title: Transforming growth factor-beta 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.
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, Yang Ming University, Taipei, Taiwan.
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Kuo
authors.forename: Cheng-Hsi
authors.initials: CH
authors.lastname: Su
authors.forename: Chin-Yi
authors.initials: CY
authors.lastname: Liu
authors.forename: Tien-Hua
authors.initials: TH
authors.lastname: Chen
authors.forename: Chie-Pein
authors.initials: CP
authors.lastname: Chen
authors.forename: Hwai-Shi
authors.initials: HS
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000032:analysis / Q000502:physiology*; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14