miR‑532‑5p promotes breast cancer proliferation and migration by targeting RERG

Huang,Lei; Tang,Xiaoqiao; Shi,Xianbiao; Su,Lei

doi:10.3892/etm.2019.8186

miR‑532‑5p promotes breast cancer proliferation and migration by targeting RERG

Authors:
- Lei Huang
- Xiaoqiao Tang
- Xianbiao Shi
- Lei Su
View Affiliations

Affiliations: Department of Breast and Thyroid Surgery, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China
Published online on: November 12, 2019 https://doi.org/10.3892/etm.2019.8186
Pages: 400-408

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

Aberrant expression of microRNAs (miRNAs/miRs) mediates the initiation and progression of breast cancer. Therefore, it is important to investigate the molecular mechanisms of miRNAs and their effects on breast cancer progression. In the present study, miR‑532‑5p was highly expressed in breast cancer tissues compared with normal tissues. In addition, expression of ras‑related and estrogen‑regulated growth inhibitor (RERG), a tumor suppressor in breast cancer, was negatively correlated with miR‑532‑5p expression. Inhibition of miR‑532‑5p significantly elevated RERG at both mRNA and protein levels and inactivated the mitogen‑activated protein kinase (MAPK)/ERK signaling pathway. Overexpression of miR‑532‑5p decreased RERG expression and activated the MAPK/ERK signaling in breast cancer cell line MDA‑MB‑231. Bioinformatic analysis indicated that RERG 3'‑untraslated region contained a putative binding site for miR‑532‑5p. Dual luciferase assay further validated RERG as a target gene of miR‑532‑5p. Notably, downregulation of miR‑532‑5p inhibited MDA‑MB‑231 cell proliferation and migration, which was partially attenuated upon RERG knockdown. In conclusion, the current study revealed an oncogenic role of miR‑532‑5p in breast cancer cells via direct targeting of RERG expression.

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	McDermott AM, Miller N, Wall D, Martyn LM, Ball G, Sweeney KJ and Kerin MJ: Identification and validation of oncologic miRNA biomarkers for luminal A-like breast cancer. PLoS One. 9:e870322014. View Article : Google Scholar : PubMed/NCBI
3	Notas G, Pelekanou V, Kampa M, Alexakis K, Sfakianakis S, Laliotis A, Askoxilakis J, Tsentelierou E, Tzardi M, Tsapis A and Castanas E: Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors. Mol Oncol. 9:1744–1759. 2015. View Article : Google Scholar : PubMed/NCBI
4	Ahmed S, Sami A and Xiang J: HER2-directed therapy: Current treatment options for HER2-positive breast cancer. Breast Cancer. 22:101–116. 2015. View Article : Google Scholar : PubMed/NCBI
5	Karlsson E, Veenstra C, Emin S, Dutta C, Pérez-Tenorio G, Nordenskjöld B, Fornander T and Stål O: Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Res Treat. 153:31–40. 2015. View Article : Google Scholar : PubMed/NCBI
6	Boulbes DR, Chauhan GB, Jin Q, Bartholomeusz C and Esteva FJ: CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat. 151:501–513. 2015. View Article : Google Scholar : PubMed/NCBI
7	O'Reilly EA, Gubbins L, Sharma S, Tully R, Guang MH, Weiner-Gorzel K, McCaffrey J, Harrison M, Furlong F, Kell M and McCann A: The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin. 3:257–275. 2015. View Article : Google Scholar : PubMed/NCBI
8	Venkatesh T, Suresh PS and Tsutsumi R: Non-coding RNAs: Functions and applications in endocrine-related cancer. Mol Cell Endocrinol. 416:88–96. 2015. View Article : Google Scholar : PubMed/NCBI
9	Calore F, Lovat F and Garofalo M: Non-coding RNAs and cancer. Int J Mol Sci. 14:17085–17110. 2013. View Article : Google Scholar : PubMed/NCBI
10	Yates LA, Norbury CJ and Gilbert RJ: The long and short of microRNA. Cell. 153:516–519. 2013. View Article : Google Scholar : PubMed/NCBI
11	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
12	Kanwar JR, Mahidhara G and Kanwar RK: MicroRNA in human cancer and chronic inflammatory diseases. Front Biosci (Schol Ed). 2:1113–1126. 2010. View Article : Google Scholar : PubMed/NCBI
13	Lowery AJ, Miller N, Devaney A, McNeill RE, Davoren PA, Lemetre C, Benes V, Schmidt S, Blake J, Ball G and Kerin MJ: MicroRNA signatures predict oestrogen receptor, progesterone receptor and HER2/neu receptor status in breast cancer. Breast Cancer Res. 11:R272009. View Article : Google Scholar : PubMed/NCBI
14	Cui S, Liao X, Ye C, Yin X, Liu M, Hong Y, Yu M, Liu Y, Liang H, Zhang CY and Chen X: ING5 suppresses breast cancer progression and is regulated by miR-24. Mol Cancer. 16:892017. View Article : Google Scholar : PubMed/NCBI
15	Shi Y, Luo X, Li P, Tan J, Wang X, Xiang T and Ren G: miR-7-5p suppresses cell proliferation and induces apoptosis of breast cancer cells mainly by targeting REGγ. Cancer Lett. 358:27–36. 2015. View Article : Google Scholar : PubMed/NCBI
16	Raychaudhuri M, Bronger H, Buchner T, Kiechle M, Weichert W and Avril S: MicroRNAs miR-7 and miR-340 predict response to neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 162:511–521. 2017. View Article : Google Scholar : PubMed/NCBI
17	Tsai HP, Huang SF, Li CF, Chien HT and Chen SC: Differential microRNA expression in breast cancer with different onset age. PLoS One. 13:e01911952018. View Article : Google Scholar : PubMed/NCBI
18	Finlin BS, Gau CL, Murphy GA, Shao H, Kimel T, Seitz RS, Chiu YF, Botstein D, Brown PO, Der CJ, et al: RERG is a novel ras-related, estrogen-regulated and growth-inhibitory gene in breast cancer. J Biol Chem. 276:42259–42267. 2001. View Article : Google Scholar : PubMed/NCBI
19	Ho JY, Hsu RJ, Liu JM, Chen SC, Liao GS, Gao HW and Yu CP: MicroRNA-382-5p aggravates breast cancer progression by regulating the RERG/Ras/ERK signaling axis. Oncotarget. 8:22443–22459. 2017. View Article : Google Scholar : PubMed/NCBI
20	Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, et al: Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33:e1792005. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Kasinski AL and Slack FJ: miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res. 72:5576–5587. 2012. View Article : Google Scholar : PubMed/NCBI
23	Tung SL, Huang WC, Hsu FC, Yang ZP, Jang TH, Chang JW, Chuang CM, Lai CR and Wang LH: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway. Oncogenesis. 6:e3262017. View Article : Google Scholar : PubMed/NCBI
24	Kong W, He L, Richards EJ, Challa S, Xu CX, Permuth-Wey J, Lancaster JM, Coppola D, Sellers TA, Djeu JY and Cheng JQ: Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer. Oncogene. 33:679–689. 2014. View Article : Google Scholar : PubMed/NCBI
25	Allen KE and Weiss GJ: Resistance may not be futile: microRNA biomarkers for chemoresistance and potential therapeutics. Mol Cancer Ther. 9:3126–3136. 2010. View Article : Google Scholar : PubMed/NCBI
26	Zhu L, Xue F, Xu X, Xu J, Hu S, Liu S, Cui Y and Gao C: MicroRNA-198 inhibition of HGF/c-MET signaling pathway overcomes resistance to radiotherapy and induces apoptosis in human non-small-cell lung cancer. J Cell Biochem. 119:7873–7886. 2018. View Article : Google Scholar : PubMed/NCBI
27	Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, et al: MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 65:7065–7070. 2005. View Article : Google Scholar : PubMed/NCBI
28	Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ, Barbosa-Morais NL, Teschendorff AE, Green AR, Ellis IO, et al: MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 8:R2142007. View Article : Google Scholar : PubMed/NCBI
29	Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K and Croce CM: Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA. Proc Natl Acad Sci USA. 109:3024–3029. 2012. View Article : Google Scholar : PubMed/NCBI
30	Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, Bayani N, Wang NJ, Neve RM, Guan Y, et al: Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 69:565–572. 2009. View Article : Google Scholar : PubMed/NCBI
31	Zhao W, Ma N, Wang S, Mo Y, Zhang Z, Huang G, Midorikawa K, Hiraku Y, Oikawa S, Murata M and Takeuchi K: RERG suppresses cell proliferation, migration and angiogenesis through ERK/NF-κB signaling pathway in nasopharyngeal carcinoma. J Exp Clin Cancer Res. 36:942017. View Article : Google Scholar : PubMed/NCBI
32	Wang AG, Fang W, Han YH, Cho SM, Choi JY, Lee KH, Kim WH, Kim JM, Park MG, Yu DY, et al: Expression of the RERG gene is gender-dependent in hepatocellular carcinoma and regulated by histone deacetyltransferases. J Korean Med Sci. 21:891–896. 2006. View Article : Google Scholar : PubMed/NCBI
33	Zhang Y, Ren S, Yuan F, Zhang K, Fan Y, Zheng S, Gao Z, Zhao J, Mu T, Zhao S, et al: miR-135 promotes proliferation and stemness of oesophageal squamous cell carcinoma by targeting RERG. Artif Cells Nanomed Biotechnol. 46 (Suppl):1210–1219. 2018. View Article : Google Scholar : PubMed/NCBI