SRF-miR‑29b-MMP2 axis inhibits NSCLC invasion and metastasis

Wang,Hong-Yan; Tu,Yong-Sheng; Long,Jie; Zhang,Hui-Qiu; Qi,Cui-Ling; Xie,Xiao-Bin; Li,Shu-Hua; Zhang,Ya-Jie

doi:10.3892/ijo.2015.3034

SRF-miR‑29b-MMP2 axis inhibits NSCLC invasion and metastasis

Authors:
- Hong-Yan Wang
- Yong-Sheng Tu
- Jie Long
- Hui-Qiu Zhang
- Cui-Ling Qi
- Xiao-Bin Xie
- Shu-Hua Li
- Ya-Jie Zhang
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Affiliations: Department of Pathology, School of Basic Sciences, Guangzhou Medical University, Guangdong 510180, P.R. China, Department of Physiology, School of Basic Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China
Published online on: June 5, 2015 https://doi.org/10.3892/ijo.2015.3034
Pages: 641-649

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Abstract

MicroRNAs play key roles in tumour metastasis. miR‑29b was previously reported to act as a tumour suppressor or an oncogene in diverse cancers. However, its accurate function and mechanism in metastasis of no-small cell lung cancer (NSCLC) are not well known. In this study, we describe the function of miR‑29b in NSCLC metastasis and its regulatory mechanisms. We found that miR‑29b is downregulated in high-metastatic NSCLC cells and low-expression of miR‑29b in primary NSCLC tissue was correlated with lymph node metastasis. Both gain- and loss-of-function study indicated overexpression of miR‑29b could suppress migration and invasion abilities of high-metastatic NSCLC cells, while downregulation of miR‑29b expression promoted migration and invasion of low-metastatic NSCLC cells in vitro. Moreover, introduction of miR‑29b inhibited high‑metastatic NSCLC cells, in vivo, metastasis to liver and lungs. Mechanistically, miR‑29b, induced by the transcription factor SRF, posttranscriptionally downregulates MMP2 expression by directly targeting its 3'-untranslated regions. These findings indicate a new regulatory mode, whereby miR‑29b, which is inhibited by its upstream transcription factor SRF, was able to promote its direct target MMP2 leading to NSCLC invasion and metastasis.

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1	Shao C, Lu C, Chen L, Koty PP, Cobos E and Gao W: p53-dependent anticancer effects of leptomycin B on lung adenocarcinoma. Cancer Chemother Pharmacol. 67:1369–1380. 2011. View Article : Google Scholar
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
3	Steeg PS: Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 3:55–63. 2003. View Article : Google Scholar : PubMed/NCBI
4	Ambros V and Chen X: The regulation of genes and genomes by small RNAs. Development. 134:1635–1641. 2007. View Article : Google Scholar : PubMed/NCBI
5	Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S, et al: miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol. 12:247–256. 2010.PubMed/NCBI
6	Ma L: Role of miR-10b in breast cancer metastasis. Breast Cancer Res. 12:2102010. View Article : Google Scholar : PubMed/NCBI
7	Li J, Zhang Y, Zhang W, Jia S, Tian R, Kang Y, Ma Y and Li D: Genetic heterogeneity of breast cancer metastasis may be related to miR-21 regulation of TIMP-3 in translation. Int J Surg Oncol. 2013:8750782013.PubMed/NCBI
8	Zhang Y, Yang P, Sun T, Li D, Xu X, Rui Y, Li C, Chong M, Ibrahim T, Mercatali L, et al: miR-126 and miR-126^* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol. 15:284–294. 2013. View Article : Google Scholar : PubMed/NCBI
9	Liu S, Howell PM and Riker AI: Up-regulation of miR-182 expression after epigenetic modulation of human melanoma cells. Ann Surg Oncol. 20:1745–1752. 2013. View Article : Google Scholar
10	Nass D, Rosenwald S, Meiri E, Gilad S, Tabibian-Keissar H, Schlosberg A, Kuker H, Sion-Vardy N, Tobar A, Kharenko O, et al: MiR-92b and miR-9/9^* are specifically expressed in brain primary tumors and can be used to differentiate primary from metastatic brain tumors. Brain Pathol. 19:375–383. 2009. View Article : Google Scholar :
11	Kristensen H, Haldrup C, Strand S, Mundbjerg K, Mortensen MM, Thorsen K, Ostenfeld MS, Wild PJ, Arsov C, Goering W, et al: Hypermethylation of the GABRE-miR-452-miR-224 promoter in prostate cancer predicts biochemical recurrence after radical prostatectomy. Clin Cancer Res. 20:2169–2181. 2014. View Article : Google Scholar : PubMed/NCBI
12	Reis ST, Pontes-Junior J, Antunes AA, Dall’Oglio MF, Dip N, Passerotti CC, Rossini GA, Morais DR, Nesrallah AJ, Piantino C, et al: miR-21 may acts as an oncomir by targeting RECK, a matrix metalloproteinase regulator, in prostate cancer. BMC Urol. 12:142012. View Article : Google Scholar : PubMed/NCBI
13	Bullock MD, Pickard KM, Nielsen BS, Sayan AE, Jenei V, Mellone M, Mitter R, Primrose JN, Thomas GJ, Packham GK, et al: Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression. Cell Death Dis. 4:e6842013. View Article : Google Scholar : PubMed/NCBI
14	Wang HY, Zheng SQ, Tu YS and Zhang YJ: Bioinformatics analysis of metastasis-related miR-29b. Chin J Clin Oncol. 41:1021–1025. 2014.
15	Hou Y, Zou Q, Ge R, Shen F and Wang Y: The critical role of CD133(+)CD44(+/high) tumor cells in hematogenous metastasis of liver cancers. Cell Res. 22:259–272. 2012. View Article : Google Scholar :
16	Angelastro JM and Lamé MW: Overexpression of CD133 promotes drug resistance in C6 glioma cells. Mol Cancer Res. 8:1105–1115. 2010. View Article : Google Scholar : PubMed/NCBI
17	He A, Qi W, Huang Y, Feng T, Chen J, Sun Y, Shen Z and Yao Y: CD133 expression predicts lung metastasis and poor prognosis in osteosarcoma patients: A clinical and experimental study. Exp Ther Med. 4:435–441. 2012.PubMed/NCBI
18	Kim ST, Sohn I, Do IG, Jang J, Kim SH, Jung IH, Park JO, Park YS, Talasaz A, Lee J, et al: Transcriptome analysis of CD133-positive stem cells and prognostic value of survivin in colorectal cancer. Cancer Genomics Proteomics. 11:259–266. 2014.PubMed/NCBI
19	Mizugaki H, Sakakibara-Konishi J, Kikuchi J, Moriya J, Hatanaka KC, Kikuchi E, Kinoshita I, Oizumi S, Dosaka-Akita H, Matsuno Y, et al: CD133 expression: A potential prognostic marker for non-small cell lung cancers. Int J Clin Oncol. 19:254–259. 2014. View Article : Google Scholar
20	Wu DW, Hsu NY, Wang YC, Lee MC, Cheng YW, Chen CY and Lee H: c-Myc suppresses microRNA-29b to promote tumor aggressiveness and poor outcomes in non-small cell lung cancer by targeting FHIT. Oncogene. Jun 9–2014.(Epub ahead of print). View Article : Google Scholar
21	Wang B, Li W, Liu H, Yang L, Liao Q, Cui S, Wang H and Zhao L: miR-29b suppresses tumor growth and metastasis in colorectal cancer via downregulating Tiam1 expression and inhibiting epithelial-mesenchymal transition. Cell Death Dis. 5:e13352014. View Article : Google Scholar : PubMed/NCBI
22	Zheng JJ, Yu FJ, Dong PH, Bai YH and Chen BC: Expression of miRNA-29b and its clinical significances in primary hepatic carcinoma. Zhonghua Yi Xue Za Zhi. 93:888–891. 2013.(In Chinese). PubMed/NCBI
23	Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R and Wu CW: Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 17:353–360. 1997. View Article : Google Scholar : PubMed/NCBI
24	Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y, et al: MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet. 6:e10008792010. View Article : Google Scholar : PubMed/NCBI
25	Chang DK, Lin CT, Wu CH and Wu HC: A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer. PLoS One. 4:e41712009. View Article : Google Scholar : PubMed/NCBI
26	Torng PL, Lee YC, Huang CY, Ye JH, Lin YS, Chu YW, Huang SC, Cohen P, Wu CW and Lin CT: Insulin-like growth factor binding protein-3 (IGFBP-3) acts as an invasion-metastasis suppressor in ovarian endometrioid carcinoma. Oncogene. 27:2137–2147. 2008. View Article : Google Scholar
27	Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, et al: MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell. 13:48–57. 2008. View Article : Google Scholar : PubMed/NCBI
28	Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, Hung SC, Chang YL, Tsai ML, Lee YY, et al: Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One. 3:e26372008. View Article : Google Scholar : PubMed/NCBI
29	Qian Q, Wang Q, Zhan P, Peng L, Wei SZ, Shi Y and Song Y: The role of matrix metalloproteinase 2 on the survival of patients with non-small cell lung cancer: A systematic review with meta-analysis. Cancer Invest. 28:661–669. 2010. View Article : Google Scholar : PubMed/NCBI
30	Fang JH, Zhou HC, Zeng C, Yang J, Liu Y, Huang X, Zhang JP, Guan XY and Zhuang SM: MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology. 54:1729–1740. 2011. View Article : Google Scholar : PubMed/NCBI
31	Gebeshuber CA, Zatloukal K and Martinez J: miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep. 10:400–405. 2009. View Article : Google Scholar : PubMed/NCBI
32	Kuo CH, Goldberg MD, Lin SL, Ying SY and Zhong JF: Identify intronic microRNA with bioinformatics. Methods Mol Biol. 936:77–82. 2013. View Article : Google Scholar
33	Beck H, Flynn K, Lindenberg KS, Schwarz H, Bradke F, Di Giovanni S and Knöll B: Serum response factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics. Proc Natl Acad Sci USA. 109:E2523–E2532. 2012. View Article : Google Scholar : PubMed/NCBI
34	Lee HJ, Yun CH, Lim SH, Kim BC, Baik KG, Kim JM, Kim WH and Kim SJ: SRF is a nuclear repressor of Smad3-mediated TGF-beta signaling. Oncogene. 26:173–185. 2007. View Article : Google Scholar
35	Choi HN, Kim KR, Lee JH, Park HS, Jang KY, Chung MJ, Hwang SE, Yu HC and Moon WS: Serum response factor enhances liver metastasis of colorectal carcinoma via alteration of the E-cadherin/beta-catenin complex. Oncol Rep. 21:57–63. 2009.
36	Kim KR, Bae JS, Choi HN, Park HS, Jang KY, Chung MJ and Moon WS: The role of serum response factor in hepatocellular carcinoma: An association with matrix metalloproteinase. Oncol Rep. 26:1567–1572. 2011.PubMed/NCBI
37	Verone AR, Duncan K, Godoy A, Yadav N, Bakin A, Koochekpour S, Jin JP and Heemers HV: Androgen-responsive serum response factor target genes regulate prostate cancer cell migration. Carcinogenesis. 34:1737–1746. 2013. View Article : Google Scholar : PubMed/NCBI
38	Walker T, Nolte A, Steger V, Makowiecki C, Mustafi M, Friedel G, Schlensak C and Wendel HP: Small interfering RNA-mediated suppression of serum response factor, E2-promotor binding factor and survivin in non-small cell lung cancer cell lines by non-viral transfection. Eur J Cardiothorac Surg. 43:628–634. 2013. View Article : Google Scholar
39	Zhao X, He L, Li T, Lu Y, Miao Y, Liang S, Guo H, Bai M, Xie H, Luo G, et al: SRF expedites metastasis and modulates the epithelial to mesenchymal transition by regulating miR-199a-5p expression in human gastric cancer. Cell Death Differ. 21:1900–1913. 2014. View Article : Google Scholar : PubMed/NCBI