LOXL2 status correlates with tumor stage and regulates integrin levels to promote tumor progression in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the most common histologically defined subtype of renal cell carcinoma (RCC). To define the molecular mechanism in the progression of ccRCC, we focused on LOX-like protein 2 (LOXL2), which is critical for the first step in collagen and elastin cross-linking. Using exon array analysis and quantitative validation, LOXL2 was shown to be significantly upregulated in clinical specimens of human ccRCC tumor tissues, compared with adjacent noncancerous renal tissues, and this elevated expression correlated with the pathologic stages of ccRCC. RNAi-mediated knockdown of LOXL2 resulted in marked suppression of stress-fiber and focal adhesion formation in ccRCC cells. Moreover, LOXL2 siRNA knockdown significantly inhibited cell growth, migration, and invasion. Mechanistically, LOXL2 regulated the degradation of both integrins alpha 5 (ITGAV5) and beta 1 (ITGB1) via protease-and proteasome-dependent systems. In clinical ccRCC specimens, the expression levels of LOXL2 and integrin alpha 5 correlated with the pathologic tumor grades. In conclusion, LOXL2 is a potent regulator of integrin alpha 5 and integrin beta 1 protein levels and functions in a tumor-promoting capacity in ccRCC. (C)2014 AACR.