensity. As a result, a total of 447 genes were found to be differentially expressed between PA and normal tissue adjacent to PA. Among them, 185 genes were up-regulated and 262 genes were down-regulated in PA. By constructing a network from the differentially expressed genes, some genes, such as Gli2 and CTNNB1, were identified as being at the core of the network. In addition, differential gene expression was validated for 2 up-regulated genes, Gli2 and LOX, using real-time PCR and the results were consistent with those of the cDNA microarray analysis thus verifying the credibility of the microarray data. Therefore, our microarray data may provide clues for finding novel genes involved in the development of PA, and shed light on finding new targets for diagnosis and therapy of PA. Further characterization of these differentially expressed genes will be useful in understanding the genetic basis for PA.
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Enhancing radiosensitivity of human pulmonary adenocarcinoma cell line A549 by CpG ODN1826.
Cancer Biother. Radiopharm.
PUBLISHED: 03-02-2011
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Preclinical and early clinical trials indicate that synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODN) have potent immunostimulatory effects and can enhance the anticancer activity of a variety of cancer treatments. In this study, CpG ODN1826 was used to increase the radiosensitivity of human pulmonary adenocarcinoma cell line A549, and some underlying mechanisms were also detected. With the treatment of CpG ODN on A549 cells, there was an upregulation of CD40, CD80, CD86, and MHC-II on A549 cells in association with Th1 cytokine production. Further, the protein level of toll-like receptor (TLR)-4 was decreased, whereas TLR-9 was enhanced. Flow cytometry results showed that CpG ODN could increase mitochondrial membrane potential and subsequently promote the apoptosis of A549 cells, resulting in increased radiosensitivity. These results suggest a regulatory role of CpG ODN1826 in enhancing the radiosensitivity of A549 cells by activating the adaptive and innate immune responses, thereby providing a new potential strategy to the treatment of malignant tumors.
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Inhibiting adenoid cystic carcinoma cells growth and metastasis by blocking the expression of ADAM 10 using RNA interference.
J Transl Med
PUBLISHED: 08-08-2010
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Adenoid cystic carcinoma is one of the most common types of salivary gland cancers. The poor long-term prognosis for patients with adenoid cystic carcinoma is mainly due to local recurrence and distant metastasis. Disintegrin and metalloprotease 10 (ADAM 10) is a transmembrane protein associated with metastasis in a number of diverse of cancers. The aim of this study was to analyze the relationship between ADAM 10 and the invasive and metastatic potentials as well as the proliferation capability of adenoid cystic carcinoma cells in vitro and in vivo.
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Establishment and characterization of an HPV16 E6/E7-expressing oral squamous cell carcinoma cell line with enhanced tumorigenicity.
Med. Oncol.
PUBLISHED: 04-06-2010
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Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial region. The mechanism of carcinogenesis of OSCC is still unclear. Based on the previous cell line, HIOEC-B(a)P-96 (HB96), which we obtained by HPV16 E6/E7-immortalized human oral epithelial cells (HIOEC) and benzo(a)pyrene inducement, we prepared a new HB-second generation cancer cell line (HB-2) by continuous passage. Its characteristics such as morphology, proliferation activity, karyotype, and tumorigenesis were studied. The HB-2 cells displayed uncontrolled cell division and lost contact inhibition leading to cell overlap. Cells were polygonal and unevenly shaped, with an increased nucleus versus plasma ratio. Increased proliferative activity was confirmed by MTT assays. The tumorigenicity was confirmed by tumor growth experiments in nude mice. Therefore, the HB-2 and HB96 cell lines are useful tools to study the mechanism of carcinogenesis of OSCC in vitro for future genomic and proteomic analyses.
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The ErbB3 binding protein EBP1 regulates ErbB2 protein levels and tamoxifen sensitivity in breast cancer cells.
Breast Cancer Res. Treat.
PUBLISHED: 03-24-2010
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The ErbB2/3 heterodimer plays a critical role in breast cancer progression and in the development of endocrine resistance. EBP1, an ErbB3 binding protein, inhibits HRG-stimulated breast cancer growth, decreases ErbB2 protein levels and contributes to tamoxifen sensitivity. We report here that ectopic expression of EBP1 in Estrogen Receptor (ER) positive breast cancers that express ErbB2 at both high and low levels decreased ErbB2 protein levels. ErbB2 protein expression was also increased in mammary glands of Ebp1 knock out mice. To define the mechanism of ErbB2 down regulation, we examined the effects of EBP1 on ErbB2 mRNA levels, transcription of the ErbB2 gene and ErbB2 protein stability. We found that ectopic expression of EBP1 decreased steady state levels of endogenous ErbB2 mRNA in all cell lines tested. EBP1 overexpression decreased the activity of an ErbB2 promoter reporter in cells which overxpress ErbB2. However, reporter activity was unchanged or increased in cells which express low endogenous levels of ErbB2. We also found that ectopic expression of EBP1 accelerated ErbB2 protein degradation and enhanced ErbB2 ubiquitination in cells which express both low and high levels of ErbB2. Treatment with proteasome inhibitors prevented this decrease in ErbB2 protein levels. Ablation of EBP1 expression led to tamoxifen resistance that was abrogated by inhibition of ErbB2 activity. These results suggest that EBP1 inhibits expression of ErbB2 protein levels by multiple mechanisms and that EBP1s effects on tamoxifen sensitivity are mediated in part by its ability to modulate ErbB2 levels.
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RNAi-mediated ADAM9 gene silencing inhibits metastasis of adenoid cystic carcinoma cells.
Tumour Biol.
PUBLISHED: 03-23-2010
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A disintegrin and metalloproteinase 9 (ADAM9) is a type I transmembrane protein that has been associated with cancer development and metastases. Here, we show that ADAM9 is highly expressed in metastatic cancer tissues and in an adenoid cystic carcinoma cell line with a high metastatic potential. Using RNA interference for gene silencing, we show that ADAM9 is essential for in vitro cancer cell proliferation and invasion as well as in vivo cancer metastasis in an experimental murine model of lung metastases. These data indicate that ADAM9 is potentially an important new therapeutic target for the prevention of tumor metastases in adenoid cystic carcinoma.
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MiR-145, a new regulator of the DNA fragmentation factor-45 (DFF45)-mediated apoptotic network.
Mol. Cancer
PUBLISHED: 02-25-2010
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MicroRNA-145 (miR-145) is considered to play key roles in many cellular processes, such as proliferation, differentiation and apoptosis, by inhibiting target gene expression. DNA Fragmentation Factor-45 (DFF45) has been found to be the substrate of Caspase-3, and the cleavage of DFF45 by caspase-3 during apoptosis releases DFF40 that degrades chromosomal DNA into nucleosomal fragments. There are currently no in-depth studies on the relationship between miR-145 and the DFF45 gene.
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Mice transgenic with SV40-late-promoter-driven Polyomavirus Middle T oncogene exclusively develop hemangiomas.
Transgenic Res.
PUBLISHED: 09-26-2009
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In order to develop a model system of infantile hemangioma, transgenic mice were developed carrying the Polyomavirus Middle T (PyMT) gene driven by the SV40 late promoter. From the 520 fertilized eggs surviving microinjection, there were 25 live births. Three of these showed the hemangioma phenotype and carried and expressed the PyMT gene; the remaining descendants were normal. The tumors showed abnormal vascular proliferation with cavernous hemangioma-like structures in the skin surface, tongue, ear mucosa and gastric mucosal tissue in the transgenic mice with hemangioma phenotype. Immunohistochemical staining for Ki-67 was negative, showing the tumors were hemangiomas rather than angiosarcomas. None of the PyMT transgenic mice survived beyond 4 weeks. Previously reported PyMT transgenic mice under the control of various promoters induce many tumor types including hemangiomas. PyMT driven by the SV40 late promoter is an improved model system because it only induces hemangiomas. However, it is limited by the post-natal lethality. Thus, conditional variants of this model system would be desirable.
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The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma.
BMC Cancer
PUBLISHED: 09-25-2009
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Gambogic acid (GA) is a major active ingredient of gamboge, a widely used traditional Chinese medicine that has been reported to be a potent cytotoxic agent against some malignant tumors. Many studies have shown that the NF-kappa B signaling pathway plays an important role in anti-apoptosis and the drug resistance of tumor cells during chemotherapy. In this study, the effects and mechanisms of GA and the NF-kappa B inhibitor celastrol on oral cancer cells were investigated.
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Potential therapeutic strategy for oral squamous cell carcinoma by ErbB3-binding protein 1 gene transfer.
J. Cancer Res. Clin. Oncol.
PUBLISHED: 07-05-2009
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An ErbB3-binding protein 1 (Ebp1), was shown to be a potent tumor suppressor in breast and prostate cancer cells. We hypothesized that the inhibitory properties of the Ebp1 gene could be beneficial if ectopically expressed in oral squamous cell carcinoma (OSCC) cells.
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Prognostic significance of Bcl-2 and Bax protein expression in the patients with oral squamous cell carcinoma.
J. Oral Pathol. Med.
PUBLISHED: 06-17-2009
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The aim of this study was to investigate the expression of the apoptosis-inhibitory Bcl-2 protein and the apoptosis-promoting Bax protein and to identify their association with the clinical parameters and prognosis of the patients with oral squamous cell carcinoma (OSCC).
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Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes.
Cancer Lett.
PUBLISHED: 01-30-2009
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To characterize the biological features of side population (SP) in oral squamous cell carcinoma (OCC), SP and non-SP were sorted and compared. The SP cells were more clonogenic and in nude mice, only 10,000 SP cells were needed for tumor development compared to 1,000,000 non-SP cells. The SP cells expressed higher levels of ABCG2, ABCB1, CD44, Oct-4, Bmi-1, NSPc1 and CK19. The SP cells generated SP and non-SP populations, whereas the non-SP cells generated only non-SP. These findings provide the first evidence that SP in OCC possesses tumor stem cell phenotypes and may play an important role in OCC tumorigenesis.
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Inhibition of cyclin D1 expression by cyclin D1 shRNAs in human oral squamous cell carcinoma cells is associated with increased cisplatin chemosensitivity.
Int. J. Cancer
PUBLISHED: 01-16-2009
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Cyclin D1 is a well-known cell cycle regulator. Recently, its pro-survival function has been revealed in several tumors. Because increasing expression of cyclin D1 is a common event in oral squamous cell carcinoma (OSCC) and has been correlated with cisplatin resistance, we investigated if cyclin D1 inhibition could increase cisplatin chemosensitivity of OSCC. Five cyclin D1 shRNAs were prepared and 3 were selected for subsequent experiments. IC50 values for cisplatin were determined by an MTT assay. Cisplatin-induced apoptosis and cell cycle block were investigated. A tumor transplantation model was generated to examine the cisplatin sensitivity of Tca/cisplatin after in vivo cyclin D1 silencing. The role of nuclear factor-kappaB (NF-kappaB) and cyclin-dependent kinase 4 (CDK4) in cyclin D1-mediated cisplatin resistance was also examined. The most effective shRNA resulted in 84.51% knockdown of the cyclin D1 protein level. After the transfection with the 2 most effective shRNAs, the cisplatin IC50 decreased from 5.88 microg/ml to 1.36 microg/ml and 2.47 microg/ml, although overexpression of cyclin D1 rendered OSCC cells more resistant to cisplatin treatment (IC50 increased from 6.43 microg/ml to 12.24 microg/ml). This decreasing IC50 was correlated with the down-regulation of cisplatin-induced NF-kappaB activity in cyclin D1 knockdown cells, and was independent of CDK4 function. In vivo tumor transplantation models also confirmed a cisplatin-sensitizing effect of cyclin D1 shRNA in OSCC. A TUNEL assay validated the increase in apoptosis as induced by cisplatin in cyclin D1 knockdown cells. Cyclin D1 may be an important target for future therapy in patients with OSCC.
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Dysregulated miR-363 affects head and neck cancer invasion and metastasis by targeting podoplanin.
Int. J. Biochem. Cell Biol.
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Head and neck squamous cell carcinoma (HNSCC) is characterised by an elevated capacity for tumour invasion and lymph node metastasis and the cause remains to be determined. Recent studies suggest that microRNAs can regulate the evolution of malignant behaviours by regulating multiple target genes. In this study, we have first confirmed that miR-363 is down-regulated in HNSCC tissues with lymph node metastasis and cell lines with highly invasive capacity. We used bioinformatics, cellular and molecular methods to predict and prove that miR-363 directly targeted to podoplanin (PDPN) and caused up-regulation of PDPN in HNSCC. MSP assay showed that DNA promoter methylation was involved in silencing the miR-363 in HNSCC. Furthermore, we provided evidence to demonstrate that PDPN dysregulation caused by down-regulation of miR-363 contributes to HNSCC invasion and metastasis. These data reveal a key role of miR-363-PDPN in HNSCC metastasis and support biological and clinical links between miR-363-PDPN and HNSCC.
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Downregulation of miR-153 contributes to epithelial-mesenchymal transition and tumor metastasis in human epithelial cancer.
Carcinogenesis
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The epithelial-mesenchymal transition (EMT) is a crucial step in epithelial cancer invasion and metastasis. The aims of this study were to investigate and validate unidentified micro RNAs (miRNAs) that regulate EMT and to reveal their clinical relevance in epithelial cancer patients. By applying miRNA array screening in a natural epithelial-mesenchymal phenotype cell line pair and in a transforming growth factor ?-induced EMT cell model, we found miR-153 was markedly downregulated in the cells that underwent an EMT. A close association was confirmed between inhibition of miR-153 and the EMT phenotype, as well as the invasive ability of epithelial cancer cells. Ectopic expression of miR-153 in mesenchymal-like cells resulted in an epithelial morphology change with decreased cellular invasive ability. On the contrary, transfection of a miR-153 inhibitor in epithelial-like cells led to a mesenchymal phenotype change. In vivo ectopic expression of miR-153 significantly inhibited tumor cell metastasis formation. Data from the dual-luciferase reporter gene assay showed, for the first time, that SNAI1 and ZEB2 were direct targets of miR-153. Inverse correlations were also observed between miR-153 and SNA1 and ZEB2 levels in oral cancer patients samples. Furthermore, low expression level of miR-153 was found to be significantly related to metastasis and poor prognosis in oral cancer patients. These data demonstrate that miR-153 is a novel regulator of EMT by targeting SNAI1 and ZEB2 and indicate its potential therapeutic value for reducing cancer metastasis.
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Gambogic acid as a non-competitive inhibitor of ATP-binding cassette transporter B1 reverses the multidrug resistance of human epithelial cancers by promoting ATP-binding cassette transporter B1 protein degradation.
Basic Clin. Pharmacol. Toxicol.
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Gambogic acid (GA) is known for its anti-cancer activity in a phase II clinical trial. However, the detailed molecular mechanisms of its anti-multidrug resistance remain unclear. The present study was designed to study the relationship between GA and multidrug-resistant protein ATP-binding cassette transporter B1 (ABCB1). GA dose dependently inhibited ABCB1 activity levels in the in vitro Pgp-Glo assay system and increased the cellular accumulation of ABCB1 substrate adriamycin. Although GA had no significant influence on ABCB1 mRNA in the real-time PCR assay, Western blot detection indicated the compound reduced ABCB1 protein levels. Further study showed the proteasome inhibitor MG-132 reversed the GA-decreased ABCB1 level and prolonged half-life of ABCB1. It was also found that GA coordinated with other anti-cancer drugs (such as adriamycin, docetaxel, verapamil and protopanaxadiol) to enhance cellular cytotoxicity on human epithelial cancer cell lines with higher ABCB1 expression levels. These data suggest that GA functions as a non-competitive inhibitor of ABCB1 by directly inhibiting and reducing its expression levels by promoting protein degradation through post-translational proteasome pathway. The results of this study will aid in the understanding of the synergistic effects of combining GA with other drugs as a new anti-multidrug-resistant agent.
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Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis.
Mol. Cancer
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Toll-like receptor 4 (TLR4) is expressed on immune cells as a sensor that recognizes lipopolysaccharide (LPS), a microbial conserved component. It has recently been determined that the expression of TLR4 is also found in various types of tumor cells. Cisplatin is a widely used chemotherapeutic agent for oral squamous cell carcinoma (OSCC) treatment. However, the mechanisms responsible for cisplatin resistance are not well understood.
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Activation of Toll-like receptor 3 induces apoptosis of oral squamous carcinoma cells in vitro and in vivo.
Int. J. Biochem. Cell Biol.
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Toll-like receptors are well known as molecular sensors of pathogen-associated molecular patterns. They control activation of the innate immune response and subsequently shape the adaptive immune response. Recent publications have demonstrated that Toll-like receptors also play important roles in multiple human cancers, yet their function in oral squamous cell carcinoma remains unclear. In this study, we showed that both oral squamous cell carcinoma cell lines and tissues from oral squamous carcinoma patients express relatively high levels of Toll-like receptor 3. We also found that synthetic dsRNA-polyinosinic-polycytidilic acid, a Toll-like receptor 3 ligand, induced apoptosis of oral squamous carcinoma cells mainly via Toll-like receptor 3, through interferon-? production and activation of caspases 3 and 9. Moreover, in an oral squamous cell carcinoma xenograft mouse model, we demonstrated for the first time that activation of Toll-like receptor 3 inhibited oral squamous cell carcinoma tumor growth in vivo. Therefore, the direct proapoptotic activity of Toll-like receptor 3 in human oral squamous carcinoma cells may make this protein a viable therapeutic target in the treatment of oral squamous cell carcinoma.
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Epigenetic and genetic alterations-based molecular classification of head and neck cancer.
Expert Rev. Mol. Diagn.
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The long-term survival rates for patients diagnosed with advanced head and neck cancer (HNC) remain poor. Many perplexing factors, including etiology and comorbidity, lead to different molecular malfunctions of HNC cells and determine the prognosis of the disease. Traditional diagnostic methods are limited in that they fail to provide an effective classification diagnosis, such as a more precise prediction of prognosis and decisions for personalized treatment regimens. Recently, molecular biology techniques, especially epigenetic and genetic techniques, have been developed that have enabled us to gain a greater insight into the molecular pathways underlying the cancers. Translating the research into a format that will facilitate effective molecular classification, support personalized treatment and determine prognosis remains a challenge. In this review, the authors provide an overview of cancer epigenetic and genetic alterations, tissue banks, and several promising biomarkers or candidates that may ultimately prove to be beneficial in a clinical setting for patients with HNC.
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Expression of VEGF-receptors in TMJ synovium of rabbits with experimentally induced internal derangement.
Br J Oral Maxillofac Surg
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Our aim was to evaluate the expression of vascular endothelial growth factor receptors (VEGFRs) in the synovium of the temporomandibular joints (TMJ) of rabbits with experimentally induced internal derangement. Internal derangement was experimentally induced in 52 rabbit TMJ, and established on the right side of TMJ while the left side was used as the control. Each joint and its control was evaluated by magnetic resonance imaging (MRI) and endoscopy. The synovial tissues on both sides were harvested after one, two, three, and four weeks. The expression of VEGFRs mRNA was investigated in the experimental joint and its control using real-time polymerase chain reaction (PCR). Internal derangement was successfully confirmed in 45 of the 52 of the experimental joints (87%) on the right side by MRI and endoscopy. In the first and fourth week, the VEGFR-2 mRNA expression was higher in the experimental joints than in the controls (P=0.008 and P=0.02). Meanwhile, the VEGFR-1 mRNA expression was up-regulated in the experimental group compared with the controls during the fourth week (P=0.02). However, we found no significant differences in VEGFR-3 mRNA expression in the two groups during the first and fourth weeks. During the second and third weeks, the mRNA expression of the three receptors did not differ significantly among the groups. Our data have shown increased expression of VEGFR-1 and VEGFR-2 mRNA in the synovium of rabbit TMJ with internal derangement, which indicates that VEGFR-1 and VEGFR-2 may have important roles in the processes of internal derangement and formation of adhesions.
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Gambogic acid is a novel anti-cancer agent that inhibits cell proliferation, angiogenesis and metastasis.
Anticancer Agents Med Chem
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Gambogic acid (GA) is a caged xanthone that is derived from Garcinia hanburyi and functions as a strong apoptotic inducer in many types of cancer cells. The distinct effectiveness of GA has led to its characterization as a novel anti-cancer agent. There is an increasing number of research studies focused on elucidating the molecular mechanisms of GA-induced anti-cancer effects, and several critical signaling pathways have been reported to be influenced by GA treatment. In this review, we summarize the multiple functional effects of GA administration in cancer cells including the induction of apoptosis, the inhibition of proliferation and the prevention of cancer metastasis and tumor angiogenesis.
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