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Transforming Growth Factor β1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7–Infected Cervical Epithelial Cells

Departments of ¹ Anatomy, ² Obstetrics and Gynaecology, ³ Pathology, ⁴ Medicine, and ⁵ Clinical Oncology, The University of Hong Kong, Hong Kong, SAR, China

Requests for reprints: Annie L.M. Cheung, Department of Anatomy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong, SAR, China. Phone: 852-2819-9293; Fax: 852-2817-0857; E-mail: lmcheung{at}hkucc.hku.hk.

Key Words: TGF-β1 • HPV • telomere • chromosomal instability • cervical • immortalization

Uterine cervical cancer, the second most frequently occurring cancer in women worldwide, is tightly associated with the expression of high-risk human papillomavirus [mainly human papillomavirus (HPV)-16 and HPV18] oncogenes E6 and E7 and characteristically exhibits chromosomal instability. However, the mechanisms underlying chromosomal instability in cervical cancer are still not fully understood. In this study, we observed that two of three human cervical epithelial cell lines expressing HPV16 E6E7 became immortalized without extensive chromosomal instability and crisis. The introduction of transforming growth factor (TGF)-β1, a multiple functional cytokine/growth factor, in the culture medium induced crisis, which was associated with massive chromosomal end-to-end fusions and other structural aberrations. The distributions of structural aberrations on individual chromosomes were significantly correlated with the profiles of telomere signal–free ends. The immortalized cells that emerged from the TGF-β1–induced crisis showed multiple clonal structural aberrations that were not observed in cells without TGF-β1 treatment. Overexpression of the catalytic subunit of telomerase (hTERT) abolished the effects of TGF-β1 on chromosomal instability. Interestingly, another HPV16 E6E7–expressing cervical cell line that experienced crisis and telomere dysfunction under ordinary culture condition had a higher level of autocrine TGF-β1 production than the other two crisis-free immortalized cell lines. Blocking the TGF-β1 pathway by an inhibitor of TGF-β1 receptor type I prevented the crisis and telomere-mediated chromosomal instability. In addition, more dramatic telomere shortening was observed in cervical intraepithelial neoplasias having higher expression of TGF-β1 in vivo. These results together suggest an important role of TGF-β1 in the early process of cervical carcinogenesis. [Cancer Res 2008;68(17):7200–9]