Hepatitis B virus X protein upregulates Lin28A/Lin28B through Sp-1/c-Myc to enhance the proliferation of hepatoma cells

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.

MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma

“…Several studies, however, have reported that MYC, a family member of MYCN, can directly induce LIN28B expression via binding to an E-box sequence in its promoter region [27,28], and a similar mode of action for MYCN has been proposed [9,29]. To verify whether MYCN indeed binds the LIN28B promoter region and activates its transcription, we have evaluated direct interaction in the MYCN3 cell line, a neuroblastoma model of doxycycline-inducible MYCN overexpression.…”

MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR

“…As a heterogeneous tumor, HCC develops through the activation of multiple pathways and molecular alterations [24,25] . The development and progression of HCC is a complicated process that involves the deregulation of multiple genes that are essential to cellular biological processes.…”

Lin28b Is Sufficient to Drive Liver Cancer and Necessary for Its Maintenance in Murine Models

“…Gain and loss of function studies in cancer cell lines have established that Lin28 can promote growth, invasion, and metastasis (Guo et al, 2006; Liang et al, 2010; Wang et al, 2010; You et al, 2013). Transgenic Lin28b overexpression leads to lymphoma and neuroblastoma development in mice, suggesting that in particular contexts Lin28b is alone sufficient to drive cancer (Beachy et al, 2012; Molenaar et al, 2012).…”