The HBx oncoprotein of hepatitis B virus potentiates cell transformation by inducing c-Myc-dependent expression of the RNA polymerase I transcription factor UBF

Virology Journal

Vijay Kumar¹  Surendra Kumar Shukla¹  Pallavi Rajput¹ 

[1] Virology Group, International Centre for Genetic engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India

关键词: Cell transformation;    Cell proliferation;    c-Myc;    rDNA transcription;    Upstream Binding Factor;    Hepatitis B virus;    HBx;   

Others  :  1224951
DOI  :  10.1186/s12985-015-0293-5

 received in 2015-01-21, accepted in 2015-03-31,  发布年份 2015

【 摘 要 】

Background

The HBx oncoprotein of hepatitis B virus has been implicated in the development and progression of hepatocellular carcinoma (HCC). HBx engages multiple signalling and growth-promoting pathways to induce cell proliferation and enhance ribosome biogenesis. Interestingly, the levels of Upstream Binding Factor (UBF) required for rDNA transcription and ribosome biogenesis are found elevated in the HCC patients. However, the molecular mechanism of UBF overexpression under the HBx microenvironment and consequent cell transformation remains elusive.

Methods

The UBF gene expression was investigated after co-expressing HBx in immortalized human hepatocytes (IHH) and human hepatoma Huh7 cells. Gene expression analysis involved estimation of mRNA level by real-time PCR, western blotting of protein, chromatin immune-precipitation assay, BrdU incorporation assay and soft agar colony formation assay. UBF expression was also investigated in an HBx transgenic mouse model of HCC to get a better mechanistic insight under more physiological conditions.

Results

Ectopic expression of HBx in IHH as well as Huh7 cells led to a marked increase in UBF expression both at mRNA and protein levels. Elevated levels of UBF were also observed in the hepatic tumors of HBx transgenic mice. Our ChIP studies revealed a marked increase in the occupancy of c-Myc on the UBF gene promoter in the presence of HBx and increase in its transcription. Enhanced UBF expression under the HBx microenvironment led to a marked increase in cell proliferation and transformation of IHH cells.

Conclusions

Our study provides some compelling evidences in support of HBx-mediated increase in UBF levels that abets oncogenic onslaught in hepatic cells by increasing rDNA transcription and ribosome biogenesis.

【 授权许可】

   
2015 Rajput et al.; licensee BioMed Central.

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