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MiR-492 promotes chemoresistance to CDDP and metastasis by targeting inhibiting DNMT3B and induces stemness in gastric cancer.

ABSTRACT: OBJECTIVE:Metastasis and chemoresistance indicate treatment fail and progresses in gastric cancer (GC) patients. However, the molecular mechanisms of chemoresistance and metastasis remain unclear in GC. Thus, identifying the biological indicators of chemoresistance and metastasis is particularly important. MATERIALS AND METHODS:We establish a role for miR-492 in GC metastasis and chemoresistance through experiments in vitro and in vivo. RESULTS:We identified miR-492 overexpression in GC specimens and cell lines, the miR-492 expression level was inversely correlated with the prognosis of GC patients. The inhibition of miR-492 suppressed GC cell invasion and enhanced the sensitivity of gastric cancer cells to CDDP treatment. In contrast, miR-492 overexpression significantly stimulated GC cell invasion and contributed to chemoresistance development. In addition, our research results indicated that the inhibition of miR-492 stimulates GC stemness, and the overexpression of miR-492 induces GC stemness. Importantly, our experiments demonstrated that miR-492 inhibitor suppressed tumor formation, and the combination treatment of miR-492 inhibitor and CDDP significantly inhibited tumor growth in vivo. Furthermore, we demonstrated that miR-492 exerts its anticancer role by targeting DNMT3B in GC. CONCLUSIONS:Our results suggested that inhibiting miR-492 is a novel strategy to control tumor metastasis and chemoresistance in GC.

SUBMITTER: Wu S

PROVIDER: S-EPMC7064790 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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miR-492 promotes chemoresistance to CDDP and metastasis by targeting inhibiting DNMT3B and induces stemness in gastric cancer.

Wu Shuai S Xie Jian J Shi Hao H Wang Zi-Wei ZW

Bioscience reports 20200301 3

<h4>Objective</h4>Metastasis and chemoresistance indicate treatment fail and progresses in gastric cancer (GC) patients. However, the molecular mechanisms of chemoresistance and metastasis remain unclear in GC. Thus, identifying the biological indicators of chemoresistance and metastasis is particularly important.<h4>Materials and methods</h4>We establish a role for miR-492 in GC metastasis and chemoresistance through experiments in vitro and in vivo.<h4>Results</h4>We identified miR-492 overexp ...[more]

PMID: 32065219

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Project description:BackgroundWe previously reported an inverse relationship between B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and Raf kinase inhibitory protein (RKIP), which is associated with the prognosis of gastric cancer (GC). In this study, we further explored the microRNA (miRNA) regulatory mechanism between Bmi-1 and RKIP.MethodsMicroarray analysis was first carried out to identify miRNA profiles that were differentially expressed in cells overexpressing Bmi-1. Then, miRNAs that could regulate RKIP were identified. Quantitative real-time PCR (qRT-PCR) and Western blotting were performed to measure the expression of Bmi-1, miR-155, miR-27a and RKIP. RKIP was confirmed as a target of miR-27a and miR-155 through luciferase reporter assays, qRT-PCR and Western blotting. The effects of the Bmi-1/miR-27a/RKIP and Bmi-1/miR-155/RKIP axes on tumor growth, proliferation, migration, invasion, colony-formation ability, metastasis and chemoresistance were investigated both in vitro and in vivo.ResultsThe downregulation of RKIP by Bmi-1 occurred at the protein but not mRNA level. This indicates probable posttranscriptional regulation. miRNA expression profiles of cells with ectopic expression of Bmi-1 were analyzed and compared to those of control cells by microarray analysis. A total of 51 upregulated and 72 downregulated miRNAs were identified. Based on publicly available algorithms, miR-27a and miR-155 were predicted, selected and demonstrated to target RKIP. Bmi-1, miR-27a and miR-155 are elevated in human GC and associated with poor prognosis of GC, while RKIP is expressed at lower levels in GC and correlated with good prognosis. Then, in vitro tests shown that in addition to regulating RKIP expression via miR-27a and miR-155, Bmi-1 was also able to regulate the migration, invasion, proliferation, colony-formation ability and chemosensitivity of GC cells through the same pathway. Finally, the in vivo test showed similar results, whereby the knockdown of the Bmi-1 gene led to the inhibition of tumor growth, metastasis and chemoresistance through miR-27a and miR-155.ConclusionsBmi-1 was proven to induce the expression of miR-27a and miR-155 and thus promote tumor metastasis and chemoresistance by targeting RKIP in GC. Overall, miR-27a and miR-155 might be promising targets for the screening, diagnosis, prognosis, treatment and disease monitoring of GC.

Dataset Information

MiR-492 promotes chemoresistance to CDDP and metastasis by targeting inhibiting DNMT3B and induces stemness in gastric cancer.

Publications

miR-492 promotes chemoresistance to CDDP and metastasis by targeting inhibiting DNMT3B and induces stemness in gastric cancer.

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