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Originally published online as doi:10.2353/ajpath.2007.061138 on June 28, 2007

Published online before print June 28, 2007
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(American Journal of Pathology. 2007;171:667-681.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061138

Hypoxia-Inducible Factor-1 Facilitates Cervical Cancer Progression in Human Papillomavirus Type 16 Transgenic Mice

Zhi Hong Lu*, Jason D. Wright{dagger}, Brian Belt{dagger}, Robert D. Cardiff{ddagger} and Jeffrey M. Arbeit*{dagger}§¶||

From the Division of Urologic Surgery,* the Department of Obstetrics and Gynecology,{dagger} Division of Gynecologic Oncology, the Department of Surgery,§ the Siteman Cancer Center, and the Program in Cell Biology,|| Washington University School of Medicine, St. Louis, Missouri; and the Center for Comparative Medicine,{ddagger} University of California, Davis, California

Advanced cervical cancer remains a vexing clinical challenge despite screening programs. Many of these cancers are hypoxic, and expression of the {alpha} subunit of the major regulator of the hypoxic cellular response, the transcription factor hypoxia-inducible factor-1 (HIF-1), is correlated with poor prognosis. Here, we tested a functional role for HIF-1{alpha} in pathogenesis of cervical cancer in estrogen-treated transgenic mice. Double-transgenic (DTG) mice developed locally invasive cervical cancers 70 times larger than K14-HPV16 mice. In vivo bromodeoxyuridine incorporation was elevated in DTG cancers without a significant increase in apoptosis. HIF-1{alpha} gain of function did not up-regulate canonical HIF-1 targets in premalignant DTG cervices, in contrast to elevation of these targets in K14-HIF-1{alpha} transgenic cervices. The DTG transcriptional signature included up-regulation of mRNAs encoding cytokines and chemokines, immune signaling molecules, extracellular proteases, and cell motility factors, as well as reduced expression of cell adhesion and epithelial differentiation genes. Importantly, a set of gene markers derived from the DTG transcriptome predicted cervical cancer progression in patients. This study suggests a novel paradigm for HIF-1 function evident in multistage carcinogenesis as opposed to established malignancies, including interaction with viral oncogenes to induce multiple genomic networks in premalignancy that fosters the development of advanced cervical cancer.






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Copyright © 2007 by the American Society for Investigative Pathology.