Abstract
Hepatitis B virus X protein (HBx) plays critical roles in the pathogenesis of hepatocellular carcinoma (HCC). Here, we were interested in knowing whether the oncogene Lin28A and its homolog Lin28B are involved in the hepatocarcinogenesis mediated by HBx. We showed that the expression levels of Lin28A and Lin28B were increased in clinical HCC tissues, HepG2.2.15 cell line and liver tissues of p21-HBx transgenic mice. Interestingly, the expression levels of HBx were positively associated with those of Lin28A/Lin28B in clinical HCC tissues. Moreover, the overexpression of HBx resulted in the upregulation of Lin28A/Lin28B in hepatoma HepG2/H7402 cell lines by transient transfection, suggesting that HBx was able to upregulate Lin28A and Lin28B. Then, we examined the mechanism by which HBx upregulated Lin28A and Lin28B. We identified that the promoter region of Lin28A regulated by HBx was located at nt -235/-66 that contained Sp-1 binding element. Co-immunoprecipitation showed that HBx was able to interact with Sp-1 in HepG2-X cells. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that HBx could bind to the promoter of Lin28A, which failed to work when Sp-1 was silenced. Electrophoretic mobility shift assay (EMSA) further identified that HBx was able to interact with Sp-1 element in Lin28A promoter via transcription factor Sp-1. In addition, we found that c-Myc was involved in the activation of Lin28B mediated by HBx. In function, Lin28A/Lin28B played important roles in HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. In conclusion, HBx activates Lin28A/Lin28B through Sp-1/c-Myc in hepatoma cells. Lin28A/Lin28B serves as key driver genes in HBx-induced hepatocarcinogenesis.
Highlights
The infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC),[1] in which HBV X protein (HBx) plays critical and multiple roles in the pathogenesis of HCC
To elucidate the significance of Lin28A expression in hepatoma, we examined the levels of Lin28A in hepatoma cell lines and HCC tissues
We focused on the investigation of the function of Lin28A and its homolog Lin28B in the development of HBx-induced HCC
Summary
The infection of hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma (HCC),[1] in which HBV X protein (HBx) plays critical and multiple roles in the pathogenesis of HCC. HBx modulates transcription, signal transduction, cell cycle progress, apoptosis, proliferation and migration by directly or indirectly interacting with various transcription factors (such as activator protein 1, nuclear factor-kB, c-Myc, Sp-1 and ATF/CREB) or proteins of signal pathways.[2,3,4] Our laboratory has reported that arachidonic acid metabolism, extracellular signal-related kinases, sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase, 5-lipoxygenase, cyclooxygenase-2, Yes-associated protein (YAP) and long noncoding RNA highly upregulated in liver cancer (HULC) are involved in the HBx-induced hepatoma.[5,6,7,8] Therapeutically, HBx is an important target for HBV-induced HCC. Several reports have demonstrated that Lin28A is able to bind to a crowd of mRNAs, including the mRNAs of IGF-2, Oct[4] and several cell cycle-related factors, to regulate their translation.[9,10,11,12,13] In addition, Lin28A can bind to the terminal loops of the precursor of the let-7 family microRNAs and blocks their processing into mature form.[14,15]
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