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Oncogenic human papillomaviruses block expression of the B-cell translocation gene-2 tumor suppressor gene
Claire Cullmann1, Karin Hoppe-Seyler, Susanne Dymalla
1Molecular Therapy of Virus-Associated Cancers, German Cancer Research Center, Heidelberg, Germany.
Abstract:
Human papillomavirus (HPV)-induced carcinogenesis is critically dependent on the activities of the viral E6 and E7 oncogenes. Here, we demonstrate that expression of the putative tumor suppressor gene B-cell translocation gene-2 (BTG2) is reinduced in HPV16- and HPV18-positive cancer cells on silencing of viral oncogene expression, indicating that BTG2 is repressed by oncogenic HPVs. Inhibition of BTG2 expression was mediated by the HPV E6 oncogene and occurred in a p53-dependent manner. Luciferase reporter gene analyses revealed that BTG2 repression takes place at the transcriptional level and is dependent on the integrity of the major p53-response element within the BTG2 promoter. Ectopic expression of BTG2 acted antiproliferative in cervical cancer cells. Tissue specimens commonly exhibited reduced BTG2 protein levels in HPV-positive high-grade lesions (CIN2/3) and cervical carcinomas, when compared with normal cervical epithelium. These findings identify the antiproliferative BTG2 gene as a novel cellular target blocked by the HPV E6 oncoprotein.
Insights
Human papillomavirus (HPV) oncogenes repress the tumor suppressor gene BTG2. Silencing HPV oncogenes reinduces BTG2, which has antiproliferative effects in cervical cancer cells.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Human papillomavirus (HPV) oncoproteins E6 and E7 drive cancer development.
- The tumor suppressor gene B-cell translocation gene-2 (BTG2) plays a role in cell proliferation.
Purpose of the Study:
- To investigate the regulation of BTG2 expression by oncogenic HPV.
- To determine the mechanism by which HPV affects BTG2.
- To assess the potential of BTG2 as a therapeutic target in HPV-driven cancers.
Main Methods:
- Silencing of HPV oncogene expression in HPV-positive cancer cells.
- Luciferase reporter gene assays to analyze transcriptional regulation.
- Ectopic expression of BTG2 in cervical cancer cells.
- Analysis of BTG2 protein levels in clinical tissue specimens.
Main Results:
- BTG2 expression is repressed by oncogenic HPV, specifically mediated by the HPV E6 oncoprotein in a p53-dependent manner.
- HPV-mediated BTG2 repression occurs at the transcriptional level, involving the p53-response element in the BTG2 promoter.
- Ectopic BTG2 expression exhibited antiproliferative activity in cervical cancer cells.
- Reduced BTG2 protein levels were observed in HPV-positive high-grade lesions and cervical carcinomas.
Conclusions:
- The antiproliferative gene BTG2 is a novel cellular target suppressed by the HPV E6 oncoprotein.
- BTG2 repression is a key mechanism in HPV-induced carcinogenesis.
- Restoring BTG2 function may offer a therapeutic strategy for HPV-driven cervical cancers.
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