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

• Published in: Molecular cancer research 2014-12, Vol.12 (12), p.1807-1817
• Main Authors: Hase, Hiroaki, Jingushi, Kentaro, Ueda, Yuko, Kitae, Kaori, Egawa, Hiroshi, Ohshio, Ikumi, Kawakami, Ryoji, Kashiwagi, Yuri, Tsukada, Yohei, Kobayashi, Takumi, Nakata, Wataru, Fujita, Kazutoshi, Uemura, Motohide, Nonomura, Norio, Tsujikawa, Kazutake
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Amino Acid Oxidoreductases - genetics; Amino Acid Oxidoreductases - metabolism; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Integrin alpha5 - metabolism; Integrin beta1 - metabolism; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Male; Middle Aged
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-14-0233

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 α5 (ITGAV5) and β1 (ITGB1) via protease- and proteasome-dependent systems. In clinical ccRCC specimens, the expression levels of LOXL2 and integrin α5 correlated with the pathologic tumor grades. In conclusion, LOXL2 is a potent regulator of integrin α5 and integrin β1 protein levels and functions in a tumor-promoting capacity in ccRCC. This is the first report demonstrating that LOXL2 is highly expressed and involved in ccRCC progression by regulating the levels of integrins α5 and β1.