title: CYP1B1 promotes tumorigenesis via altered expression of CDC20 and DAPK1 genes in renal cell carcinoma.
abstract: BACKGROUND
  Cytochrome P450 1B1 (CYP1B1) has been shown to be up-regulated in many types of cancer including renal cell carcinoma (RCC). Several reports have shown that CYP1B1 can influence the regulation of tumor development; however, its role in RCC has not been well investigated. The aim of the present study was to determine the functional effects of CYP1B1 gene on tumorigenesis in RCC.
  
  
  METHODS
  Expression of CYP1B1 was determined in RCC cell lines, and tissue microarrays of 96 RCC and 25 normal tissues. To determine the biological significance of CYP1B1 in RCC progression, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses.
  
  
  RESULTS
  First, we confirmed that CYP1B1 protein expression was significantly higher in RCC cell lines compared to normal kidney tissue. This trend was also observed in RCC samples (p < 0.01). Interestingly, CYP1B1 expression was associated with tumor grade and stage. Next, we silenced the gene in Caki-1 and 769-P cells by RNA interference and performed various functional analyses to determine the biological significance of CYP1B1 in RCC progression. Inhibition of CYP1B1 expression resulted in decreased cell proliferation, migration and invasion of RCC cells. In addition, reduction of CYP1B1 induced cellular apoptosis in Caki-1. We also found that these anti-tumor effects on RCC cells caused by CYP1B1 depletion may be due to alteration of CDC20 and DAPK1 expression based on gene microarray and confirmed by real-time PCR. Interestingly, CYP1B1 expression was associated with CDC20 and DAPK1 expression in clinical samples.
  
  
  CONCLUSIONS
  CYP1B1 may promote RCC development by inducing CDC20 expression and inhibiting apoptosis through the down-regulation of DAPK1. Our results demonstrate that CYP1B1 can be a potential tumor biomarker and a target for anticancer therapy in RCC.
authors.affiliation: Department of Urology Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501, Izumo, Japan. mitsui@med.shimane-u.ac.jp.|Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. mitsui@med.shimane-u.ac.jp.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Mitsui
authors.affiliation: Department of Oral Biology, Yonsei University College of Density, Seoul, South Korea. ichang@yuhs.ac.|Department of Urology, Osaka University Graduate School of Medicine, 565-0871, Suita, Japan. ichang@yuhs.ac.
authors.forename: Inik
authors.initials: I
authors.lastname: Chang
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, 565-0871, Suita, Japan. fukuharajua@gmail.com.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Urology Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501, Izumo, Japan. mhiraki@med.shimane-u.ac.jp.
authors.forename: Miho
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Department of Urology Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501, Izumo, Japan. naoko-a@med.shimane-u.ac.jp.
authors.forename: Naoko
authors.initials: N
authors.lastname: Arichi
authors.affiliation: Department of Urology Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501, Izumo, Japan. hiyasumo@med.shimane-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yasumoto
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. hiroucsf@gmail.com.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. socihiro.yamamura@va.gov.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. varahram.shahryari@ncire.org.
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. guoren.deng@ucsf.edu.
authors.forename: Guoren
authors.initials: G
authors.lastname: Deng
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. darrynwong@ucla.edu.
authors.forename: Darryn K
authors.initials: DK
authors.lastname: Wong
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. shankhan999@yahoo.com.
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
authors.affiliation: Department of Urology Shimane University Faculty of Medicine, 89-1 Enya-cho, 693-8501, Izumo, Japan. hshiina@med.shimane-u.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. rdahiya@gmail.com.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.affiliation: Department of Urology, San Francisco Veterans Affairs Medical Center and University of California San Francisco, Bldg 42 Rm 109, San Francisco, CA, 94121, USA. Yuichiro.tanaka@ucsf.edu.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064199:Cdc20 Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics* / Q000378:metabolism; D064550:Death-Associated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D015854:Up-Regulation
chemical_list: D064199:Cdc20 Proteins; C577488:CDC20 protein, human; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases