title: MMP-9 is increased in the pathogenesis of gastric cancer by the mediation of HER2.
abstract: Human epidermal growth factor receptor 2 (HER2) overexpression is not only closely associated with the tumor growth, but is also related to tumor invasion. We here aimed to investigate the mechanism of HER2 mediation in the pathogenesis of gastric cancer. The human gastric cancer cell lines SGC-7901, MKN-45, AGS, the immortalized cell line GES-1 derived from normal gastric mucosa. Cell transfection and selection of stable cell lines and the gene and protein levels of HER2 and Matrix metalloproteinase-9 (MMP-9) were examined to determine the molecular relationship between them in the pathogenesis of gastric cancer. The human gastric cancer cell lines SGC-7901, MKN-45, AGS, the immortalized cell line GES-1 derived from normal gastric mucosa. Cell transfection and selection of stable cell lines and the gene and protein levels of HER2 and MMP-9 were examined to determine the molecular relationship between them in the pathogenesis of gastric cancer. We demonstrated that vector-based shRNA significantly knocked down the expression of HER2 and considerably inhibited both the migration and invasion of gastric cancer cells. HER2 knockdown resulted in the downregulation of the expression of MMP-9, whereas HER2 overexpression improved the transcription of MMP-9 through the activation of an MMP-9 promoter. The promoter region of MMP-9 between -2500 and -2000 bp was found to be crucial for the upregulation of HER2-mediated transcription. Furthermore, a truncated promoter (-70 to +63) did not display any transcriptional activity. Cell invasion activity was almost completely inhibited when MMP-9 was knocked down. Conversely, the overexpression of MMP-9 partly rescued the invasion ability of cell strains with knockdown HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-9 may be required to effectively block HER2 signaling in gastric cancer therapy.
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: Y-Q
authors: YQ
authors: Shan
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: R-C
authors: RC
authors: Ying
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: C-H
authors: CH
authors: Zhou
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: A-K
authors: AK
authors: Zhu
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: J
authors: J
authors: Ye
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: W
authors: W
authors: Zhu
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: T-F
authors: TF
authors: Ju
authors: 1] Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, China [2] Affiliated Hangzhou Hospital, Nanjing Medical University, Hangzhou, China.
authors: H-C
authors: HC
authors: Jin
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D004790:Enzyme Induction; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D015533:Transcriptional Activation
chemical_list: D020780:Matrix Metalloproteinase 9; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C579270:MMP9 protein, human
references: Mol Biol Rep. 2010 Jan;37(1):197-205
references: 19562509
references: Cancer Biol Ther. 2009 Jun;8(11):1002-9
references: 19305146
references: Tumori. 2013 Mar-Apr;99(2):249-56
references: 23748822
references: Ann Clin Lab Sci. 2014 Spring;44(2):158-66
references: 24795054
references: Zhonghua Nei Ke Za Zhi. 2009 Feb;48(2):114-7
references: 19549464
references: Postepy Hig Med Dosw (Online). 2009 Jun 05;63:258-65
references: 19502687
references: Carcinogenesis. 2009 Aug;30(8):1305-13
references: 19493905
references: Neoplasma. 2014;61(3):291-8
references: 24824930
references: J Transl Med. 2013 Jun 20;11:153
references: 23787075
references: Neoplasma. 2014;61(3):257-64
references: 24824926
references: Int J Oncol. 2014 Jul;45(1):282-90
references: 24756245
references: J Cell Mol Med. 2010 Mar;14(3):621-35
references: 19413886
references: World J Surg. 2014 Aug;38(8):2058-64
references: 24696059
references: BMC Cell Biol. 2009 Apr 16;10 :27
references: 19371443
references: Cancer. 2009 Oct 15;115(20):4667-78
references: 19569245
references: Clin Chem Lab Med. 2009;47(8):993-1000
references: 19569980
references: J Gastroenterol Hepatol. 2009 Sep;24(9):1527-33
references: 19383080
references: Oncol Rep. 2010 Jul;24(1):89-95
references: 20514448
references: Mol Med Rep. 2013 Jul;8(1):11-6
references: 23715597
references: World J Gastroenterol. 2014 Apr 28;20(16):4586-96
references: 24782611
references: Asian Pac J Cancer Prev. 2013;14(4):2269-72
references: 23725125
references: Hepatogastroenterology. 2014 Mar-Apr;61(130):518-24
references: 24901174
references: J Hepatobiliary Pancreat Surg. 2009;16(4):493-501
references: 19360371
references: J Physiol Pharmacol. 2013 Apr;64(2):157-65
references: 23756390
references: Cancer Biomark. 2013;13(1):21-8
references: 23736018
references: Oncol Rep. 2014 May;31(5):2312-20
references: 24676680
references: Expert Opin Investig Drugs. 2009 Jul;18(7):945-55
references: 19466878
references: DNA Cell Biol. 2009 Jun;28(6):295-301
references: 19317620
references: J Oncol. 2014;2014:582140
references: 24669218
references: Int J Oncol. 2013 Aug;43(2):629-37
references: 23754208
references: Oncol Rep. 2014 Jul;32(1):403-10
references: 24807047
references: Oncol Rep. 2014 Jul;32(1):45-9
references: 24841138
references: Helicobacter. 2013 Oct;18(5):347-55
references: 23714108
references: J Gastroenterol. 2014 Jun;49(6):1011-25
references: 23800944
references: Cancer Sci. 2010 Aug;101(8):1807-12
references: 20500517
references: J Cancer Res Clin Oncol. 2014 Aug;140(8):1305-13
references: 24804817
references: Int J Mol Sci. 2013 Jun 24;14(7):13005-21
references: 23797661