title: Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial-mesenchymal transition.
abstract: One of the most fundamental biological processes in tumor metastasis is the process of epithelial-mesenchymal transition (EMT). During EMT, zinc-finger-family of transcription factors such as Snail, Slug and Twist, and matrix metalloproteinases (MMPs) are upregulated, and this correlates with increased tumor cell invasion and motility. We previously obtained a highly invasive A431-III tumor subline, which is a rich source of MMP-9 and observed a plausible link between MMP levels and the promotion of EMT. To gain further understanding of EMT, we investigated the contribution of distinct MMPs to the induction of EMT. Exposing A431, cervical carcinoma parental cells, to MMP-9 stimulated a phenotypic alteration and cells became spindle-like as shown for A431-III cells. In the present communication, we document changes in gene expression profiles of A431-P and A431-III cells, including those of genes involved in cell adhesion, cytoskeleton reorganization, polarity, migration and transcription. Treatment of both A431-P and A431-III cells with GM6001, a broad spectrum MMP inhibitor, resulted in the diminution of vimentin and fibronectin, indicating a role for MMP-9 in the induction of EMT. Abrogation of MMP-9-mediated cell-cell contact in both A431-P and A431-III cells using MMP-9 siRNA resulted in decreased cell invasion, motility and altered cytoskeleton arrangement together with a reduction in Snail expression. Knockdown of Snail resulted in similar changes along with diminished MMP-9 expression. These data suggest a higher capacity of MMP-9 than that of Snail in eliciting the development of EMT in A431 cells. Based on these findings, we speculate that the overexpression of MMP-9 in A431-III cells might directly induce (or stimulate) EMT and that the transcriptional factor, Snail, could cooperatively engage in this phenomenon.
authors.affiliation: Institute of Biochemical Sciences, School of Life Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Tsai
authors.forename: Chithan C
authors.initials: CC
authors.lastname: Kandaswami
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Lee
authors.forename: Chang-Jen
authors.initials: CJ
authors.lastname: Huang
authors.forename: Jiuan-Jiuan
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Ming-Ting
authors.initials: MT
authors.lastname: Lee
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D020780:Matrix Metalloproteinase 9