Oncogenic Human Papillomaviruses Activate the Tumor-Associated Lens Epithelial-Derived Growth Factor (LEDGF) Gene

PLoS Pathogens

Magnus von Knebel Doeberitz¹  Miriam Reuschenbach¹  Manuel Llano²  Rosita Accardi³  Massimo Tommasino³  Claudia Lohrey⁴  Karin Hoppe-Seyler⁴  Felix Hoppe-Seyler⁴  Jenny Leitz⁴  Anja Honegger⁴ 

[1] Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany;Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, United States of America;International Agency for Research on Cancer, World Health Organization, Lyon, France;Molecular Therapy of Virus-Associated Cancers (F065), Program Infection and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

关键词: HeLa cells;    Oncogenes;    Small interfering RNAs;    Keratinocytes;    Human papillomavirus;    HPV-16;    Cervical cancer;    DNA damage;   

DOI  :  10.1371/journal.ppat.1003957

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic.

【 授权许可】

CC BY