Human papillomavirus 16 E2 interacts with neuregulin receptor degradation protein 1 affecting ErbB-3 expression in vitro and in clinical samples of cervical lesions. (May 2016)

• Record Type: Journal Article
• Authors: Paolini, Francesca; Curzio, Gianfranca; Melucci, Elisa; Terrenato, Irene; Antoniani, Barbara; Carosi, Mariantonia; Mottolese, Marcella; Vici, Patrizia; Mariani, Luciano; Venuti, Aldo
• Is Part Of: European journal of cancer. Volume 58(2016)
• Page Start: 52
• Page End: 61
• Publication Date: 2016-05
• Subjects: HPV -- E2 protein -- W12 cell line -- Nrdp-1 -- ErbB-3 -- Cervical cancer -- CIN -- IHC -- EGFR; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2016.02.001
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: The ErbB tyrosine kinase receptors play a key role in regulating many cellular functions and human papillomaviruses (HPVs) may interact with transductional pathway of different growth factor receptors. Here, these interactions were analysed in W12 cell line carrying HPV 16 genome and in clinical samples. W12 cells, in which HPV16 becomes integrated during passages, were utilised to detect viral and ErbB family expression at early (W12E) and late passages (W12G). Interestingly, a strong reduction of ErbB-3 expression was observed in W12G. Loss of the E2 and E5 viral genes occurs in W12G and this may affect ErbB-3 receptor expression. E2 and E5 rescue experiments demonstrated that only E2 gene was able to restore ErbB-3 expression. E2 is a transcriptional factor but the expression levels of ErbB3 were unaffected and ErbB-3 promoter did not show any consensus sequence for E2, thus E2 may interact in another way with ErbB3. Indeed, HPV 16 E2 can modulate ErbB-3 by interacting with the ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp-1) that is involved in the regulation of this receptor, via ubiquitination and degradation. E2 co-immunoprecipitated in a complex with Nrdp-1 leading to hypothesise an involvement of this interaction in ErbB-3 regulation. In addition, 90% of the clinical samples with integrated virus and E2 loss showed no or low ErbB-3 positivity, confirming in vitro results. In conclusion, the new discovered interaction of HPV-16 E2 with Nrdp-1 may affect ErbB-3 expression. Highlights: We showed epidermal growth factor receptor up- and ErbB-3 down-regulation in W12 cells after human papillomavirus (HPV) integration. HPV16 E2 interacts with the RING finger E3 ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp-1). E2/Nrdp-1 interaction renders ErbB-3 free to circulate to the cell membrane. Clinical samples with pure episomal HPV16 are highly positive for ErbB-3. Clinical samples with totally integrated HPV16 were negative for ErbB-3.