title: LOXL2 status correlates with tumor stage and regulates integrin levels to promote tumor progression in ccRCC.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hase
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan. jingushi-kk@phs.osaka-u.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jingushi
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kitae
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Egawa
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Ohshio
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kawakami
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kashiwagi
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Tsukada
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, Yamadaoka, Osaka, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakata
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, Yamadaoka, Osaka, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, Yamadaoka, Osaka, Japan.
authors.forename: Motohide
authors.initials: M
authors.lastname: Uemura
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, Yamadaoka, Osaka, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.affiliation: Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Kazutake
authors.initials: K
authors.lastname: Tsujikawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000594:Amino Acid Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged
chemical_list: D039482:Integrin alpha5; D019012:Integrin beta1; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human