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: C Oneyama, E Morii, D Okuzaki, Y Takahashi, J Ikeda, N Wakabayashi, H Akamatsu, M Tsujimoto, T Nishida, K Aozasa, M Okada
• Journal: Oncogene (Oncogene) Vol. 31 Issue 13 Pg. 1623-35 (Mar 29 2012) ISSN: 1476-5594 [Electronic] England
• PMID: 21860426 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MIRN542 microRNA, mouse
• MicroRNAs
• integrin-linked kinase
• Protein-Tyrosine Kinases
• CSK Tyrosine-Protein Kinase
• Focal Adhesion Kinase 1
• src-Family Kinases
• CSK protein, human
• Protein Serine-Threonine Kinases

Topics

• Animals
• CSK Tyrosine-Protein Kinase
• Cell Adhesion (drug effects)
• Cell Line
• Colonic Neoplasms (genetics)
• Disease Progression
• Focal Adhesion Kinase 1 (metabolism)
• Humans
• Mice
• MicroRNAs (metabolism)
• Neoplasm Invasiveness (genetics)
• Neoplasms (genetics, metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Up-Regulation
• src-Family Kinases