XMRV accelerates cellular proliferation, transformational activity, and invasiveness of prostate cancer cells by downregulating p27Kip1

Authors

  • Jui Pandhare-Dash,

    1. Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center For AIDS Research (CFAR), Meharry Medical College School of Medicine, Nashville, Tennessee
    2. Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
    Search for more papers by this author
  • Chinmay K. Mantri,

    1. Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center For AIDS Research (CFAR), Meharry Medical College School of Medicine, Nashville, Tennessee
    2. Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
    Search for more papers by this author
  • Yuanying Gong,

    1. Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
    Search for more papers by this author
  • Zhenbang Chen,

    1. Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
    Search for more papers by this author
  • Chandravanu Dash

    Corresponding author
    1. Laboratory of Retrovirology and Epigenetics, Center for AIDS Health Disparities Research, Vanderbilt-Meharry Center For AIDS Research (CFAR), Meharry Medical College School of Medicine, Nashville, Tennessee
    2. Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
    • Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, 1005 Dr. DB Todd Jr Blvd., Nashville, TN 37208.
    Search for more papers by this author

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. p27Kip1 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 p27Kip1. Downstream analyses illustrated that XMRV infection upregulates miR221 and miR222 expression that target p27Kip1 mRNA.

CONCLUSIONS

We propose that downregulation of p27Kip1 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. Prostate 72:886–897, 2012. © 2011 Wiley Periodicals, Inc.

Ancillary