1. Different DNA damage and cell cycle checkpoint control in low- and high-risk human papillomavirus infections of the vulva
- Author
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Lindy A.M. Santegoets, Annelinde Terlou, Marc van Beurden, Theo J.M. Helmerhorst, Leen J. Blok, Claudia Heijmans-Antonissen, Peter J. van der Spek, Sigrid M. A. Swagemakers, Patricia C. Ewing, Willem I. van der Meijden, Romy van Baars, Obstetrics & Gynecology, Pathology, and Dermatology more...
- Subjects
Cancer Research ,Cell cycle checkpoint ,DNA Repair ,DNA damage ,DNA repair ,Biology ,Alphapapillomavirus ,Vulva ,Histones ,SDG 3 - Good Health and Well-being ,medicine ,Biomarkers, Tumor ,Humans ,Cervix ,Cyclin-Dependent Kinase Inhibitor p16 ,Fanconi Anemia Complementation Group A Protein ,BRCA1 Protein ,Fanconi Anemia Complementation Group D2 Protein ,Gene Expression Profiling ,Papillomavirus Infections ,HPV infection ,virus diseases ,Cell Cycle Checkpoints ,Cell cycle ,Vulvar intraepithelial neoplasia ,medicine.disease ,Virology ,female genital diseases and pregnancy complications ,Gene expression profiling ,medicine.anatomical_structure ,Oncology ,Condylomata Acuminata ,DNA, Viral ,Cancer research ,Female ,Rad51 Recombinase ,Vulvar Diseases ,Tumor Suppressor Protein p53 ,DNA Damage - Abstract
Human papillomavirus (HPV) infections may result in benign hyperplasia, caused by low-risk HPV types, or (pre)malignant lesions caused by high-risk HPV types. The molecular basis of this difference in malignant potential is not completely understood. Here, we performed gene profiling of different HPV infected vulvar tissues (condylomata acuminata (n = 5), usual type vulvar intraepithelial neoplasia (uVIN) (n = 9)) and control samples (n = 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz (R), Partek (R) and Ingenuity (R) Software. Results were validated by real-time RT-PCR and immunostaining. Although similarities were observed between gene expression profiles of low- and high-risk HPV infected tissues (e.g., absence of estrogen receptor in condylomata and uVIN), high-risk HPV infected tissues showed more proliferation and displayed more DNA damage than tissues infected with low-risk HPV. These observations were confirmed by differential regulation of cell cycle checkpoints and by increased expression of DNA damage-biomarkers p53 and ?H2AX. Furthermore, FANCA, FANCD2, BRCA1 and RAD51, key players in the DNA damage response, were significantly upregulated (p < 0.05). In addition, we compared our results with publicly available gene expression profiles of various other HPV-induced cancers (vulva, cervix and head-and-neck). This showed p16INK4a was the most significant marker to detect a high-risk HPV infection, but no other markers could be found. In conclusion, this study provides insight into the molecular basis of low- and high-risk HPV infections and indicates two main pathways (cell cycle and DNA damage response) that are much stronger affected by high-risk HPV as compared to low-risk HPV. more...
- Published
- 2012