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MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6.

ABSTRACT: Clinical management of metastatic prostate cancer remains a challenge. Activation of apoptosis signaling pathways via signal transducer and activator of transcription 6 (STAT6) has been hypothesized to be a therapeutic strategy for patients with metastatic prostate cancer. The ONCOMINE® prostate cancer database and two Gene Expression Omnibus datasets (Gene Series 40026 and 21032) were re-analyzed to determine the expression levels of STAT6 and microRNA (miR)-135a in prostate cancer. The current study investigated the induced overexpression of miR-135a in prostate cancer cell lines to detect its function in prostate cell apoptosis using Hoechst staining and fluorescence-activated cell sorting and examined the expression levels of STAT6 and its DNA binding ability using western blotting and an electrophoretic mobility shift assay. In analysis of the ONCOMINE® database, STAT6 expression levels in prostate cancer tissue were higher compared with those in normal prostate gland tissue and were associated with the overall survival rate and biochemical relapse rate following radical prostatectomy. Additionally, there was an inverse correlation between miR-135a and STAT6 expression levels in prostate cancer cell lines. miR-135a was able to induce prostate cancer cell apoptosis via targeting STAT6 mRNA and subsequently repressing protein expression and phosphorylation, which also altered the transcriptional factor function of STAT6 through its DNA-binding capabilities. In conclusion, miR-135a may function as a tumor-suppressing miRNA in prostate cancer and its anti-oncogenic activity may involve the direct targeting and inhibition of STAT6.

SUBMITTER: Xu B

PROVIDER: S-EPMC6341792 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6.

Xu Bin B Lu Xiaoming X Zhao Yuming Y Liu Chunhui C Huang Xiaoming X Chen Shuqiu S Zhu Weidong W Zhang Lihua L Chen Ming M

Oncology letters 20181204 2

Clinical management of metastatic prostate cancer remains a challenge. Activation of apoptosis signaling pathways via signal transducer and activator of transcription 6 (STAT6) has been hypothesized to be a therapeutic strategy for patients with metastatic prostate cancer. The ONCOMINE<sup>®</sup> prostate cancer database and two Gene Expression Omnibus datasets (Gene Series 40026 and 21032) were re-analyzed to determine the expression levels of STAT6 and microRNA (miR)-135a in prostate cancer. ...[more]

PMID: 30675252

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Project description:The transcription factor STAT6 is strongly expressed in various tumours and is most highly expressed in human malignant lymphomas and pancreatic, colorectal, prostate and breast cancers. STAT6 is associated with cancer cell proliferation, an increased malignancy and poor prognosis. Thus, techniques aimed at reducing or blocking STAT6 expression may be useful in treating STAT6high cancers. Among these cancers, colorectal and breast cancers represent two of the most common worldwide and their incidence is increasing every year. In 2018, colorectal and breast cancers represented 10.2% and 11.6% of all new cases of cancer diagnosed, respectively. In this study, four proprietary STAT6 specific small interfering RNA (siRNA) sequences were tested in vitro using the human colon adenocarcinoma cell line, HT-29, and the breast/duct carcinoma cell line, ZR-75-1. Decreases in STAT6 mRNA and protein levels were analysed to confirm the transfection was successful and STAT6 knockdown effects were measured by analysing cell proliferation and apoptosis. Results showed that 100nM siRNA concentration was the most effective and, although all individual sequences were capable of significantly inhibiting cell proliferation, STAT6 siRNA sequences 1 and 4 had the largest effects. STAT6 silencing also significantly induced apoptotic events. In conclusion, these results demonstrate that STAT6 siRNA sequences are capable of inhibiting proliferation of and inducing apoptosis of HT-29 colorectal cancer cells and ZR-75-1 breast cancer cells, halving the number of cancer cells in a short period of time. These experiments will be repeated in other STAT6high cancers in vitro, and animal studies in immunocompromised mice have been planned using xenografts of STAT6-expressing human colorectal and breast cancer cells. The STAT6 siRNA sequences therefore represent a potential treatment for STAT6high colorectal and breast cancers and a wide variety of other STAT6-expressing cancers.

Dataset Information

MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6.

Publications

MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6.

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