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MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma.

ABSTRACT: Background:Pancreatic ductal adenocarcinoma (PDAC) is a lethal human malignancy, and previous researches support the contribution of microRNA (miRNA) to cancer progression. MiR-122-5p is reported to participate in the regulation of various cancers, while the function of miR-122-5p in PDAC remains unclear. In this study, we investigated the precise mechanism of miR-122-5p involved in PDAC pathogenesis. Methods:The expression levels of miR-122-5p were detected in human PDAC tissues and cell lines by miRNA RT-PCR. The effects of miR-122-5p on cell proliferation were explored by MTT assays, colony formation assays and flow cytometry assays. The ability of migration and invasion was determined by transwell assays. Dual Luciferase reporter assay was performed to validate the direct interaction between miR-122-5p and its target gene. The related molecules of cell cycle, apoptosis and epithelial-mesenchymal transition (EMT) were examined with qRT-PCR and western blot. In addition, xenograft mouse models were applied to explore the effects of miR-122-5p in vivo. Results:MiR-122-5p was underexpressed, while CCNG1 was highly expressed in PDAC tissues and cells. MiR-122-5p was negatively correlated with TNM stage, tumor size and lymph node metastasis in PDAC patients. Overexpression of miR-122-5p suppressed the proliferation, migration and invasion in vitro and inhibited tumorigenesis in vivo. Furthermore, CCNG1 was a direct target of miR-122-5p. Upregulated CCNG1 could partially reverse the effects caused by miR-122-5p. Moreover, miR-122-5p inhibited EMT through downregulation of CCNG1. Conclusion:Overexpression of miR-122-5p could inhibit cell proliferation, migration, invasion, and EMT by downregulating CCNG1 in PDAC, suggesting a potential therapeutic target for PDAC.

SUBMITTER: Dai C

PROVIDER: S-EPMC7106816 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma.

Dai Chen C Zhang Yan Y Xu Zhihua Z Jin Mengxian M

Cancer cell international 20200330

<h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is a lethal human malignancy, and previous researches support the contribution of microRNA (miRNA) to cancer progression. MiR-122-5p is reported to participate in the regulation of various cancers, while the function of miR-122-5p in PDAC remains unclear. In this study, we investigated the precise mechanism of miR-122-5p involved in PDAC pathogenesis.<h4>Methods</h4>The expression levels of miR-122-5p were detected in human PDAC tissues ...[more]

PMID: 32256207

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Project description:BackgroundPancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC).MethodsWe first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data.ResultsWe first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed (P < 0.05) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) (P < 0.05, respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control (P < 0.05, respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression.ConclusionIn conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour.MethodsWe determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium iodide assays).ResultsWe found higher expression of P2X7R protein in PDAC compared to HPDE cells. P2X7R had notable disparate effects on PDAC survival. Firstly, high concentrations of ATP or the specific P2X7R agonist, BzATP, had cytotoxic effects in all cell lines, and cell death was mediated by necrosis. Moreover, the P2X7R-pore antagonist, A438079, prevented ATP-induced pore formation and cell death. Second, in basal conditions and with low concentrations of ATP/BzATP, the P2X7R allosteric inhibitor AZ10606120 reduced proliferation in all PDAC cell lines. P2X7R also affected other key characteristics of cancer cell behavior. AZ10606120 reduced cell migration and invasion in PDAC cell lines compared to that of untreated/vehicle-treated control cells, and stimulation with sub-millimolar concentrations of ATP or BzATP substantially increased cell invasion.ConclusionsPDAC cell lines overexpress P2X7R and the receptor plays crucial roles in cell survival, migration and invasion. Therefore, we propose that drugs targeting P2X7R could be exploited in therapy of pancreatic cancer.

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MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma.

Publications

MicroRNA-122-5p inhibits cell proliferation, migration and invasion by targeting CCNG1 in pancreatic ductal adenocarcinoma.

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