Transforming growth factor‐β induces CD44 cleavage that promotes migration of MDA‐MB‐435s cells through the up‐regulation of membrane type 1‐matrix metalloproteinase

Abstract

CD44, a transmembrane receptor for hyaluronic acid, is implicated in various adhesion-dependent cellular processes, including cell migration, tumor cell metastasis and invasion. Recent studies demonstrated that CD44 expressed in cancer cells can be proteolytically cleaved at the ectodomain by membrane type 1-matrix metalloproteinase (MT1-MMP) to form soluble CD44 and that CD44 cleavage plays a critical role in cancer cell migration. Here, we show that transforming growth factor-beta (TGF-beta), a multifunctional cytokine involved in cell proliferation, differentiation, migration and pathological processes, induces MT1-MMP expression in MDA-MB-435s cells. TGF-beta-induced MT1-MMP expression was blocked by the specific extracellular regulated kinase-1/2 (ERK1/2) inhibitor PD98059 and the specific phosphoinositide 3-OH kinase (PI3K) inhibitor LY294002. In addition, treatment with SP600125, an inhibitor for c-Jun NH(2)-terminal kinase (JNK), resulted in a significant inhibition of MT1-MMP production. These data suggest that ERK1/2, PI3K, and JNK likely play a role in TGF-beta-induced MT1-MMP expression. Interestingly, treatment of MDA-MB-435s cells with TGF-beta resulted in a colocalization of MT1-MMP and CD44 in the cell membrane and in an increased level of soluble CD44. Using an electric cell-substrate impedance sensing cell-electrode system, we demonstrated that TGF-beta treatment promotes MDA-MB-435s cell migration, involving MT1-MMP-mediated CD44 cleavage. MT1-MMP siRNA transfection-inhibited TGF-beta-induced cancer cell transendothelial migration. Thus, this study contributes to our understanding of molecular mechanisms that play a critical role in tumor cell invasion and metastasis.