HBV Integration-mediated Cell Apoptosis in HepG2.2.15

Xiaoge Hu; Jiahong Jiang; Chao Ni; Qiuran Xu; Song Ye; Junjie Wu; Feimin Ge; Yong Han; Yinyuan Mo; Dongsheng Huang; Liu Yang

doi:10.7150/jca.30493

HBV Integration-mediated Cell Apoptosis in HepG2.2.15

J Cancer. 2019 Jul 10;10(17):4142-4150. doi: 10.7150/jca.30493. eCollection 2019.

Authors

Xiaoge Hu^{1

2}, Jiahong Jiang¹, Chao Ni^{1

3}, Qiuran Xu^{1

2}, Song Ye⁴, Junjie Wu^{1

2}, Feimin Ge⁵, Yong Han^{1

2}, Yinyuan Mo⁶, Dongsheng Huang^{1

2

3}, Liu Yang^{1

2}

Affiliations

¹ Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P. R. China.
² Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P. R. China.
³ Department of General surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P. R. China.
⁴ Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Secondary Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P. R. China.
⁵ Department of Pharmacy, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P. R. China.
⁶ Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the second leading cause of cancer deaths in the word. Hepatitis B virus (HBV) infection plays an important role in the development of HCC. However, the mechanisms by which HBV integration affects host cells remain poorly understood. HepG2.2.15 cell line is derived from HCC cell line HepG2 with stable transfection HBV expression. In this study, HepG2.2.15 cells showed decreased proliferation, G1 cell cycle arrest and increased apoptosis, when compared to HepG2 cells. HBV capture sequencing was conducted in both genome and transcriptome level, followed by RNA expression sequencing in HepG2.2.15. Here, CAMSAP2/CCDC12/DPP7/OR4F3 were found to be targets for HBV integration in both genome and transcriptome level, accompanied by alteration in their expression when compared to HepG2. Among these genes, DPP7 was the only one gene with HBV integration into its exon, meanwhile DPP7 expression level was also downregulated in HepG2.2.15 as compared to HepG2. Furthermore, DPP7 knockdown resulted in increased apoptosis through upregulation of the Bax/Bcl2 ratio in HepG2 cells. Our results suggest that HBV integration of DPP7 was involved in cell apoptosis.

Keywords: HepG2.2.15; Hepatitis B virus; apoptosis; cell cycle; proliferation; viral integration.