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MiR-133a-5p inhibits androgen receptor (AR)-induced proliferation in prostate cancer cells via targeting FUsed in Sarcoma (FUS) and AR.

ABSTRACT: Androgens and androgen receptors are vital factors involved in prostate cancer progression, and androgen ablation therapies are commonly employed to treat advanced prostate cancer. Previously, FUsed in Sarcoma (FUS) was identified as an AR-interacting protein that enhances AR transcriptional activity. In the present study, we attempted to identify miRNAs that might target both FUS and AR to inhibit FUS and AR expression. Based on TCGA data and the online tools UALCAN, Kaplan Meier-plotter (KMplot), LncTar and miRWalk prediction, miR-133a-5p was selected. MiR-133a-5p expression was significantly downregulated in prostate cancer, and low miR-133a-5p expression was correlated with low survival probability. As predicted by LncTar and miRWalk, miR-133a-5p could bind to the 3'UTR of FUS and AR to inhibit their expression. MiR-133a-5p overexpression significantly suppressed the cell viability of the AR-positive prostate cancer cell lines VCaP and LNCaP, inhibited the expression of FUS, AR, as well as AR downstream targets IGF1R and EGFR. More importantly, miR-133a inhibition increased cancer cell proliferation as well as the expression of AR and AR downstream factors, while FUS knockdown exerted an opposite effect; the effect of miR-133a on cancer cell proliferation and AR could be significantly reversed by FUS knockdown. Moreover, IGF1R and EGFR knockdown reversed the effect of the miR-133a-5p inhibition. In summary, miR-133a-5p inhibits AR-positive prostate cancer cell proliferation by targeting FUS/AR, thus improving the resistance of prostate cancer to androgen ablation therapies, which requires further in vivo validation. We provided a novel miRNA regulation mechanism for proliferation regulation in AR-positive prostate cancer cells.

SUBMITTER: Zheng L

PROVIDER: S-EPMC7012176 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Sirtuin-7 (SIRT7) is associated with the maintenance of tumorigenesis. However, its functional roles and oncogenic mechanisms in prostate cancer (PCa) are poorly understood. Here, we investigated the roles and underlying molecular mechanisms of SIRT7 in PCa cell growth and androgen-induced autophagy. METHODS:The LNCap and 22Rv1 PCa cell lines were subjected to quantitative reverse transcription (RT)-PCR to characterize their genes encoding SIRT7, AR, and SMAD4. The proteins produced from these genes were quantified by western blotting and immunoprecipitation analysis. SIRT7-depleted cells were produced by transfection with plasmid vectors bearing short hairpin RNAs against SIRT7. The proliferation of each cell line was assessed by CCK8 and EdU assays. Autophagic flux was tracked by mRFP-GFP-LC3 adenovirus under an immunofluorescence microscope. Apoptosis was evaluated by flow cytometry. Tumors were induced in mouse axillae by injection of the cell lines into mice. Tumor morphology was examined by immunohistochemistry and relative tumor growth and metastases were compared by a bioluminescence-based in vivo imaging system. RESULTS:SIRT7 depletion significantly inhibited cell proliferation, androgen-induced autophagy, and invasion in LNCap and 22Rv1 cells (in vitro) and mouse xenograft tumors induced by injection of these cells (in vivo). SIRT7 knockdown also increased the sensitivity of PCa cells to radiation. Immunohistochemical analysis of 93 specimens and bioinformatic analysis revealed that SIRT7 expression was positively associated with androgen receptor (AR). Moreover, the AR signal pathway participated in SIRT7-mediated regulation of PCa cell proliferation, autophagy, and invasion. SIRT7 depletion downregulated the AR signal pathway by upregulating the level of SMAD4 protein in PCa cells. CONCLUSION:SIRT7 plays an important role in the development and progression of human PCa and may be a promising prognostic marker for prostate cancer.

Project description:Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.

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MiR-133a-5p inhibits androgen receptor (AR)-induced proliferation in prostate cancer cells via targeting FUsed in Sarcoma (FUS) and AR.

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