title: Integrin α7 binds tissue inhibitor of metalloproteinase 3 to suppress growth of prostate cancer cells.
abstract: Integrin α7 (ITGA7) is a tumor-suppressor gene that is critical for suppressing the growth of malignant tumors; however, the mechanisms allowing ITGA7 to suppress the growth of cancer cells remain unclear. Herein, we show that ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells. The ITGA7-TIMP3 binding led to a decreased protein level of tumor necrosis factor α, cytoplasmic translocation of NF-κB, and down-regulation of cyclin D1. These changes led to an accumulation of cells in G0/G1 and a dramatic suppression of cell growth. Knocking down TIMP3 or ITGA7/TIMP3 binding interference largely abrogated the signaling changes induced by ITGA7, whereas a mutant ITGA7 lacking TIMP3 binding activity had no tumor-suppressor activity. Interestingly, knocking down ITGA7 ligand laminin β1 enhanced ITGA7-TIMP3 signaling and the downstream tumor-suppressor activity, suggesting the existence of a counterbalancing role between extracellular matrix and integrin signaling. As a result, this report demonstrates a novel and critical signaling mechanism of ITGA7, through the TIMP3/NF-κB/cyclin D1 pathway.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Lang-Zhu
authors.initials: LZ
authors.lastname: Tan
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Joel
authors.initials: J
authors.lastname: Nelson
authors.forename: Yan P
authors.initials: YP
authors.lastname: Yu
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Luo
mesh_terms: D020816:Amino Acid Motifs; D015703:Antigens, CD / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D007797:Laminin; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C085725:integrin alpha7; D019938:Cyclin D1