Functional implication of sequence variation in the long control region and E2 gene among human papillomavirus type 18 variants

Abstract

Cervical cancer incidence remains highly frequent in developing countries. It is possible that populations of these countries are exposed to more oncogenic human papillomavirus (HPV) variants. Functional differences among high-risk HPV variants have been described, suggesting repercussions on their oncogenic potential. In this report, we demonstrate that the long control region (LCR) of HPV18 variants has distinct transcriptional activities in different cervical cancer cell lines. African (Af)-LCR possessed the lowest transcriptional activity; its sequence harbors the highest number of nucleotide changes among the HPV18 variants analyzed. Some of these embedded in identified transcription-factor-binding sites, suggesting a less aggressive biological activity possibly involved in a slower progression of cervical lesions. Asian-Amerindian LCR showed distinct activities among cell types, while European LCR activity was similar in cell lines tested. Despite multiple nucleotide substitutions found in HPV18 E2 variant genes, their repressive activities over homologous LCRs were not distinct among variants.

Whole-Genome Sequence Analysis of Human Papillomavirus Type 18 from Infected Thai Women

“…Some researchers reported that E2 variations were insignificant between controls with no past and current history of cervical abnormalities and tumor cases [20] . Multiple nucleotide substitutions found in HPV18-E2 variants were not affected by activities over homologous LCR among HPV18 variants [19] . Moreover, based on variation, the rate of dN/dS alterations was not found significant for all coding regions.…”

“…In addition, the proteins displaying most nonsynonymous amino acids were detected in E2 and L2 as reported for HPV16 in a previous study [17] . López-Saavedra et al [19] indicated that the E2 viral protein is essential for regulating LCR activity and transcription of viral genes. Some researchers reported that E2 variations were insignificant between controls with no past and current history of cervical abnormalities and tumor cases [20] .…”

“…Thus, our data did not perform and analyze amino acid variation on the E2 gene. However, E2 variation could affect other biological functions such as viral replication or interaction with other cellular proteins [19] .…”

Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis

“…Greater understanding of these interactions could help estimate the associated risk of developing CC. Few reports support the presence of partial or imperfect palindromes of responsive elements representing GREs and EREs (Garcia-Carranca et al 1988, Mitrani-Rosenbaum et al 1989, Chen et al 1996, MoralesPeza et al 2002, Burk et al 2003, Moodley et al 2003, Baldwin et al 2006, López-Saavedra et al 2009). However, these palindromes are only putative hormone-responsive element-like sequences.…”

“…Limitations of the study by Mitrani-Rosenbaum and coworkers are that they did not detect a notable involvement of functional EREs in the HPV genome, and their study did not include HPV 18, the other high-risk subtype. Transcription factor-binding sites were recognised in HPV 18 variants with distinct functional activities (López-Saavedra et al 2009). Apart from the LCR, the non-coding upstream regulatory region (URR) of HPV also harbours responsive elements that serve as target sites to potentially bind to cellular factors (Chan et al 1989, Mitrani-Rosenbaum et al 1989, Chen et al 1996.…”