title: Inhibition of epidermal growth factor receptor signaling prohibits metastasis of gastric cancer via downregulation of MMP7 and MMP13.
abstract: The molecular pathway regulating gastric carcinoma (GC) invasiveness and metastasis remains elusive. Here, we detected significant increase in the phosphorylated epidermal growth factor receptor (pEGFR), MMP7, and MMP13 in the resected GC, compared with the adjacent normal tissue, in patients. Moreover, strong positive correlation was detected between pEGFR and MMP7, and between pEGFR and MMP13 in GC. To examine whether a causal link exists, we used two human GC lines, SNU-5 and AGS, to study the cross talk between EGFR signaling activation, and expression of MMP7 and MMP13. We found that EGF-induced EGFR phosphorylation activated both MMP7 and MMP13, and consequently cancer invasiveness. EGF-induced activation of MMP7 and MMP13 can be both inhibited by use of an inhibitor for EGFR. EGF-induced activation of MMP7 can be also significantly inhibited by use of an inhibitor for Akt, but not an inhibitor for ERK1/2, while EGF-induced activation of MMP13 can be significantly inhibited by use of an inhibitor for ERK1/2, but not by an inhibitor for Akt. These data suggest that EGF-induced activation of MMP7 and MMP13 in GC is through phosphatidylinositol 3-kinase (PI3K) and extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway, respectively. Our study thus highlights EGFR signaling regulated MMP7 and MMP13 activation as molecular basis for metastasis of GC, and further demonstrate that different signaling pathway cascades are involved in the downstream signaling transduction.
authors.affiliation: Department of Surgery, Wenzhou Central Hospital, Wenzhou, China.
authors.forename: Yinghai
authors.initials: Y
authors.lastname: Ye
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Zhou
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Li
authors.forename: Yinhe
authors.initials: Y
authors.lastname: Tang
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Sun
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7
references.citation: Cell Signal. 2009 Jun;21(6):892-8
references.pmid: 19385051
references.citation: Am J Pathol. 2004 Jul;165(1):35-52
references.pmid: 15215160
references.citation: Nat Med. 2003 Jun;9(6):677-84
references.pmid: 12778166
references.citation: APMIS. 1999 Jan;107(1):45-53
references.pmid: 10190279
references.citation: Oncogene. 2007 May 14;26(22):3113-21
references.pmid: 17496910
references.citation: Mol Cancer. 2010 Oct 12;9:269
references.pmid: 20939893
references.citation: J Cell Physiol. 2009 Mar;218(3):460-6
references.pmid: 19006176
references.citation: J Biol Chem. 2013 Mar 22;288(12):8636-8646
references.pmid: 23378532
references.citation: Gastroenterol Hepatol. 2003 Jan;26(1):1-7
references.pmid: 12525320
references.citation: Nature. 2011 May 19;473(7347):298-307
references.pmid: 21593862
references.citation: J Cell Physiol. 2012 Mar;227(3):1235-41
references.pmid: 21688267
references.citation: Front Biosci (Landmark Ed). 2013 Jun 01;18:803-10
references.pmid: 23747848
references.citation: Gastric Cancer. 2000 Sep 29;3(2):63-70
references.pmid: 11984713
references.citation: Tumour Biol. 2014 Apr;35(4):3463-70
references.pmid: 24282089
references.citation: Tumour Biol. 2010 Jun;31(3):149-55
references.pmid: 20300917
references.citation: BMC Cancer. 2009 Jul 09;9:224
references.pmid: 19586554
references.citation: PLoS One. 2012;7(9):e44618
references.pmid: 22957090
references.citation: Tumour Biol. 2014 Feb;35(2):1287-95
references.pmid: 24068565
references.citation: Cancer Lett. 2008 Dec 18;272(2):296-306
references.pmid: 18774637
references.citation: Oncogene. 2014 Apr 17;33(16):2123-33
references.pmid: 23644655
references.citation: Gastric Cancer. 2012 Jul;15(3):252-64
references.pmid: 22011788