title: Inhibition of fibroblast growth factor receptor signaling impairs metastasis of hepatocellular carcinoma.
abstract: The molecular mechanism underlying metastasis of hepatocellular carcinoma (HCC) remains elusive. Here, we showed that matrix metalloproteinase (MMP) 7 and MMP26 levels are significantly higher in the resected HCC than in the adjacent healthy hepatic cells from the patients. Moreover, a strong correlation of the levels of MMP7 or MMP26 with the phosphorylated fibroblast growth factor receptor 2 (FGFR2) was detected. To prove a causal link between the activation of FGFR signaling pathway and expression of MMP7 and MMP26, we used two human HCC lines, HepG2 and HuH-7, to study the underlying molecular basis. We found that FGF1-induced FGFR2 phosphorylation in either line resulted in significant activation of MMP7 and MMP26 and consequently an increase in cancer invasiveness. Inhibition of FGFR2 phosphorylation in HCC abolished FGF1-stimulated MMP7 and MMP26 expression, suggesting that activation of the FGFR signaling pathway in HCC may promote cancer metastasis by inducing MMP7 and MMP26 expression. To define the signal transduction cascades downstream of FGFR2 activation for MMP7 and MMP26 activation, we applied specific inhibitors for phosphatidylinositol-3 kinase (PI3K), extracellular signal-related kinase/mitogen-activated protein kinase (ERK/MAPK), and Jun N-terminal kinase (JNK), respectively, to the FGF1-stimulated HCC cells. We found that only inhibition of JNK significantly decreased the activation of MMP26 in response to FGF1 stimulation, and only inhibition of PI3K significantly decreased the activation of MMP7 in response to FGF1 stimulation, suggesting that the activation of the FGFR2 signaling may activate PI3K to activate MMP7 and activate JNK to activate MMP26, in HCC. Our study thus highlights the FGFR2 signaling pathway and MMP7 and MMP26 as novel therapeutic targets for HCC.
authors.affiliation: Department of Radiology, the First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Wang
authors.forename: Hongying
authors.initials: H
authors.lastname: Su
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Han
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020783:Matrix Metalloproteinase 7 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C507119:MMP27 protein, human; D053505:Matrix Metalloproteinases, Secreted; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7
references.citation: Cell Res. 2006 Sep;16(9):741
references.pmid: 16971961
references.citation: J Biol Chem. 2011 May 6;286(18):15980-8
references.pmid: 21454675
references.citation: J Biol Chem. 2004 Nov 12;279(46):47912-28
references.pmid: 15310753
references.citation: Differentiation. 2007 Sep;75(7):638-51
references.pmid: 17309601
references.citation: Tumour Biol. 1996;17(4):226-33
references.pmid: 8685603
references.citation: J Gastroenterol Hepatol. 2013 Aug;28 Suppl 1:43-8
references.pmid: 23855295
references.citation: Exp Biol Med (Maywood). 2006 Jan;231(1):20-7
references.pmid: 16380641
references.citation: Curr Pharm Biotechnol. 2008 Feb;9(1):47-54
references.pmid: 18289056
references.citation: Mol Med Rep. 2011 Nov-Dec;4(6):1201-9
references.pmid: 21805034
references.citation: APMIS. 1999 Jan;107(1):45-53
references.pmid: 10190279
references.citation: Tumour Biol. 2014 Jan;35(1):9-20
references.pmid: 24006223
references.citation: Tumour Biol. 2014 Oct;35(10):9801-6
references.pmid: 24981249
references.citation: BMC Cancer. 2013 Dec 01;13:567
references.pmid: 24289477
references.citation: J Neurosci. 2010 May 12;30(19):6595-606
references.pmid: 20463222
references.citation: Biochim Biophys Acta. 1992 Jun 10;1135(2):185-99
references.pmid: 1319744
references.citation: Nat Commun. 2013;4:2464
references.pmid: 24043118
references.citation: Tumour Biol. 1999 Mar-Apr;20(2):88-98
references.pmid: 10050107
references.citation: Biochem J. 2012 May 1;443(3):691-700
references.pmid: 22292774
references.citation: Tumour Biol. 2010 Jun;31(3):149-55
references.pmid: 20300917
references.citation: Carcinogenesis. 2004 Dec;25(12):2353-60
references.pmid: 15333466
references.citation: Thromb Haemost. 1999 Aug;82(2):748-54
references.pmid: 10605778
references.citation: J Biol Chem. 1999 May 28;274(22):15947-52
references.pmid: 10336501
references.citation: Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):E1211-20
references.pmid: 24639504
references.citation: Tumour Biol. 2014 Sep;35(9):8715-20
references.pmid: 24870599
references.citation: Arthritis Res. 2002;4(3):157-64
references.pmid: 12010565
references.citation: Cancer Res. 2013 Aug 15;73(16):5195-205
references.pmid: 23786770
references.citation: Tumour Biol. 2011 Apr;32(2):259-64
references.pmid: 21207220