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Induction of Smad1 by MT1‐MMP contributes to tumor growth
Author(s) -
Freudenberg Jaclyn A.,
Chen WenTien
Publication year - 2007
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.22754
Subject(s) - rna interference , biology , cell culture , matrix metalloproteinase , cell growth , gene silencing , downregulation and upregulation , extracellular matrix , microbiology and biotechnology , cancer research , endogeny , receptor , transfection , rna , gene , biochemistry , genetics
Abstract MT1‐MMP is a key integral membrane protease, which regulates tumor growth by cleaving extracellular matrix components, activating growth factors and receptors, and consequently, triggering downstream signals. To study what genes or pathways are mediated by endogenous MT1‐MMP during tumor growth in vivo , we stably suppressed endogenous MT1‐MMP in human tumor cells using RNA interference (RNAi). Tumor growth was significantly reduced in tumors derived from MT1‐MMP‐suppressed cells relative to control cells; the effect was rescued in cells engineered to re‐express MT1‐MMP expression. Gene expression profiling of cultured and tumor‐derived cells by DNA microarray and real‐time RT‐PCR revealed that Smad1 expression was upregulated in MT1‐MMP‐expressing cells and rapidly growing tumors; this was confirmed in 4 additional tumor cell lines. Furthermore, tumor growth of MT1‐MMP‐expressing cells was reduced when Smad1 was suppressed by RNAi. We also found that the active form, but not the latent form, of TGF‐β was capable in promoting Smad1 expression and 3D cell proliferation in MT1‐MMP‐suppressed cells. In addition, a dominant‐negative form of the TGF‐β Type II receptor reduced Smad1 expression in MT1‐MMP‐expressing cells. Thus, we propose that MT1‐MMP functions, in part, to promote tumor growth by inducing the expression of Smad1 via TGF‐β signaling. © 2007 Wiley‐Liss, Inc.