title: XMRV accelerates cellular proliferation, transformational activity, and invasiveness of prostate cancer cells by downregulating p27(Kip1).
abstract: BACKGROUND
  Xenotropic murine leukemia virus-related retrovirus (XMRV) is a recently discovered gammaretrovirus that was originally detected in prostate tumors. However, a causal relationship between XMRV and prostate cancer remains controversial due to conflicting reports on its etiologic occurrence. Even though gammaretroviruses are known to induce cancer in animals, a mechanism for XMRV-induced carcinogenesis remains unknown. Several mechanisms including insertional mutagenesis, proinflammatory effects, oncogenic viral proteins, immune suppression, and altered epithelial/stromal interactions have been proposed for a role of XMRV in prostate cancer. However, biochemical data supporting any of these mechanisms are lacking. Therefore, our aim was to evaluate a potential role of XMRV in prostate carcinogenesis.
  
  
  METHODS
  Growth kinetics of prostate cancer cells are conducted by MTT assay. In vitro transformation and invasion was carried out by soft agar colony formation, and Matrigel cell invasion assay, respectively. p27(Kip1) expression was determined by Western blot and MMP activation was evaluated by gelatin-zymography. Up-regulation of miR221 and miR222 expression was examined by real-time PCR.
  
  
  RESULTS
  We demonstrate that XMRV infection can accelerate cellular proliferation, enhance transformation, and increase invasiveness of slow growing prostate cancer cells. The molecular basis of these viral induced activities is mediated by the downregulation of cyclin/cyclin dependent kinase inhibitor p27(Kip1) . Downstream analyses illustrated that XMRV infection upregulates miR221 and miR222 expression that target p27(Kip1) mRNA.
  
  
  CONCLUSIONS
  We propose that downregulation of p27(Kip1) by XMRV infection facilitates transition of G1 to S, thereby accelerates growth of prostate cancer cells. Our findings implicate that if XMRV is present in humans, then under appropriate cellular microenvironment it may serve as a cofactor to promote cancer progression in the prostate.
authors.affiliation: Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center For AIDS Research (CFAR), Meharry Medical College School of Medicine, 1005 Dr. DB Todd Jr Blvd., Nashville, TN 37208, USA.
authors.forename: Jui
authors.initials: J
authors.lastname: Pandhare-Dash
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mantri
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Gong
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
authors.forename: Chandravanu
authors.initials: C
authors.lastname: Dash
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D058008:Xenotropic murine leukemia virus-related virus / Q000502:physiology*
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D045726:Metalloproteases; D035683:MicroRNAs; D012333:RNA, Messenger; C525709:MIR221, human; C525710:MIR222, human