Multiple-integrations of HPV16 genome and altered transcription of viral oncogenes and cellular genes are associated with the development of cervical cancer

Xulian Lu; Qiaoai Lin; Mao Lin; Ping Duan; Lulu Ye; Jun Chen; Xiangmin Chen; Lifang Zhang; Xiangyang Xue

doi:10.1371/journal.pone.0097588

Multiple-integrations of HPV16 genome and altered transcription of viral oncogenes and cellular genes are associated with the development of cervical cancer

PLoS One. 2014 Jul 3;9(7):e97588. doi: 10.1371/journal.pone.0097588. eCollection 2014.

Authors

Xulian Lu¹, Qiaoai Lin², Mao Lin³, Ping Duan⁴, Lulu Ye⁵, Jun Chen², Xiangmin Chen⁶, Lifang Zhang², Xiangyang Xue⁵

Affiliations

¹ Department of Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Pathology, Zhuji People's Hospital of Zhejiang Province, Zhuji, Zhejiang, China.
² Department of Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
³ Department of Microbiology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang, China; Fuda Cancer Hospital Affiliated to the Medical College of Jinan University, Guangzhou, Guangdong, China.
⁴ Department of Obstetrics and Gynecology, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁵ Institute of Molecular Virology and Immunology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁶ School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Abstract

The constitutive expression of the high-risk HPV E6 and E7 viral oncogenes is the major cause of cervical cancer. To comprehensively explore the composition of HPV16 early transcripts and their genomic annotation, cervical squamous epithelial tissues from 40 HPV16-infected patients were collected for analysis of papillomavirus oncogene transcripts (APOT). We observed different transcription patterns of HPV16 oncogenes in progression of cervical lesions to cervical cancer and identified one novel transcript. Multiple-integration events in the tissues of cervical carcinoma (CxCa) are significantly more often than those of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Moreover, most cellular genes within or near these integration sites are cancer-associated genes. Taken together, this study suggests that the multiple-integrations of HPV genome during persistent viral infection, which thereby alters the expression patterns of viral oncogenes and integration-related cellular genes, play a crucial role in progression of cervical lesions to cervix cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Female
Gene Expression Regulation, Neoplastic*
Gene Expression Regulation, Viral*
Genome, Viral*
Human papillomavirus 16 / metabolism*
Humans
Oncogene Proteins / biosynthesis*
Oncogene Proteins / genetics
Papillomavirus Infections / genetics
Papillomavirus Infections / metabolism*
Papillomavirus Infections / pathology
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / metabolism*
Uterine Cervical Neoplasms / pathology
Uterine Cervical Neoplasms / virology
Viral Proteins / biosynthesis*
Viral Proteins / genetics

Substances

Oncogene Proteins
Viral Proteins

Grants and funding

This work is supported by grants from the National Natural Science Foundation of China (81001343, 81172463), the Department of Education of Zhejiang Province (Y200907403) and Wenzhou Science and Technology Bureau (Y20090103, Y20100175 and H20100063). These sponsors provided the funding for the experiments and the collection of specimens. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.