Human papilloma virus (HPV) E7-mediated attenuation of retinoblastoma (Rb) induces hPygopus2 expression via Elf-1 in cervical cancer

• Published in: Molecular cancer research 2013-01, Vol.11 (1), p.19-30
• Main Authors: Tzenov, Youlian R, Andrews, Phillip G, Voisey, Kim, Popadiuk, Paul, Xiong, Jieying, Popadiuk, Catherine, Kao, Kenneth R
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Transformation, Viral - genetics; Ephrin-A2 - genetics; Ephrin-A2 - metabolism; Female; Human papillomavirus 16 - genetics; Human papillomavirus 16 - metabolism; Human papillomavirus 18 - genetics; Human papillomavirus 18 - metabolism; Humans; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - metabolism; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomavirus Infections - pathology; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Transfection; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.mcr-12-0510

The human papillomavirus (HPV) is the etiologic agent of cervical cancer. In this study, we provide evidence for the human Pygopus (hPygo)2 gene as a cellular biomarker for HPV-related disease. In a tumor microarray of cervical cancer progression, hPygo2 levels were greater in high-grade lesions and squamous cell carcinomas than in normal epithelia. Similarly, hPygo2 mRNA and protein levels were greater in HPV-positive cervical cancer cells relative to uninfected primary cells. RNA interference (RNAi)-mediated depletion of HPV-E7 increased whereas E74-like factor (Elf)-1 RNAi decreased association of Retinoblastoma (Rb) tumor suppressor with the hPygo2 promoter in cervical cancer cell lines. Transfection of dominant-active Rb inhibited Elf-1-dependent activation of hPygo2, whereas Elf-1 itself increased hPygo2 expression. Chromatin immunoprecipitation assays showed that Rb repressed hPygo2 by inhibiting Elf-1 at the Ets-binding site in the hPygo2 promoter. These results suggested that abrogation of Rb by E7 resulted in derepression of Elf-1, which in turn stimulated expression of hPygo2. Thus, initiation of hPygo2 expression by Elf-1 was required for proliferation of cervical cancer cells and its expression therefore may act as a surrogate marker for dysplasia.