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Increased production and secretion of HGF α‐chain and an antagonistic HGF fragment in a human breast cancer progression model
Author(s) -
Wright Theodore G.,
Singh Vinay K.,
Li John J.,
Foley Jonathan H.,
Miller Fred,
Jia Zongchao,
Elliott Bruce E.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24364
Subject(s) - hepatocyte growth factor , cancer research , autocrine signalling , tyrosine phosphorylation , c met , tumor progression , cell culture , biology , receptor tyrosine kinase , carcinogenesis , cancer , secretion , medicine , endocrinology , receptor , signal transduction , microbiology and biotechnology , genetics
Invasive human breast carcinomas frequently coexpress increased hepatocyte growth factor (HGF) and its receptor Met, suggesting that establishment of an autocrine HGF loop is important in malignant disease. This study examines the expression patterns of HGF and Met activation during tumorigenesis and metastasis using a MCF10A‐based model of Ha‐Ras ‐induced human breast cancer progression. Deregulation of cadherin‐based cell‐cell adhesions, decreased expression of cytokeratins 8/18 and increased activity of matrix metalloproteinases such as MMP‐2 occurs in premalignant and malignant (metastatic) cell lines compared to the parental nonmalignant cell line. Compared to the benign parent cell line, premalignant and malignant cell lines exhibit increased secretion of full length HGF α‐chain and elevated Met tyrosine phosphorylation in complete medium. Interestingly, the premalignant and malignant cells also secrete a ∼55 kDa HGF fragment. Epitope mapping of the ∼55 kDa HGF fragment supports the presence of the N‐terminal domain of the HGF α‐chain with a truncation in the C‐terminal domain. The ∼55 kDa HGF fragment shows mobility in SDS‐PAGE faster than HGF α‐chain, but slightly slower than NK4, a previously established full antagonist of HGF. The separated ∼55 kDa HGF fragment binds to animmobilized Met‐IgG fusion protein, and inhibits both HGF/Met‐IgG binding and HGF‐induced Met‐tyrosine phosphorylation. These results are the first demonstration of an antagonistic ∼55 kDa HGF fragment secreted during breast carcinoma progression, which may have a negative regulatory effect on HGF signaling in premalignant breast epithelial cells. © 2009 UICC