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MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer

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Tumor Biology


The molecular mechanism underlying cancer invasiveness and metastasis of gastric carcinoma remains elusive. Here, we reported significant decrease in microRNA (miRNA)-34a and significant increase in phosphorylated epidermal growth factor receptor (EGFR) and matrix metalloproteinase-7 (MMP7) in the resected gastric carcinoma from the patients, compared with adjacent normal tissue. Moreover, strong correlation was detected among these three factors. To examine whether a causal link exists, we used two human gastric carcinoma lines, SNU-5 and HGC27, to study the molecular basis of miRNA-34a, EGFR signaling, and MMP7 activation. We found that EGF-induced EGFR phosphorylation in SNU-5 or HGC27 cells activated MMP7 and consequently cancer invasiveness. Both an inhibitor for EGFR and an inhibitor for Akt significantly inhibited the EGF-induced activation of MMP7, suggesting a phosphatidylinositol 3-kinase (PI3K) signaling cascade dependent pathway. Moreover, miRNA-34a levels were not affected by EGF-induced EGFR phosphorylation. However, overexpression of miRNA-34a antagonized EGF-induced MMP7 activation without affecting EGFR phosphorylation in SNU-5 or HGC27 cells. Taken together, our data suggest that miRNA-34 inhibits EGFR signaling via downstream PI3K signaling cascades to regulate MMP7 expression in gastric carcinoma. Thus, miRNA-34a, EGFR, and MMP7 appear to be promising therapeutic targets for preventing the metastasis of gastric carcinoma.

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  1. Zhao X, Li X, Yuan H. MicroRNAs in gastric cancer invasion and metastasis. Front Biosci. 2013;18:803–10.

    Article  CAS  Google Scholar 

  2. Cardoso AP, Pinto ML, Pinto AT, Oliveira MI, Pinto MT, Goncalves R, et al. Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y(1086), c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. Oncogene. 2014;33:2123–33.

    Article  CAS  PubMed  Google Scholar 

  3. Hotz B, Keilholz U, Fusi A, Buhr HJ, Hotz HG. In vitro and in vivo antitumor activity of cetuximab in human gastric cancer cell lines in relation to epidermal growth factor receptor (EGFR) expression and mutational phenotype. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2012;15:252–64.

    CAS  Google Scholar 

  4. Kim JW, Kim HP, Im SA, Kang S, Hur HS, Yoon YK, et al. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 2008;272:296–306.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2009;218:460–6.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li Z, Zhang D, Zhang H, Miao Z, Tang Y, Sun G, et al. Prediction of peritoneal recurrence by the mRNA level of CEA and MMP-7 in peritoneal lavage of gastric cancer patients. Tumour Biol. 2014;35:3463–70.

    Article  CAS  PubMed  Google Scholar 

  9. Shi M, Liu D, Duan H, Han C, Wei B, Qian L, et al. Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer. Mol Cancer. 2010;9:269.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Koskensalo S, Mrena J, Wiksten JP, Nordling S, Kokkola A, Hagstrom J, et al. MMP-7 overexpression is an independent prognostic marker in gastric cancer. Tumour Biol. 2010;31:149–55.

    Article  CAS  PubMed  Google Scholar 

  11. Zhao C, Bu X, Zhang N, Wang W. Downregulation of SFRP5 expression and its inverse correlation with those of MMP-7 and MT1-MMP in gastric cancer. BMC Cancer. 2009;9:224.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Di Leva G, Croce CM. MiRNA profiling of cancer. Curr Opin Genet Dev. 2013;23:3–11.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pereira DM, Rodrigues PM, Borralho PM, Rodrigues CM. Delivering the promise of miRNA cancer therapeutics. Drug Discov Today. 2013;18:282–9.

    Article  CAS  PubMed  Google Scholar 

  14. Peng Y, Guo JJ, Liu YM, Wu XL. MicroRNA-34a inhibits the growth, invasion and metastasis of gastric cancer by targeting PDGFR and met expression. Biosci Rep. 2014.

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Cao W, Fan R, Wang L, Cheng S, Li H, Jiang J, et al. Expression and regulatory function of miRNA-34a in targeting survivin in gastric cancer cells. Tumour Biol. 2013;34:963–71.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Wen Wang.

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Gang Liu and Chuanshen Jiang have equal contribution.

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Liu, G., Jiang, C., Li, D. et al. MiRNA-34a inhibits EGFR-signaling-dependent MMP7 activation in gastric cancer. Tumor Biol. 35, 9801–9806 (2014).

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