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Targeting the Human Papillomavirus E6 and E7 Oncogenes by E2 promotes Cellular Motility and Invasion

Morrison, Monique A.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313696290

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Developmental Biology.
Cervical cancer is the second most common cancer in women worldwide with over 500,000 new cases reported annually. Almost all cervical cancers are caused by the mucosatropic high risk human papillomaviruses (HPV). Integration of HPV DNA into the cellular genome is common in such cancers and results in the loss of expression of the viral E2 protein and increased expression of the E6 and E7 oncogenes. E6 and E7 are essential for the initiation and maintenance of cervical cancer. E6 is known to degrade p53, while E7 degrades members of the pRB family. E2 on the other hand is a negative transcriptional regulator of E6 and E7. Together, the oncogenes inhibit cellular senescence and apoptosis, enhance immortalization, and along with other oncogenic events promote transformation. E2 expression in cancer cells results in transcriptional E6/E7 repression, the re-activation of their respective tumor suppressor targets p53 and pRb, and subsequent senescence induction in cervical cancer cells. Consequently, viral oncogene suppression via E2 has been hailed as a promising approach for the treatment of HPV positive tumors. Herein we show that surprisingly, E2 expression in HPV positive cervical cancer cells stimulates cellular motility and invasion. Migration correlated with the dynamic formation of cellular protrusions, and was dependent upon cell-to-cell contact. While E2 expressing migratory cells were senescent, migration was not a general feature of cellular senescence or cell cycle arrest, and was specifically observed in HPV positive cervical cancer cells. Finally, E2 motility required E6/E7 repression, but E6/E7 knockdown alone was not sufficient to cause migration. Interestingly, E2-expressing cells were not only themselves motile, but conferred increased motility to neighboring HeLa cervical cancer cells. These findings may be clinically important as viral E2 expression is already in clinical trials for the treatment of cervical and other HPV associated diseases. Taken together, our data demonstrate that repression of the viral oncogenes by E2 stimulates the motility of E6/E7-targeted cells as well as adjacent non-targeted cancer cells, thus raising the possibility that E2 expression may unfavorably increase the local invasiveness of HPV positive tumors.
Susanne Wells, PhD (Committee Chair)
Susan Waltz, PhD (Committee Member)
Kathryn Wikenheiser-Brokamp, MD,PhD (Committee Member)
Christopher Wylie, PhD (Committee Member)
Yi Zheng, PhD (Committee Member)
99 p.
Molecular Biology
Human Papillomavirus; E6 and E7 oncogenes; Invasion; E2; Migration; Metastasis

Recommended Citations

Citations

  • Morrison, M. A. (2011). Targeting the Human Papillomavirus E6 and E7 Oncogenes by E2 promotes Cellular Motility and Invasion [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313696290

    APA Style (7th edition)

  • Morrison, Monique. Targeting the Human Papillomavirus E6 and E7 Oncogenes by E2 promotes Cellular Motility and Invasion. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313696290.

    MLA Style (8th edition)

  • Morrison, Monique. "Targeting the Human Papillomavirus E6 and E7 Oncogenes by E2 promotes Cellular Motility and Invasion." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1313696290

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.