title: MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression.
abstract: The tyrosine kinase c-Src is upregulated in various human cancers; however, the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. Here we show that downregulation of microRNA (miR)-542-3p is tightly associated with tumor progression via c-Src-related oncogenic pathways. In c-Src-transformed fibroblasts and human cancer cells that overexpress c-Src, miR-542-3p is substantially downregulated, and the ectopic expression of miR-542-3p suppresses tumor growth. We identified the integrin-linked kinase (ILK) as a conserved target of miR-542-3p. ILK upregulation promotes cell adhesion and invasion by activating the integrin-focal adhesion kinase (FAK)/c-Src pathway, and can also contribute to tumor growth via the AKT and glycogen synthase kinase 3β pathways. MiR-542-3p expression is downregulated by the activation of c-Src-related signaling molecules, including epidermal growth factor receptor, K-Ras and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase. In human colon cancer tissues, downregulation of miR-542-3p is significantly correlated with the upregulation of c-Src and ILK. Our results suggest that the novel c-Src-miR-542-3p-ILK-FAK circuit plays a crucial role in controlling tumor progression.
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. coneyama@biken.osaka-u.ac.jp
authors.forename: C
authors.initials: C
authors.lastname: Oneyama
authors.forename: E
authors.initials: E
authors.lastname: Morii
authors.forename: D
authors.initials: D
authors.lastname: Okuzaki
authors.forename: Y
authors.initials: Y
authors.lastname: Takahashi
authors.forename: J
authors.initials: J
authors.lastname: Ikeda
authors.forename: N
authors.initials: N
authors.lastname: Wakabayashi
authors.forename: H
authors.initials: H
authors.lastname: Akamatsu
authors.forename: M
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: T
authors.initials: T
authors.lastname: Nishida
authors.forename: K
authors.initials: K
authors.lastname: Aozasa
authors.forename: M
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000235:genetics; D018450:Disease Progression; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015854:Up-Regulation; D019061:src-Family Kinases; D000099200:Scaffold Protein ILK
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000099200:Scaffold Protein ILK; C572448:MIRN542 microRNA, mouse; C000631346:CSK protein, human