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

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The Prostate

Original Article

XMRV accelerates cellular proliferation,

transformational activity, and invasiveness

of prostate cancer cells by downregulating

p27Kip1

Jui Pandhare-Dash1,2, Chinmay K. Mantri1,2, Yuanying

Gong2, Zhenbang Chen2, Chandravanu Dash1,2,*

Article first published online: 19 SEP 2011

DOI: 10.1002/pros.21491

Copyright © 2011 Wiley-Liss, Inc.

Keywords: XMRV;p27Kip1;CDK;miR221/222;MMP

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.