HER2-mediated upregulation of MMP-1 is involved in gastric cancer cell invasion.
HER2 overexpression is associated with metastasis-the main cause of death in individuals with gastric cancer. In this study, 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-1, while HER2 overexpression improved the transcription of MMP-1 through the activation of an MMP-1 promoter. The promoter region of MMP-1 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-1 was knocked down. Conversely, the overexpression of MMP-1 partly rescued the invasion ability of cell strains with knocked-down HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-1 may be required to effectively block HER2 signaling in gastric cancer therapy.
Bao
Wei
W
State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an 710032, China.
Fu
Hai-Jing
HJ
Jia
Lin-Tao
LT
Zhang
Yong
Y
Li
Wei
W
Jin
Bo-Quan
BQ
Yao
Li-Bo
LB
Chen
Si-Yi
SY
Yang
An-Gang
AG
D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D055785:Gene Knockdown Techniques; D018734:Genes, erbB-2; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D017931:DNA Primers; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C522361:MMP2 protein, human; C522360:MMP1 protein, human