Genetic variability and functional implication of the long control region in HPV-16 variants in Southwest China
et al. (2017) Genetic variability and functional
implication of the long control region in HPV-16
variants in Southwest China. PLoS ONE 12(8):
e0182388. https://doi.org/10.1371/journal.
pone.0182388
Genetic variability and functional implication of the long control region in HPV-16 variants in Southwest China
Juemin Xi 0 1
Junying Chen 0 1
Miaoling Xu 1
Hongying Yang 1
Jia Luo 0 1
Yue Pan 0 1
Xiaodan Wang 0 1
Lijuan Qiu 0 1
Jiajia Yang 0 1
Qiangming Sun 0 1
0 Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College , Kunming , People's Republic of China, 2 Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases , Kunming , People's Republic of China, 3 Yunnan Key Laboratory of Vector-borne Infectious Disease , Kunming , People's Republic of China, 4 The First Affiliated Hospital of Kunming Medical University , Kunming , People's Republic of China, 5 The Third Affiliated Hospital of Kunming Medical University, Yunnan Provincial Tumor Hospital , Kunming , People's Republic of China, 6 Kunming Medical University , Kunming , People's Republic of China
1 Editor: Maria Lina Tornesello, Fondazione IRCCS Istituto Nazionale dei Tumori , ITALY
HPV-16 long control region (LCR) has been shown to be the most variable region of the HPV-16 genome and may play important roles in viral persistence and the development of cervical cancer. This study aimed to assess the risk of HPV-16 LCR variants for cervical cancer in women of Southwest China. 2146 cervical scrapings of volunteer outpatients and 74 cervical cancer tissues were screened.14 entire HPV-16 LCRs from asymptomatic carriers and 34 entire HPV-16 LCRs from cervical cancer patients were successfully amplified and sequenced to align to others described. 58 different point mutations were detected in 54 nucleotide sites of HPV-16 LCR. G7193T and G7521A variants, accounting for 100% of the infections, were predicted to locate at the binding site for FOXA1 and SOX9, respectively. A7730C variant which showed a high mutation frequency in cervical cancer was predicted to be a binding site for the cellular transcription factor PHOX2A. In addition, phylogenetic analysis displayed a high prevalence of A lineage in HPV-16 LCR in this Southwest China population. This study may help understanding of the intrinsic geographical relatedness and the correlations between LCR mutations and the development of carcinogenic lesions in Southwest China population. And it provides useful data for the further study of the biological function of HPV-16 LCR variants.
Introduction
Human papillomavirus type 16 (HPV-16) is prevalent worldwide and is the main etiological
agent of cervical cancer [
1
]. HPV-16 variants have been grouped into the four major variant
lineages and nine sublineages: (1) lineage A, including A1, A2, A3 (previously known as
European) and A4 (Asian) sublineages; (2) lineage B, including B1 (Afr1a) and B2 (Afr1b)
no. 2012ZX09104-302, http://www.most.gov.cn/),
the Natural Science Foundation of Yunnan Province
(grant no. 2009ZC187M, 2012FB188 and
2016FA029, http://www.ynstc.gov.cn/). The
funders had no role in study design, data collection
and analysis, decision to publish, or preparation of
the manuscript.
sublineages; (3) lineage C (African-2); and (4) lineage D, including D1 (North American,
NA1), D2 (Asian-American, AA2), and D3 (Asian-American, AA1) sublineages [
2
].
HPV-16 is a capsid-enclosed circular double-stranded DNA virus from the papillomavirus
family with a genome approximately 7.9 kb in length, consisting of an early region (E6, E7, E1,
E2, E4, E5), a late region (L2, L1), a small non-coding region (NCR) localized between E5 and
L2, and a long control region (LCR) [
3
], which is approximately 850 bp in length and is the
most variable region of HPV-16.
The LCR region contains the early promoter and various transcriptional regulatory sites for
both viral and cellular proteins [4±6], such as E2, YY1, Oct-1, NF1, transcriptional enhancer
factor-1 (TEF-1), and others. Based principally on the LCR sequences, several studies from the
United States, Germany, and Europe have suggested that certain LCR variants of HPV-16 may
play an important role in viral persistence and the development of cervical cancer. For
example, the E2 protein has been shown to be primarily a transcriptional repressor, and mutations
of the E2 binding sites in LCR reduced P97 E2-mediated repression [
7,8
]. A study by Dong
et al. implied that deletions or mutations of YY1-binding sites played a significant role in the
over-expression of viral oncogenes and tumor progression [
9,10
]. Thus far, little has been
reported on the HPV-16 LCR variants in China.
In this study, samples from asymptomatic carriers and cervical cancer patients were
obtained from women in Southwest China, and polymorphic sites within the HPV-16 LCR
were detected and compared to investigate the association of specific LCR mutations with th (...truncated)