Viral-Human Chimeric Transcript Predisposes Risk to Liver Cancer Development and Progression

Lau, Chi Chiu; Sun, Tingting; Ching, Arthur K.; He, Mian; Li, Jing‐Woei; Wong, Alissa Michelle Go; Co, Ngai Na; Chan, Anthony Wing–Hung; Li, Pik-Shan; Lung, Raymond Wai Ming; Tong, Joanna H.M.; Lai, Paul B.S.; Chan, Henry Lik‐Yuen; To, Ka‐Fai; Chan, Ting‐Fung; Wong, Nathalie

doi:10.1016/j.ccr.2014.01.030

Cited by 255 publications

(313 citation statements)

References 35 publications

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“…The results of the present study expand on a previous study demonstrating that the chimeric HBx-LINE-1 functions as a hybrid RNA and promotes tumorigenesis in HCC (16). A (20).…”

Section: Discussionsupporting

confidence: 85%

“…Therefore, it was hypothesized that transcripts of retrotransposons L1 may also influence lung carcinogenesis. The present study focused on the role L1 RNA may serve in lung carcinogenesis without HBV infection, which is different from HBx-LINE-1 causing hepatocarcinogenesis (16). It has previously been demonstrated that L1PA16 RNA binds to PSF protein, which is part of the LINE retrotransposons family (10).…”

Section: Binding Ability Of L1 Rna and Psf Protein In Vitromentioning

confidence: 99%

“…It has been suggested that HBV may cause HCC by integrating into L1 retrotransposons and lead to L1 transcription (16). Therefore, it was hypothesized that transcripts of retrotransposons L1 may also influence lung carcinogenesis.…”

Section: Binding Ability Of L1 Rna and Psf Protein In Vitromentioning

confidence: 99%

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Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Zhao

2017

Experimental and Therapeutic Medicine

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Abstract. Hepatocellular carcinoma (HCC) has one of the highest mortality rates among numerous types of cancer. It has been demonstrated that in hepatitis B (HBV)-associated HCC, the expression of chimeric fusion transcript HBx-long interspersed nuclear element-1 (LINE-1) initiated by HBV integration is correlated with hepatocarcinogenesis and poor patient survival rates. Furthermore, increased rates of LINE-1 hypomethylation have been detected in HCC tissues compared with adjacent tissues. This suggests that individual LINE-1 RNA (L1 RNA) serves an important role in the processes of hepatocarcinogenesis. The present study assessed the epigenic interaction between L1 RNA and polypyrimidine tract-binding protein-associated splicing factor (PSF) in the A549 human alveolar epithelial and 16HBE human bronchial epithelial cell lines. In addition, changes in the transcriptional regulatory activity of PSF on its target gene, proto-oncogene G antigen 6 (GAGE6), were investigated following overexpression of L1 RNA, as well as its impact on cell-proliferative capacity, carried out by plotting cell growth curves and 5-ethynyl-2'-deoxyuridine assay. It was observed that L1 RNA specifically bound to the RNA binding domain of PSF and released the GAGE6 promoter region from the DNA-binding domain of PSF. This increased the transcription of GAGE6 and led to the promotion of cell proliferation as well as colony formation. Furthermore, at least two binding sites specific for PSF were identified on L1 RNA. In conclusion, the transcriptional regulatory activity of L1 RNA may partially result in cell transformation, and endogenous L1 RNA may function as an important regulatory factor in the process of tumorigenesis.

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“…The results of the present study expand on a previous study demonstrating that the chimeric HBx-LINE-1 functions as a hybrid RNA and promotes tumorigenesis in HCC (16). A (20).…”

Section: Discussionsupporting

confidence: 85%

Section: Binding Ability Of L1 Rna and Psf Protein In Vitromentioning

confidence: 99%

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Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Zhao

2017

Experimental and Therapeutic Medicine

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“…2 Hepatitis B virus X protein (HBx) encoded by the X gene of HBV plays a pivotal role in the onset and progression of HBV-associated HCC. 3 HBx can regulate multiple biological events, including cell proliferation, apoptosis, migration and invasion. 4 HBx gene is frequently integrated into the host genome in a 3 0 -end-deleted form, yielding a carboxyl-terminal truncated isoform (ctHBx).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma

Gong

Feng

Song

et al. 2015

Cancer Biology & Therapy

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Protein phosphatase 2A (PP2A) is a heterotrimeric protein phosphatase consisting of a 36-k D catalytic C subunit (PP2Ac). This study aimed to explore the prognostic and biological significance of PP2Ac in human hepatocellular carcinoma (HCC). High PP2Ac expression was significantly (P < 0.01) associated with serum hepatitis B surface antigen positivity, serum hepatitis B e antigen positivity, liver cirrhosis, moderate to poor differentiation grade, advanced disease stage, intrahepatic metastasis, and early recurrence in HCC. Multivariate analysis revealed PP2Ac as an independent prognostic factor for overall survival. Enforced expression of hepatitis B virus X protein (HBx) and its carboxyl-terminal truncated isoform induced PP2Ac expression in HCC cells. Co-immunoprecipitation assay revealed a direct interaction between PP2Ac and HBx. Small interfering RNA-mediated knockdown of PP2Ac significantly inhibited in vitro cell proliferation, colony formation, migration, and invasion and reduced tumor growth in an xenograft mouse model. In contrast, overexpression of PP2Ac promoted HCC cell proliferation, colony formation, and tumorigenesis. Additionally, silencing of PP2Ac impaired the growth-promoting effects on HepG2 HCC cells elicited by overexpression of carboxyl-terminal truncated HBx. Gene expression profiling analysis showed that PP2Ac downregulation modulated the expression of numerous genes involved in cell cycle and apoptosis regulation. Collectively, PP2Ac upregulation has a poor prognostic impact on the overall survival of HCC patients and contributes to the aggressiveness of HCC. PP2Ac may represent a potential therapeutic target for HCC.

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“…In human breast and colon cancer cell lines, the expression of this LCT was found to be associated with decreased TFPI-2 expression. 9 In hepatitis B virus-positive HCC tissues, Lau et al 70 detected a 674 bp chimeric HBx-L1 transcript that is driven by viral HBx promoter and correlates with unfavorable prognosis of patients. Subsequent functional investigations revealed that HBx-L1 functions as an lncRNA to promote cell mobility in HCC cells through epithelial-to-mesenchymal transition and to promote chemical-induced hepatocarcinogenesis in a mouse model via activation of the Wnt/β-catenin pathway (Figure 2e, bottom).…”

Section: Functions Of L1s In Cancer Retrotransposition-dependent Funcmentioning

confidence: 99%

LINE-1 in cancer: multifaceted functions and potential clinical implications

Han

et al. 2016

Genetics in Medicine

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ReviewThe human genome is abundant with interspersed repetitive sequences originated from retrotransposons. Until now, three categories of retrotransposons have remained unequivocally active: LINE-1(L1), Alu, and SVA elements. The first one is autonomous-capable of self-propagation through RNA intermediates-and the latter two are nonautonomous and thus rely on L1 for mobilization. There are approximately 500,000 L1 copies in the human genome, composing 17% of human DNA.

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Viral-Human Chimeric Transcript Predisposes Risk to Liver Cancer Development and Progression

Cited by 255 publications

References 35 publications

Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro

Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma

LINE-1 in cancer: multifaceted functions and potential clinical implications

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