The molecular mechanism underlying activation of MMP9 in non-small cell lung cancer (NSCLC) cells, which controls cancer invasiveness and metastasis, remains elusive. Here, we reported significant decrease in miR-129 and significant increases in phosphorylated EGFR and MMP9 in the resected NSCLC from the patients, compared with adjacent normal tissue. Moreover, strong correlations were detected among these three factors, the relationship of which was examined in two human NSCLC lines, A549 and H460. We found that EGF-induced EGFR phosphorylation in A549 or H460 cells activated MMP9 and, consequently, cancer invasiveness. The EGF-induced activation of MMP9 was efficiently inhibited either by an EGFR inhibitor or by an Akt inhibitor. However, miR-129 level was not affected by EGF stimulation. In addition, overexpression of miR-129 antagonized EGF-induced MMP9 activation without affecting EGFR phosphorylation in A549 or H460 cells. Taken together, our data suggest that miR-129 inhibits EGFR signaling through PI3K signal transduction cascades to regulate MMP9 expression in NSCLC. Thus, miR-129, EGFR, and MMP9 appear to be promising therapeutic targets for preventing the metastasis of NSCLC.
Non-small cell lung cancer MiR-129 Epidermal growth factor receptor MMP9
This is a preview of subscription content, log in to check access.
This work was financially supported by the Natural Science Foundation of China No. 30971306 and Nantong Social Development Project No. S9910.
Zarogoulidis K, Zarogoulidis P, Darwiche K, Boutsikou E, Machairiotis N, Tsakiridis K, et al. Treatment of non-small cell lung cancer (nsclc). J Thorac Dis. 2013;5:S389–96.PubMedPubMedCentralGoogle Scholar
Mitsudomi T, Suda K, Yatabe Y. Surgery for nsclc in the era of personalized medicine. Nat Rev Clin Oncol. 2013;10:235–44.CrossRefPubMedGoogle Scholar
Pallis AG, Syrigos KN. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of nsclc. Lung Cancer. 2013;80:120–30.CrossRefPubMedGoogle Scholar
Jian H, Liu B, Zhang J. Hypoxia and hypoxia-inducible factor 1 repress sema4b expression to promote non-small cell lung cancer invasion. Tumour Biol. 2014;35:4949–55.CrossRefPubMedGoogle Scholar
Jian H, Zhao Y, Liu B, Lu S. Sema4b inhibits mmp9 to prevent metastasis of non-small cell lung cancer. Tumour Biol 2014;35:11051–11056.Google Scholar
Wang W, Wu X, Tian Y. Crosstalk of ap4 and tgfbeta receptor signaling in nsclc. Tumour Biol 2015;36:447–452.Google Scholar
Pei J, Lou Y, Zhong R, Han B. Mmp9 activation triggered by epidermal growth factor induced foxo1 nuclear exclusion in non-small cell lung cancer. Tumour Biol. 2014;35:6673–8.CrossRefPubMedGoogle Scholar
Jassem J, Dziadziuszko R. Egfr inhibitors for wild-type egfr nsclc: to use or not to use? Lancet Oncol. 2013;14:916–7.CrossRefPubMedGoogle Scholar
Stella GM, Scabini R, Inghilleri S, Cemmi F, Corso S, Pozzi E, et al. Egfr and kras mutational profiling in fresh non-small cell lung cancer (nsclc) cells. J Cancer Res Clin Oncol. 2013;139:1327–35.CrossRefPubMedGoogle Scholar
Kim S, Choi JH, Lim HI, Lee SK, Kim WW, Cho S, et al. Egf-induced mmp-9 expression is mediated by the jak3/erk pathway, but not by the jak3/stat-3 pathway in a skbr3 breast cancer cell line. Cell Signal. 2009;21:892–8.CrossRefPubMedGoogle Scholar
Wu J, Qian J, Li C, Kwok L, Cheng F, Liu P, et al. Mir-129 regulates cell proliferation by downregulating cdk6 expression. Cell Cycle. 2010;9:1809–18.CrossRefPubMedGoogle Scholar
Lieber M, Smith B, Szakal A, Nelson-Rees W, Todaro G. A continuous tumor-cell line from a human lung carcinoma with properties of type ii alveolar epithelial cells. Int J Cancer. 1976;17:62–70.CrossRefPubMedGoogle Scholar
Schuller HM, Falzon M, Gazdar AF, Hegedus T. Cell type-specific differences in metabolic activation of n-nitrosodiethylamine by human lung cancer cell lines. IARC Sci Publ. 1987;138–40.Google Scholar
Xiao X, Gaffar I, Guo P, Wiersch J, Fischbach S, Peirish L, et al. M2 macrophages promote beta-cell proliferation by up-regulation of smad7. Proc Natl Acad Sci U S A. 2014;111:E1211–20.CrossRefPubMedPubMedCentralGoogle Scholar
Vlahos CJ, Matter WF, Hui KY, Brown RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one (ly294002). J Biol Chem. 1994;269:5241–8.PubMedGoogle Scholar
Cao W, Yang W, Fan R, Li H, Jiang J, Geng M, et al. Mir-34a regulates cisplatin-induce gastric cancer cell death by modulating PI3K/Akt/survivin pathway. Tumour Biol. 2014;35:1287–95.CrossRefPubMedGoogle Scholar
Liang Y, Liu M, Wang P, Ding X, Cao Y. Analysis of 20 genes at chromosome band 12q13: Racgap1 and mcrs1 overexpression in nonsmall-cell lung cancer. Genes Chromosom Cancer. 2013;52:305–15.CrossRefPubMedGoogle Scholar