MicroRNA‑21‑5p induces the metastatic phenotype of human cervical carcinoma cells in vitro by targeting the von Hippel‑Lindau tumor suppressor

Cai,Lina; Wang,Wuliang; Li,Xiaomei; Dong,Tieli; Zhang,Qing; Zhu,Baojv; Zhao,Hu; Wu,Shubiao

doi:10.3892/ol.2018.7937

MicroRNA‑21‑5p induces the metastatic phenotype of human cervical carcinoma cells in vitro by targeting the von Hippel‑Lindau tumor suppressor

Authors:
- Lina Cai
- Wuliang Wang
- Xiaomei Li
- Tieli Dong
- Qing Zhang
- Baojv Zhu
- Hu Zhao
- Shubiao Wu
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China, Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
Published online on: February 2, 2018 https://doi.org/10.3892/ol.2018.7937
Pages: 5213-5219

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

Numerous studies have indicated that microRNAs (miRs), a group of small non‑coding RNAs, are determining regulatory elements involved in the pathogenesis of various types of cancer, including cervical cancer (CC). Although miR‑21‑5p upregulation has been demonstrated to associate with tumorigenesis by controlling the expression of oncogenic and tumor suppressor genes, only a small number of studies have investigated the expression of miR‑21‑5p and its functional role in CC. The objective of the present study was to investigate the effect of miR‑21‑5p on the proliferation, apoptosis, migration and invasion of CC cells, and the potential underlying molecular mechanism of these effects. The measurement of miR‑21‑5p levels using quantitative polymerase chain reaction revealed that miR‑21‑5p was markedly increased in CC cell lines compared with normal cells. Upon silencing of miR‑21‑5p, a marked suppression of the proliferation, migration and invasion of CaSki cells was observed, with induction of cell apoptosis. These effects were reversed with miR‑21‑5p overexpression. A database search followed by a luciferase reporter assay ascertained that the 3'‑untranslated region of the von Hippel‑Lindau tumor suppressor (VHL) mRNA sequence was a direct target of miR‑21‑5p. Furthermore, silencing of VHL neutralized the effects of miR‑21‑5p inhibition. These observations suggested that miR‑21‑5p is an oncogene that is able to promote the metastatic phenotype of CC cells through downregulation of VHL expression, which may present a path to novel therapeutic stratagems for the CC therapy.

View Figures

View References

1	Sherris J, Herdman C and Elias C: Cervical cancer in the developing world. West J Med. 175:231–233. 2001. View Article : Google Scholar : PubMed/NCBI
2	Huang P, Xi J and Liu S: MiR-139-3p induces cell apoptosis and inhibits metastasis of cervical cancer by targeting NOB1. Biomed Pharmacother. 83:850–856. 2016. View Article : Google Scholar : PubMed/NCBI
3	Xu J, Zhang W, Lv Q and Zhu D: Overexpression of miR-21 promotes the proliferation and migration of cervical cancer cells via the inhibition of PTEN. Oncol Rep. 33:3108–3116. 2015. View Article : Google Scholar : PubMed/NCBI
4	Babashah S, Bakhshinejad B, Birgani MT, Pakravan K and Cho WC: Regulation of microRNAs by phytochemicals: A promising strategy for cancer chemoprevention. Curr Cancer Drug Targets. Jun 23–2017.(Epub ahead of print). PubMed/NCBI
5	Zhang H, Li T, Zheng L and Huang X: Biomarker MicroRNAs for diagnosis of oral squamous cell carcinoma identified based on gene expression data and MicroRNA-mRNA network analysis. Comput Math Methods Med. 2017:98030182017. View Article : Google Scholar : PubMed/NCBI
6	Makiguchi T, Yamada M, Yoshioka Y, Sugiura H, Koarai A, Chiba S, Fujino N, Tojo Y, Ota C, Kubo H, et al: Serum extracellular vesicular miR-21-5p is a predictor of the prognosis in idiopathic pulmonary fibrosis. Respir Res. 17:1102016. View Article : Google Scholar : PubMed/NCBI
7	Han Y, Xu GX, Lu H, Yu DH, Ren Y, Wang L, Huang XH, Hou WJ, Wei ZH, Chen YP, et al: Dysregulation of miRNA-21 and their potential as biomarkers for the diagnosis of cervical cancer. Int J Clin Exp Pathol. 8:7131–7139. 2015.PubMed/NCBI
8	Kowalczyk AE, Krazinski BE, Godlewski J, Grzegrzolka J, Kiewisz J, Kwiatkowski P, Sliwinska-Jewsiewicka A, Dziegiel P and Kmiec Z: SATB1 is down-regulated in clear cell renal cell carcinoma and correlates with miR-21-5p overexpression and poor prognosis. Cancer Genomics Proteomics. 13:209–217. 2016.PubMed/NCBI
9	Zheng G, Li N, Jia X, Peng C, Luo L, Deng Y, Yin J, Song Y, Liu H, Lu M, et al: MYCN-mediated miR-21 overexpression enhances chemo-resistance via targeting CADM1 in tongue cancer. J Mol Med (Berl). 94:1129–1141. 2016. View Article : Google Scholar : PubMed/NCBI
10	Lopes-Ramos CM, Habr-Gama A, Quevedo Bde S, Felício NM, Bettoni F, Koyama FC, Asprino PF, Galante PA, Gama-Rodrigues J, Camargo AA, et al: Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients. BMC Med Genomics. 7:682014. View Article : Google Scholar : PubMed/NCBI
11	Park SK, Park YS, Ahn JY, Do EJ, Kim D, Kim JE, Jung K, Byeon JS, Ye BD, Yang DH, et al: MiR 21–5p as a predictor of recurrence in young gastric cancer patients. J Gastroenterol Hepatol. 31:1429–1435. 2016. View Article : Google Scholar : PubMed/NCBI
12	Bellissimo T, Russo E, Ganci F, Vico C, Sacconi A, Longo F, Vitolo D, Anile M, Disio D, Marino M, et al: Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors. Cancer Biol Ther. 17:79–82. 2016. View Article : Google Scholar : PubMed/NCBI
13	Zhang J, Yao T, Wang Y, Yu J, Liu Y and Lin Z: Long noncoding RNA MEG3 is downregulated in cervical cancer and affects cell proliferation and apoptosis by regulating miR-21. Cancer Biol Ther. 17:104–113. 2016. View Article : Google Scholar : PubMed/NCBI
14	Kim WY and Kaelin WG: Role of VHL gene mutation in human cancer. J Clin Oncol. 22:4991–5004. 2004. View Article : Google Scholar : PubMed/NCBI
15	Kaelin WG Jr: The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 10:6290s–6295s. 2004. View Article : Google Scholar : PubMed/NCBI
16	Kaelin WG: The von Hippel-Lindau tumor suppressor protein: Roles in cancer and oxygen sensing. Cold Spring Harb Symp Quant Biol. 70:159–166. 2005. View Article : Google Scholar : PubMed/NCBI
17	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
18	Neal CS, Michael MZ, Rawlings LH, Van der Hoek MB and Gleadle JM: The VHL-dependent regulation of microRNAs in renal cancer. BMC Med. 8:642010. View Article : Google Scholar : PubMed/NCBI
19	Liu X, Cai X, Hu B, Mei Z, Zhang D, Ouyang G, Wang J, Zhang W and Xiao W: Forkhead transcription factor 3a (FOXO3a) modulates hypoxia signaling via up-regulation of von Hippel-Lindau gene (VHL). J Biol Chem. 291:25692–25705. 2016. View Article : Google Scholar : PubMed/NCBI
20	Welford SM, Dorie MJ, Li X, Haase VH and Giaccia AJ: Renal oxygenation suppresses VHL loss-induced senescence that is caused by increased sensitivity to oxidative stress. Mol Cell Biol. 30:4595–4603. 2010. View Article : Google Scholar : PubMed/NCBI
21	Chetram MA, Bethea DA, Odero-Marah VA, Don-Salu-Hewage AS, Jones KJ and Hinton CV: ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells. Mol Cell Biochem. 376:63–71. 2013. View Article : Google Scholar : PubMed/NCBI
22	LaGory EL, Wu C, Taniguchi CM, Ding CC, Chi JT, von Eyben R, Scott DA, Richardson AD and Giaccia AJ: Suppression of PGC-1α is critical for reprogramming oxidative metabolism in renal cell carcinoma. Cell Rep. 12:116–127. 2015. View Article : Google Scholar : PubMed/NCBI
23	Damjanovic SS, Ilic BB, Beleslin Cokic BB, Antic JA, Bankovic JZ, Milicevic IT, Rodic GS, Ilic DS, Todorovic VN, Puskas N and Tulic CD: Tuberous sclerosis complex protein 1 expression is affected by VHL Gene alterations and HIF-1α production in sporadic clear-cell renal cell carcinoma. Exp Mol Pathol. 101:323–331. 2016. View Article : Google Scholar : PubMed/NCBI
24	Xiao B, Zhou X, Ye M, Lv S, Wu M, Liao C, Han L, Kang C and Zhu X: MicroRNA566 modulates vascular endothelial growth factor by targeting Von HippelLandau in human glioblastoma in vitro and in vivo. Mol Med Rep. 13:379–385. 2016. View Article : Google Scholar : PubMed/NCBI
25	Cao Y, Zhang J, Xiong D, Wang D, Wu T, Huang A and Tang H: Hsa-miR-331-3p inhibits VHL expression by directly targeting its mRNA 3′-UTR in HCC cell lines. Acta Biochim Pol. 62:77–82. 2015. View Article : Google Scholar : PubMed/NCBI
26	Liu N, Xia WY, Liu SS, Chen HY, Sun L, Liu MY, Li LF, Lu HM, Fu YJ, Wang P, et al: MicroRNA-101 targets von Hippel-Lindau tumor suppressor (VHL) to induce HIF1α mediated apoptosis and cell cycle arrest in normoxia condition. Sci Rep. 6:204892016. View Article : Google Scholar : PubMed/NCBI
27	Ma X, Shen D, Li H, Zhang Y, Lv X, Huang Q, Gao Y, Li X, Gu L, Xiu S, et al: MicroRNA-185 inhibits cell proliferation and induces cell apoptosis by targeting VEGFA directly in von Hippel-Lindau-inactivated clear cell renal cell carcinoma. Urol Oncol. 33:169.e1–11. 2015. View Article : Google Scholar