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MiR-124 regulates STAT3-mediated cell proliferation, migration and apoptosis in bladder cancer.

ABSTRACT: The etiology and pathogenesis of bladder cancer (BCa) is complex. MicroRNA (miRNA) has been implicated in BCa. Targeting of signal transducer and activator of transcription 3 (STAT3) by miR-124 to regulate tumorigenesis has been demonstrated in other types of cancer. In the present study, miR-124 levels were downregulated in the BCa T24 cell line and STAT3 was increased in BCa cell lines. Transfection of miR-124 mimics into T24 cells significantly inhibited STAT3 expression. A luciferase assay confirmed that miR-124 directly targeted the STAT3 3'untranslated region to inhibit STAT expression. Knockdown of STAT3 expression led to increased apoptosis of T24 cells and reduced tumor growth in vitro. The results demonstrated the molecular mechanisms and biological functions of the miR-124/STAT3 signal pathway at the cellular level and indicate the potential of miR-124 as a therapeutic target for BCa.

SUBMITTER: Wang S

PROVIDER: S-EPMC6176365 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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miR-124 regulates STAT3-mediated cell proliferation, migration and apoptosis in bladder cancer.

Wang Shengxing S Wu Gang G Han Yinan Y Song Peng P Chen Jinhuo J Wu Yaoxi Y Yang Jie J Liang Peiyu P

Oncology letters 20180821 5

The etiology and pathogenesis of bladder cancer (BCa) is complex. MicroRNA (miRNA) has been implicated in BCa. Targeting of signal transducer and activator of transcription 3 (STAT3) by miR-124 to regulate tumorigenesis has been demonstrated in other types of cancer. In the present study, miR-124 levels were downregulated in the BCa T24 cell line and STAT3 was increased in BCa cell lines. Transfection of miR-124 mimics into T24 cells significantly inhibited STAT3 expression. A luciferase assay c ...[more]

PMID: 30344738

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Project description:Signal transducer and activator of transcription 3 (STAT3), a transcriptional factor involved in tumorigenesis and cancer stemness formation, contributes to drug resistance in cancer therapies. STAT3 not only mediates gene transcription but also participates in microRNA suppression. This study identified a STAT3-downstream micro RNA (miRNA) involved in drug resistance against regorafenib in colorectal cancer stem-like tumorspheres. Small RNAseq was used to investigate differential microRNAs in colorectal cancer cell-derived tumorspheres and in a STAT3-knockdown strain. The miRNA-mediated genes were identified by comparing RNAseq data with gene targets predicted using TargetScan. Assays for detecting cell viability and apoptosis were used to validate findings. The formation of colorectal cancer stem-like tumorspheres was inhibited by BBI608, a STAT3 inhibitor, but not by regorafenib. Additional investigations for microRNA expression demonstrated an increase in 10 miRNAs and a decrease in 13 miRNAs in HT29-derived tumorspheres. A comparison of small RNAseq results between tumorspheres and HT29shSTAT3 cells revealed the presence of four STAT3-mediated miRNAs in HT29-derived tumorspheres: hsa-miR-215-5p, hsa-miR-4521, and hsa-miR-215-3p were upregulated, whereas miR-30a-5p was downregulated. Furthermore, hsa-miR-4521 was associated with poor overall survival probability, and miR-30a-5p was associated with better overall survival probability in patients with rectum cancer. Comparisons of RNAseq findings between HCT116- and HT29-derived tumorspheres revealed that HSPA5 were mediated by the STAT3-miR-30a-5p axis, which is overexpressed in colorectal tumorspheres associating to anti-apoptosis. In addition, the transfection of miR-30a-5p and inhibition of HSPA5 by HA15 significantly reduced cell viability and increased apoptosis in HT29 cells. In conclusion, a STAT3-miR-30a-5p-HSPA5 axis was observed against regorafenib-mediated apoptosis in colorectal cancer tumorspheres. The expression of miR-30a-5p was repressed by STAT3; in addition, HSPA5 was identified as the target gene of miR-30a-5p and contributed to both tumorsphere formation and anti-apoptosis.

Project description:OBJECTIVE:To investigate role of microRNA-1/Golgi phosphoprotein 3/Foxo1 axis in bladder cancer. METHODS:The expression of Golgi phosphoprotein 3 was determined in both bladder cancer tissues and cell lines using quantitative real-time polymerase chain reaction and Western blotting, respectively. Golgi phosphoprotein 3 was knocked down by small hairpin RNA. MicroRNA-1 was overexpressed or inhibited by microRNA-1 mimic or inhibitor. Cell viability and proliferation were determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) and colony-formation assay. Cell apoptosis and cycle was detected using flow cytometer. The expression of microRNA-1 and Golgi phosphoprotein 3 was determined using quantitative real-time polymerase chain reaction and Western blotting was used to test the expression of Golgi phosphoprotein 3, Foxo1, p-Foxo1, AKT, p-AKT, p27, and CyclinD1. Binding between microRNA-1 and Golgi phosphoprotein 3 was confirmed by Dual-Luciferase Reporter Assay. RESULTS:MicroRNA-1 was downregulated in bladder cancer tissues, while Golgi phosphoprotein 3 was overexpressed in bladder cancer cells and tissues. In both bladder cancer 5637 and T24 cell lines, the cell viability and proliferation were dramatically reduced when Golgi phosphoprotein 3 was knocked down. The inhibition of Golgi phosphoprotein 3 remarkably promoted cell apoptosis and induced cell-cycle arrest, as well as decreased the expression of p-Foxo1, p-AKT, and CyclinD1 and increased the expression of p27. The overexpression of microRNA-1 significantly inhibited cell viability and proliferation, induced G-S cell-cycle arrest, and decreased the expression of Golgi phosphoprotein 3, p-Foxo1, and CyclinD1 and upregulated p27, while inhibition of microRNA-1 led to opposite results. Golgi phosphoprotein 3 was a direct target for microRNA-1. CONCLUSION:Overexpression of microRNA-1 inhibited cell proliferation and induced cell-cycle arrest of bladder cancer cells through targeting Golgi phosphoprotein 3 and regulation of Foxo1.

Dataset Information

MiR-124 regulates STAT3-mediated cell proliferation, migration and apoptosis in bladder cancer.

Publications

miR-124 regulates STAT3-mediated cell proliferation, migration and apoptosis in bladder cancer.

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