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Journal of Virology, September 2008, p. 8820-8827, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.02363-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins{triangledown}

Satoshi Yoshida, Naoko Kajitani, Ayano Satsuka, Hiroyasu Nakamura, and Hiroyuki Sakai*

Laboratory of Gene Analysis, Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

Received 1 November 2007/ Accepted 19 June 2008

Infection by human papillomavirus (HPV) is a major risk factor for human cervical carcinoma. However, the HPV infection alone is not sufficient for cancer formation. Cervical carcinogenesis is considered a multistep process accompanied by genetic alterations of the cell. Ras is activated in approximately 20% of human cancers, and it is related to the metastatic conversion of tumor cells. We investigated how Ras activation was involved in the malignant conversion of HPV-infected lesions. The active form of H-ras was introduced into human primary keratinocytes expressing the HPV type 18 (HPV18) oncoproteins E6 and/or E7. We analyzed the keratinocytes’ growth potentials and found that the activation of the Ras pathway induced senescence-like growth arrest. Senescence could be eliminated by high-risk E7 expression, suggesting that the pRb pathway was important for Ras-induced senescence. Then we analyzed the effect of Ras activation on epidermis development by using an organotypic "raft" culture and found that the E7 and H-ras coexpressions conferred invasive potential on the epidermis. This invasiveness resulted from the upregulation of MT1-MMP and MMP9 by H-ras and E7, respectively, in which the activation of the MEK/extracellular signal-regulated kinase pathway was involved. These results indicated that the activation of Ras or the related signal pathways promoted the malignant conversion of HPV-infected cells.

* Corresponding author. Mailing address: Laboratory of Gene Analysis, Department of Viral Oncology, Institute for Virus Research, Kyoto University, 53 Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3996. Fax: 81-75-751-4010. E-mail: hsakai{at}virus.kyoto-u.ac.jp

{triangledown} Published ahead of print on 25 June 2008.

Journal of Virology, September 2008, p. 8820-8827, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.02363-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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