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(American Journal of Pathology. 2002;161:603-610.)
© 2002 American Society for Investigative Pathology

Regular Articles

Insulin-Like Growth Factor-Binding Protein 3 Expression Increases during Immortalization of Cervical Keratinocytes by Human Papillomavirus Type 16 E6 and E7 Proteins

Allison J. Berger^*, Astrid Baege, Tracy Guillemette^*, James Deeds^*, Ron Meyer^*, Gary Disbrow, Richard Schlegel and Robert Schlegel^*

From Millennium Pharmaceuticals, Incorporated,^*Cambridge, Massachusetts; and the Department of Pathology,Georgetown University Medical Center, Washington, District of Columbia

Human papillomaviruses (HPVs) infect cervical epithelial cells and induce both benign and precancerous lesions. High-risk HPVs promote the development of cervical cancer in vivo and can immortalize cervical epithelial cells in vitro, whereas low-risk HPVs cannot. We used cDNA microarrays and quantitative polymerase chain reaction to compare cellular gene expression in primary cervical epithelial cells during a time course after retroviral transduction with either low-risk or high-risk E6/E7 genes. At early passages, cervical cells transduced with high-risk E6/E7 genes demonstrated increased expression of the cell cycle-regulated genes CDC2 and ubiquitin carrier E2-C. At later passages, these same cells exhibited dramatic increases in insulin-like growth factor-binding protein-3 (IGFBP-3) mRNA and both secreted an intracellular protein, with mRNA levels increasing 85-fold. Corroborating these in vitro studies, in situ hybridization of cervical biopsies with an IGFBP-3 riboprobe revealed high levels of expression in high-grade squamous intraepithelial neoplasia but not in normal cervical epithelium. Our in vitro results indicate that overexpression of IGFBP-3 is a late event after E6/E7 expression, and analysis of cervical lesions indicates that overexpression of this gene is also seen in vivo.

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