Abstract
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)-beta1, 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-beta1-induced crisis showed multiple clonal structural aberrations that were not observed in cells without TGF-beta1 treatment. Overexpression of the catalytic subunit of telomerase (hTERT) abolished the effects of TGF-beta1 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-beta1 production than the other two crisis-free immortalized cell lines. Blocking the TGF-beta1 pathway by an inhibitor of TGF-beta1 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-beta1 in vivo. These results together suggest an important role of TGF-beta1 in the early process of cervical carcinogenesis.
Highlights
Cervical cancer is the second most frequently occurring cancer in women worldwide and causes the highest cancer mortality among women in many developing countries [1]
The frequencies of other nonclonal structural aberrations including nonreciprocal translocations, deletions, duplications, and intra-arm dicentrics ranged from 12 to 16 per 100 metaphases. These results indicate that only minor structural chromosomal instability persisted during immortalization of the two crisis-free cervical epithelial cell lines www.aacrjournals.org expressing HPV16 E6E7
The number of chromosomes (V2) involved in clonal structural aberrations did not increase after long-term transforming growth factor (TGF)-h1 exposure (Supplementary Table 1). These results showed that ectopic hTERT overexpression in HPV16 E6E7– expressing cervical epithelial cells completely abolished the effects of Transforming growth factor h1 (TGF-h1) on telomere-mediated chromosomal instability throughout the long-term cell culture
Summary
Cervical cancer is the second most frequently occurring cancer in women worldwide and causes the highest cancer mortality among women in many developing countries [1]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Doi:10.1158/0008-5472.CAN-07-6569 high-risk human papillomavirus [mainly human papillomavirus (HPV)-16 and HPV18] is a necessary etiologic factor for cervical cancer [1, 2]. High-risk HPV types exert their oncogenic potential mainly through deregulated expression of viral oncogenes E6 and E7, which inactivate p53 and Rb proteins, respectively, by accelerating proteolytic degradation [3]. Extensive studies have shown that the expression of the viral oncogenes per se is not sufficient for cancer development. By continuous generation of new genetic alterations, chromosomal instability provides the cells with selective advantages in acquiring new features in a stepwise process toward cancer [4, 5]
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