longitudinal-intravital-imaging-through-clear-silicone-windows

Longitudinal Intravital Imaging Through Clear Silicone Windows

Intravital microscopy (IVM) enables visualization of cell movement, division, and death at single-cell resolution. IVM through surgically inserted imaging ...

Cold Spring Harbor Laboratory

Stony Brook University

Gastric cancer (GC) is one of the most common malignancies worldwide. The prognosis of GC is unsatisfied owning to widespread metastasis. P21-activated kinase 1 (PAK1), a member of serine/threonine kinases, is associated with the progression of multiple types of human cancers. Here, we demonstrated that CDK4/6 inhibitor reduced GC cell viability and decreased PAK1 expression. Consistently, PAK1 ablation increased GC cell sensitivity exposed to CDK4/6 inhibitor and promoted DNA damage. We also revealed PAK1 depletion notably affected PDK1-AKT pathway, and PDK1 overexpression totally abrogated the effect of PAK1 deletion on DNA damage in GC cells. Additionally, PDK1 overexpression also rescued the increased GC cell sensitivity towards CDK4/6 inhibitor and the cell cycle arrest caused by PAK1 depletion. Our findings, therefore, suggested that PAK1 silencing increased sensitivity to CDK4/6 inhibition in gastric cancer cells via PDK1-AKT pathway. We, therefore, thought PAK1 as a promising therapeutic target for the treatment of CDK4/6 inhibitor-resistant gastric cancer.

PAK1 silencing is synthetic lethal with CDK4/6 inhibition in gastric cancer cells via regulating PDK1 expression.

The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.

MicroRNA-4290 suppresses PDK1-mediated glycolysis to enhance the sensitivity of gastric cancer cell to cisplatin.

Gastric adenocarcinoma is a major challenge to human health worldwide. Abnormal expression of miR-621 was found in many types of cancer. This research aimed to investigate the effects and detailed molecular mechanisms of miR-621 on gastric adenocarcinoma progression. The present study first showed that miR-621 was downregulated in gastric cancer patients, and its expression level was correlated with tumor size. MiR-621 overexpression inhibited viability, colony formation and proliferation of gastric cancer cells. AURKA was identified as a direct target of miR-621. AURKA knockdown induced decrease of p-GSK-3β/GSK-3β ratio and increase of p-β-catenin/β-catenin ratio which confirmed that AURKA positively regulated GSK-3β phosphorylation. AURKA knockdown also inhibited proliferation of gastric adenocarcinoma cells. AURKA expression was negatively correlated with miR-621 level. In addition, AURKA overexpression reversed the effect of miR-621 on the growth of cancer cells. Taken together, our results suggest that miR-621 is an important tumor suppressor in gastric cancer and could be a promising target for the cancer treatment.

MiRNA-621 exerts tumor suppressor function in gastric adenocarcinoma by targeting AURKA/GSK-3β pathway.

Tumor-associated macrophages (TAMs) promote metastasis and inhibit T cells, but macrophages can be polarized to kill cancer cells. Macrophage polarization could thus be a strategy for controlling cancer. We show that macrophages from metastatic pleural effusions of breast cancer patients can be polarized to kill cancer cells with monophosphoryl lipid A (MPLA) and interferon (IFN) γ. MPLA + IFNγ injected intratumorally or intraperitoneally reduces primary tumor growth and metastasis in breast cancer mouse models, suppresses metastasis, and enhances chemotherapy response in an ovarian cancer model. Both macrophages and T cells are critical for the treatment's anti-metastatic effects. MPLA + IFNγ stimulates type I IFN signaling, reprograms CD206 TAMs to inducible NO synthase (iNOS) macrophages, and activates cytotoxic T cells through macrophage-secreted interleukin-12 (IL-12) and tumor necrosis factor alpha (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.

Activating a collaborative innate-adaptive immune response to control metastasis.

To investigate the regulation of chronic myelogenous leukemia （CML） imatinib resistant genes, in order to improve the therapeutic effect of CML imatinib resistant patients.

[Transcriptome Analysis of Chronic Myelogenous Leukemia Cell Line with Imatinib Resistance].

Mediator complex (MED) contains 28 subunits, functions as a transcription machinery through interaction with RNA polymerase II and modulates gene expression involved in cell survival and growth. MED27, as an oncogene, stimulates malignant behavior of various tumors. Role of MED27 in gastric cancer was assessed in this study. Firstly, bioinformatics analysis predicted that MED27 was elevated in gastric cancer. Gastric cancer cells also showed higher expression of MED27 than normal gastric epithelial cells. Secondly, functional assays revealed that silencing of MED27 decreased cell viability, and reduced proliferation of gastric cancer. Cell invasion and migration of gastric cancer were also inhibited by loss of MED27. Moreover, knockdown of MED27 inhibited angiogenesis of gastric cancer. Thirdly, nuclear protein of β-catenin in gastric cancer was reduced by silencing of MED27. Lastly, in vivo tumor growth of gastric cancer was suppressed by interference of MED27. In conclusion, MED27 functioned as an oncogene in gastric cancer through promoting cell metastasis and angiogenesis.

Knockdown of mediator complex subunit 27 suppresses gastric cancer cell metastasis and angiogenesis via Wnt/β-catenin pathway.

Gastric cancer (GC) is a common digestive tract cancer whose high heterogeneity and invasiveness lead to a low survival rate. Therefore, it is necessary to explore the potential molecular mechanism of GC.

Article	Year
PAK1 silencing is synthetic lethal with CDK4/6 inhibition in gastric cancer cells via regulating PDK1 expression. Human cell\| PubMed ID: 31919718	2020
MicroRNA-4290 suppresses PDK1-mediated glycolysis to enhance the sensitivity of gastric cancer cell to cisplatin. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas\| PubMed ID: 32321153	2020
MiRNA-621 exerts tumor suppressor function in gastric adenocarcinoma by targeting AURKA/GSK-3β pathway. Acta biochimica Polonica\| PubMed ID: 33629578	2021
Activating a collaborative innate-adaptive immune response to control metastasis. Cancer cell\| PubMed ID: 34478639	2021
[Transcriptome Analysis of Chronic Myelogenous Leukemia Cell Line with Imatinib Resistance]. Zhongguo shi yan xue ye xue za zhi\| PubMed ID: 34893099	2021
Knockdown of mediator complex subunit 27 suppresses gastric cancer cell metastasis and angiogenesis via Wnt/β-catenin pathway. Tissue & cell\| PubMed ID: 36371844	2022
Collagen type I alpha 2 acts as a potential diagnostic biomarker and therapeutic targets for the prognosis in gastric cancer. Discover oncology\| PubMed ID: 41917621	2026

Xiao Han

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