TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer types including lung cancer. We have previously shown that TMPRSS4 expression is increased in NSCLC and that its inhibition through shRNA reduces lung metastasis. The goal of the present study was to elucidate molecular mechanisms involved in the protumorigenic role of TMPRSS4 in NSCLC. A knock down strategy and microarray analyses were established to identify genes regulated by TMPRSS4. Among other genes, miR-205 was identified as an overexpressed gene upon TMPRSS4 downregulation. Levels of miR-205 were found to be reduced in NSCLC cells compared to non-malignant cells. miR-205 overexpression promoted the acquisition of an epithelial phenotype with increased E-cadherin and reduced fibronectin expression, probably through the regulation of transcription factors ZEB1 and ZEB2. Furthermore, miR-205 inhibited very significantly (p<0.01) tumor cell migration, invasion and metastasis formation in vivo. A further transcriptional and luciferase assays in miR-205-overexpressing cells identified integrin alpha-5 (a proinvasive protein overexpressed in tumors) as a new miR-205 target in NSCLC. We have therefore demonstrated for the first time a new molecular connection between TMPRSS4 and integrin alpha-5 through miR-205.
Citation Format: Leyre Larzabal, Miriam Redrado, Arrate Lopez de Aberasturi, Paloma Rueda, Maria J. Rodriguez, Lissette Lopez, Luis Montuenga, Alfonso Calvo. TMPRSS4 regulates levels of integrin alpha-5 in NSCLC through miR-205 activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2696. doi:10.1158/1538-7445.AM2013-2696