The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma

Li, Xiaojun; Zhang, Jiangbo; Yang, Zixian; Kang, Jingting; Jiang, Suzhen; Zhang, Ting; Chen, Tingting; Li, Meng; Lv, Quanjun; Chen, Xiangmei; McCrae, Malcolm A.; Zhang, Hui; Lu, Fengmin

doi:10.1016/j.jhep.2013.12.014

Cited by 103 publications

(120 citation statements)

References 34 publications

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“…Integration of HBV DNA into the host genome occurs at early steps of clonal tumor expansion, and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes 27, 28 . Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alteration and gene mutation.…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice

Liu

Zeng

et al. 2017

Sci Rep

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The p53 mutation and altered Pten expression are two most common genetic events in Hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC). To confirm the causative role of p53 and Pten somatic mutation in HCC development, we established CRISPR/Cas9-mediated somatic gene disruption via hydrodynamic tail vein injection, allowing for in vivo targeting p53 and Pten simultaneously in adult HBV transgenic mice. Here we demonstrated that the utility of this approach resulted in macroscopic liver tumors as early as 4 months’ post injection and most tumors harbored both p53 and Pten loss-of-function alterations. Immunohistochemical (IHC) and histopathology analysis demonstrated that the tumors were positive for Glutamine synthetase (GS), a marker of HCC and accompanied with prominent lipid accumulation. The study here indicated that CRISPR/Cas9-mediated p53 and Pten somatic mutation accelerated hepatocarcinogenesis in adult HBV transgenic mice. This method also provides a fast and convenient system for generating mouse model of HCC with HBV infection characteristics.

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Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice

Liu

Zeng

et al. 2017

Sci Rep

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“…Because HBV integrates into the host genome and the copy numbers of HBV increase as the tumor develops, monitoring HBV DNA and cccDNA has the advantage of indicating the development of malignancy. HBV infection has been associated with Ͼ80% of HCC patients (26 ); the ideal end point for treatment of chronic HBV infection is cccDNA elimination (7 ) and HBsAg loss (8 ). Our results further confirmed the oncogenicity of HBV, which supports the viewpoints that the expressions of HBV proteins themselves have oncogenic potency and that the integration of HBV DNA into the host genome promotes carcinogenic mechanisms in the host genome (26 -29 ).…”

Section: Discussionmentioning

confidence: 99%

Next Generation Digital PCR Measurement of Hepatitis B Virus Copy Number in Formalin-Fixed Paraffin-Embedded Hepatocellular Carcinoma Tissue

et al. 2015

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BACKGROUND: Hepatocellular carcinoma (HCC) is strongly associated with hepatitis B virus (HBV) infection. False-negative results are common in routine serological tests and quantitative real-time PCR because of HBV surface antigen (HBsAg) variation and low HBV copy number. Droplet digital PCR (ddPCR), a next generation digital PCR, is a novel, sensitive, and specific platform that can be used to improve HBV detection.

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“…In spite of the strong oncogenic potency of some proteins encoded by such viruses, integration‐induced aberrant expression or functional change of host genes has also been shown to play a role in virus‐related human malignancies. In line with this, our recent study has demonstrated that the function of integration‐targeted genes (ITGs), which were disrupted directly by HPV integration or the ones closest to the HPV integration site as described before, has a role in determining the oncogenicity of hepatitis B virus (HBV) integration in hepatocellular cancer . However, in HPV‐related cancers, although HPV DNA integration had been recognized as a major promoting step in malignant transformation, the possible role of ITGs has not received much attention.…”

mentioning

confidence: 86%

Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV‐related cervical carcinogenesis

Zhang

Shen

Zhao

et al. 2015

Intl Journal of Cancer

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Integration of human papillomavirus (HPV) viral DNA into the human genome has been postulated as an important etiological event during cervical carcinogenesis. Several recent reports suggested a possible role for such integration‐targeted cellular genes (ITGs) in cervical carcinogenesis. Therefore, a comprehensive analysis of HPV integration events was undertaken using data collected from 14 publications, with 499 integration loci on human chromosomes included. It revealed that HPV DNA preferred to integrate into intragenic regions and gene‐dense regions of human chromosomes. Intriguingly, the host cellular genes nearby the integration sites were found to be more transcriptionally active compared with control. Furthermore, analysis of the integration sites in the human genome revealed that there were several integration hotspots although all chromosomes were represented. The ITGs identified were found to be enriched in tumor‐related terms and pathways using gene ontology and KEGG analysis. In line with this, three of six ITGs tested were found aberrantly expressed in cervical cancer tissues. Among them, it was demonstrated for the first time that MPPED2 could induce HeLa cell and SiHa cell G1/S transition block and cell proliferation retardation. Moreover, “knocking out” the integrated HPV fragment in HeLa cell line decreased expression of MYC located ∼500 kb downstream of the integration site, which provided the first experimental evidence supporting the hypothesis that integrated HPV fragment influence MYC expression via long distance chromatin interaction. Overall, the results of this comprehensive analysis implicated that dysregulation of ITGs caused by viral integration as possibly having an etiological involvement in cervical carcinogenesis.

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The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma

Abstract: The oncogenicity of HBV integration was determined, to some extend by the function of HBV integration targeted host genes in HCC.

Cited by 103 publications

References 34 publications

CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice

CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice

Next Generation Digital PCR Measurement of Hepatitis B Virus Copy Number in Formalin-Fixed Paraffin-Embedded Hepatocellular Carcinoma Tissue

Dysregulation of host cellular genes targeted by human papillomavirus (HPV) integration contributes to HPV‐related cervical carcinogenesis

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