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

Xu,Bin; Lu,Xiaoming; Zhao,Yuming; Liu,Chunhui; Huang,Xiaoming; Chen,Shuqiu; Zhu,Weidong; Zhang,Lihua; Chen,Ming

doi:10.3892/ol.2018.9791

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

Authors:
- Bin Xu
- Xiaoming Lu
- Yuming Zhao
- Chunhui Liu
- Xiaoming Huang
- Shuqiu Chen
- Weidong Zhu
- Lihua Zhang
- Ming Chen
View Affiliations

Affiliations: Department of Urology, School of Medicine, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu 210009, P.R. China, Department of Urology, Affiliated Yancheng Hospital, School of Medicine, Southeast University, Yancheng, Jiangsu 224000, P.R. China, Department of Urology, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei 066000, P.R. China, Surgical Research Center, Institute of Urology, Southeast University Medical School, Nanjing, Jiangsu 210009, P.R. China, Department of Pathology, Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu 210009, P.R. China
Published online on: December 4, 2018 https://doi.org/10.3892/ol.2018.9791
Pages: 1889-1895

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Feldman BJ and Feldman D: The development of androgen-independent prostate cancer. Nat Rev Cancer. 1:34–45. 2001. View Article : Google Scholar : PubMed/NCBI
3	Debatin KM: Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immunother. 53:153–159. 2004. View Article : Google Scholar : PubMed/NCBI
4	Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, et al: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 324:787–790. 2009. View Article : Google Scholar : PubMed/NCBI
5	Das S, Roth CP, Wasson LM and Vishwanatha JK: Signal transducer and activator of transcription-6 (STAT6) is a constitutively expressed survival factor in human prostate cancer. Prostate. 67:1550–1564. 2007. View Article : Google Scholar : PubMed/NCBI
6	Kotb S, Mosharafa A, Essawi M, Hassan H, Meshref A and Morsy A: Circulating miRNAs 21 and 221 as biomarkers for early diagnosis of prostate cancer. Tumour Biol. 35:12613–12617. 2014. View Article : Google Scholar : PubMed/NCBI
7	Chang YL, Zhou PJ, Wei L, Li W, Ji Z, Fang YX and Gao WQ: MicroRNA-7 inhibits the stemness of prostate cancer stem-like cells and tumorigenesis by repressing KLF4/PI3K/Akt/p21 pathway. Oncotarget. 6:24017–24031. 2015. View Article : Google Scholar : PubMed/NCBI
8	Kojima S, Enokida H, Yoshino H, Itesako T, Chiyomaru T, Kinoshita T, Fuse M, Nishikawa R, Goto Y, Naya Y, et al: The tumor-suppressive microRNA-143/145 cluster inhibits cell migration and invasion by targeting GOLM1 in prostate cancer. J Hum Genet. 59:78–87. 2014. View Article : Google Scholar : PubMed/NCBI
9	Sun Q, Zhao X, Liu X, Wang Y, Huang J, Jiang B, Chen Q and Yu J: miR-146a functions as a tumor suppressor in prostate cancer by targeting Rac1. Prostate. 74:1613–1621. 2014. View Article : Google Scholar : PubMed/NCBI
10	Kobayashi N, Uemura H, Nagahama K, Okudela K, Furuya M, Ino Y, Ito Y, Hirano H, Inayama Y, Aoki I, et al: Identification of miR-30d as a novel prognostic maker of prostate cancer. Oncotarget. 3:1455–1471. 2012. View Article : Google Scholar : PubMed/NCBI
11	Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al: Integrative genomic profiling of human prostate cancer. Cancer Cell. 18:11–22. 2010. View Article : Google Scholar : PubMed/NCBI
12	Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, et al: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 34:267–273. 2003. View Article : Google Scholar : PubMed/NCBI
13	Xu B, Niu X, Zhang X, Tao J, Wu D, Wang Z, Li P, Zhang W, Wu H, Feng N, et al: miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS. Mol Cell Biochem. 350:207–213. 2011. View Article : Google Scholar : PubMed/NCBI
14	Xu B, Wang N, Wang X, Tong N, Shao N, Tao J, Li P, Niu X, Feng N, Zhang L, et al: MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer. Prostate. 72:1171–1178. 2012. View Article : Google Scholar : PubMed/NCBI
15	Garcia DM, Baek D, Shin C, Bell GW, Grimson A and Bartel DP: Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other microRNAs. Nat Struct Mol Biol. 18:1139–1146. 2011. View Article : Google Scholar : PubMed/NCBI
16	Krüger J and Rehmsmeier M: RNAhybrid: microRNA target prediction easy, fast and flexible. Nucleic Acids Res. 34:(Web Server Issue). W451–W454. 2006. View Article : Google Scholar : PubMed/NCBI
17	Rahal OM, Wolfe AR, Mandal PK, Larson R, Tin S, Jimenez C, Zhang D, Horton J, Reuben JM, McMurray JS and Woodward WA: Blocking interleukin (IL)4- and IL13-mediated phosphorylation of STAT6 (Tyr641) decreases M2 polarization of macrophages and protects against macrophage-mediated radioresistance of inflammatory breast cancer. Int J Radiat Oncol Biol Phys. 100:1034–1043. 2018. View Article : Google Scholar : PubMed/NCBI
18	Sun T, Wang X, He HH, Sweeney CJ, Liu SX, Brown M, Balk S, Lee GS and Kantoff PW: MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A. Oncogene. 33:2790–2800. 2014. View Article : Google Scholar : PubMed/NCBI
19	Zhou W, Li X, Liu F, Xiao Z, He M, Shen S and Liu S: MiR-135a promotes growth and invasion of colorectal cancer via metastasis suppressor 1 in vitro. Acta Biochim Biophys Sin (Shanghai). 44:838–846. 2012. View Article : Google Scholar : PubMed/NCBI
20	Chen Y, Zhang J, Wang H, Zhao J, Xu C, Du Y, Luo X, Zheng F, Liu R, Zhang H and Ma D: miRNA-135a promotes breast cancer cell migration and invasion by targeting HOXA10. BMC Cancer. 12:1112012. View Article : Google Scholar : PubMed/NCBI
21	Yamada Y, Hidaka H, Seki N, Yoshino H, Yamasaki T, Itesako T, Nakagawa M and Enokida H: Tumor-suppressive microRNA-135a inhibits cancer cell proliferation by targeting the c-MYC oncogene in renal cell carcinoma. Cancer Sci. 104:304–312. 2013. View Article : Google Scholar : PubMed/NCBI
22	Wu H, Huang M, Cao P, Wang T, Shu Y and Liu P: MiR-135a targets JAK2 and inhibits gastric cancer cell proliferation. Cancer Biol Ther. 13:281–288. 2012. View Article : Google Scholar : PubMed/NCBI
23	Zhou L, Qiu T, Xu J, Wang T, Wang J, Zhou X, Huang Z, Zhu W, Shu Y and Liu P: miR-135a/b modulate cisplatin resistance of human lung cancer cell line by targeting MCL1. Pathol Oncol Res. 19:677–683. 2013. View Article : Google Scholar : PubMed/NCBI
24	Holleman A, Chung I, Olsen RR, Kwak B, Mizokami A, Saijo N, Parissenti A, Duan Z, Voest EE and Zetter BR: miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo. Oncogene. 30:4386–4398. 2011. View Article : Google Scholar : PubMed/NCBI
25	Watson CJ: Stat transcription factors in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia. 6:115–127. 2001. View Article : Google Scholar : PubMed/NCBI