miR‑888 regulates cancer progression by targeting multiple targets in lung adenocarcinoma

Cao,Ji‑Xiang

doi:10.3892/or.2019.7118

miR‑888 regulates cancer progression by targeting multiple targets in lung adenocarcinoma

Authors:
- Ji‑Xiang Cao
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Affiliations: School of Life Sciences, Peking University, Beijing 100871, P.R. China
Published online on: April 16, 2019 https://doi.org/10.3892/or.2019.7118
Pages: 3367-3376

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Abstract

Aberrantly expressed miRNAs play a crucial role in the progression of lung adenocarcinoma. However, to date, the role of miR‑888 in lung adenocarcinoma progression is unclear. In the present study, the biological function of miR‑888 and its underlying mechanism in lung adenocarcinoma progression were explored. RT‑qPCR was performed to detect the expression of miR‑888 in 38 matched lung adenocarcinoma samples respectively. Next, the effects of miR‑888 on the proliferation, invasion and migration of lung adenocarcinoma A549 cells were evaluated by a series of gain‑ and loss‑of‑function assays. Our results revealed that miR‑888 was significantly upregulated in lung adenocarcinoma tissues, and its expression was markedly associated with clinical staging in patients. Moreover, ectopic expression of miR‑888 in vitro was revealed to function as a double‑edged sword in the progression of lung adenocarcinoma A549 cells by targeting multiple targets. Overexpression of miR‑888 promoted the invasion and migration of lung adenocarcinoma A549 cells by targeting E‑cadherin and tissue inhibitor of metalloproteinase 2. In addition, ectopic expression of miR‑888 inhibited the proliferation of lung adenocarcinoma A549 cells by targeting cell division cycle 7 (CDC7). In addition, the immunohistochemical results and The Cancer Genome Atlas (TCGA) database revealed that CDC7 was significantly upregulated in lung adenocarcinoma tissues, suggesting that miR‑888 may function as an oncogene in the progression of lung adenocarcinoma patients, and the miR‑888/CDC7 axis was not the dominant pathway for CDC7 regulation in patients with lung adenocarcinoma. In conclusion, our findings indicated that miR‑888 may act as a potential new therapeutic target for patients with lung adenocarcinoma.

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1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
3	Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-An update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016. View Article : Google Scholar : PubMed/NCBI
4	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
5	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
6	Hwang HW and Mendell JT: MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 94:776–780. 2006. View Article : Google Scholar : PubMed/NCBI
7	Uddin A and Chakraborty S: Role of miRNAs in lung cancer. J Cell Physiol. 2018. View Article : Google Scholar
8	Ma YS, Yu F, Zhong XM, Lu GX, Cong XL, Xue SB, Xie WT, Hou LK, Pang LJ, Wu W, et al: miR-30 family reduction maintains self-renewal and promotes tumorigenesis in NSCLC-initiating cells by targeting oncogene TM4SF1. Mol Ther. 26:2751–2765. 2018. View Article : Google Scholar : PubMed/NCBI
9	Song Q, Ji Q, Xiao J, Wang L, Chen Y, Xu Y and Jiao S: miR-409 inhibits human non-small-cell lung cancer progression by directly targeting SPIN1. Mol Ther Nucleic Acids. 13:154–163. 2018. View Article : Google Scholar : PubMed/NCBI
10	Hovey AM, Devor EJ, Breheny PJ, Mott SL, Dai D, Thiel KW and Leslie KK: miR-888: A novel cancer-testis antigen that targets the progesterone receptor in endometrial cancer. transl Oncol. 8:85–96. 2015. View Article : Google Scholar : PubMed/NCBI
11	Gao SJ, Chen L, Lu W, Zhang L, Wang L and Zhu HH: miR-888 functions as an oncogene and predicts poor prognosis in colorectal cancer. Oncol Lett. 15:9101–9109. 2018.PubMed/NCBI
12	Bobowicz M, Skrzypski M, Czapiewski P, Marczyk M, Maciejewska A, Jankowski M, Szulgo-Paczkowska A, Zegarski W, Pawłowski R, Polańska J, et al: Prognostic value of 5-microRNA based signature in T2-T3N0 colon cancer. Clin Exp Metastasis. 33:765–773. 2016. View Article : Google Scholar : PubMed/NCBI
13	Lewis H, Lance R, Troyer D, Beydoun H, Hadley M, Orians J, Benzine T, Madric K, Semmes OJ, Drake R, et al: miR-888 is an expressed prostatic secretions-derived microRNA that promotes prostate cell growth and migration. Cell Cycle. 13:227–239. 2014. View Article : Google Scholar : PubMed/NCBI
14	Huang S and Chen L: MiR-888 regulates side population properties and cancer metastasis in breast cancer cells. Biochem Biophys Res Commun. 450:1234–1240. 2014. View Article : Google Scholar : PubMed/NCBI
15	Huang S, Cai M, Zheng Y, Zhou L, Wang Q and Chen L: miR-888 in MCF-7 side population sphere cells directly targets E-cadherin. J Genet Genomics. 41:35–42. 2014. View Article : Google Scholar : PubMed/NCBI
16	Hasegawa T, Glavich GJ, Pahuski M, Short A, Semmes OJ, Yang L, Galkin V, Drake R and Esquela-Kerscher A: Characterization and evidence of the miR-888 cluster as a novel cancer network in prostate. Mol Cancer Res. 16:669–681. 2018. View Article : Google Scholar : PubMed/NCBI
17	Wang L, Liu Q, Lin D and Lai M: CD44v6 down-regulation is an independent prognostic factor for poor outcome of colorectal carcinoma. Int J Clin Exp Patho. 8:14283–14293. 2015.
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Bonte D, Lindvall C, Liu H, Dykema K, Furge K and Weinreich M: Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation. Neoplasia. 10:920–931. 2008. View Article : Google Scholar : PubMed/NCBI
20	Li Q, Xie W, Wang N, Li C and Wang M: CDC7-dependent transcriptional regulation of RAD54L is essential for tumorigenicity and radio-resistance of glioblastoma. Transl Oncol. 11:300–306. 2018. View Article : Google Scholar : PubMed/NCBI
21	Sasi NK, Bhutkar A, Lanning NJ, MacKeigan JP and Weinreich M: DDK promotes tumor chemoresistance and survival via multiple pathways. Neoplasia. 19:439–450. 2017. View Article : Google Scholar : PubMed/NCBI
22	Del Vescovo V, Grasso M, Barbareschi M and Denti MA: MicroRNAs as lung cancer biomarkers. World J Clin Oncol. 5:604–620. 2014. View Article : Google Scholar : PubMed/NCBI
23	Chen C, Xue S, Zhang J, Chen W, Gong D, Zheng J, Ma J, Xue W, Chen Y, Zhai W, et al: DNA-methylation-mediated repression of miR-766-3p promotes cell proliferation via targeting SF2 expression in renal cell carcinoma. Int J Cancer. 141:1867–1878. 2017. View Article : Google Scholar : PubMed/NCBI
24	Yang C, Ma X, Guan G, Liu H, Yang Y, Niu Q, Wu Z, Jiang Y, Bian C, Zang Y and Zhuang L: MicroRNA-766 promotes cancer progression by targeting NR3C2 in hepatocellular carcinoma. FASEB J. 33:1456–1467. 2019. View Article : Google Scholar : PubMed/NCBI
25	Masai H and Arai K: Cdc7 kinase complex: A key regulator in the initiation of DNA replication. J Cell Physiol. 190:287–296. 2002. View Article : Google Scholar : PubMed/NCBI
26	Labib K: How do Cdc7 and cyclin-dependent kinases trigger the initiation of chromosome replication in eukaryotic cells? Genes Dev. 24:1208–1219. 2010. View Article : Google Scholar : PubMed/NCBI
27	Datta A, Ghatak D, Das S, Banerjee T, Paul A, Butti R, Gorain M, Ghuwalewala S, Roychowdhury A, Alam SK, et al: p53 gain-of-function mutations increase Cdc7-dependent replication initiation. EMBO Rep. 18:2030–2050. 2017. View Article : Google Scholar : PubMed/NCBI
28	Erbayraktar Z, Alural B, Erbayraktar RS and Erkan EP: Cell division cycle 7-kinase inhibitor PHA-767491 hydrochloride suppresses glioblastoma growth and invasiveness. Cancer Cell Int. 16:882016. View Article : Google Scholar : PubMed/NCBI