Overexpression of the telomerase holoenzyme induces EMT and tumorigenesis of HPV-immortalized keratinocytes.

Abstract

Cervical cancer is the most frequent malignancy of the female genital tract and is associated with persistent infection of the uterine cervix with high-risk human papillomaviruses (HPV). The two HPV oncoproteins, E6 and E7, cooperatively immortalize cervical cells and are essential but insufficient for inducing tumorigenicity. During the progression of HPV-associated cervical dysplasia to carcinoma, the cellular telomerase reverse transcriptase (TERT) gene is activated and the TERC gene amplified. We questioned whether these increases in telomerase components might mediate the acquisition of the tumorigenic phenotype. We therefore transduced the TERT and TERC genes into E6/E7 immortalized keratinocytes that were anchorage-dependent and nontumorigenic. The resultant cells showed a profound morphological change characteristic of epithelial-mesenchymal transition as well as a corresponding increase in expression of vimentin, N-cadherin, Zinc finger E-Box binding homeobox 1, snail family transcriptional repressor 1 and matrix Metallopeptidase 2 and decrease in keratin and E-cadherin. More important, the transduced cells were now anchorage-independent and formed tumors in immunodeficient mice. Our findings indicate that overexpression of the telomerase holoenzyme in HPV-immortalized cells is sufficient to induce the complete transformed phenotype.

• Authors: Aibing Wang, Dan Zhou, Ewa Krawczyk, Tuanjie Li, Vera Simic, Jie Lu, Xuefeng Liu, Richard Schlegel, Hang Yuan
• Journal: Journal of medical virology (J Med Virol) Vol. 95 Issue 4 Pg. e28681 (04 2023) ISSN: 1096-9071 [Electronic] United States
• PMID: 36929719 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.

Chemical References

• Oncogene Proteins, Viral
• Telomerase
• Papillomavirus E7 Proteins

Topics

• Female
• Humans
• Animals
• Mice
• Oncogene Proteins, Viral (genetics)
• Telomerase (genetics, metabolism)
• Papillomavirus E7 Proteins (genetics)
• Papillomavirus Infections (complications, genetics)
• Keratinocytes (metabolism)
• Carcinogenesis (genetics, metabolism)
• Uterine Cervical Neoplasms (genetics)
• Papillomaviridae (genetics)