BINA receptor HCC is one of the most prevalent malignant tum
HCC is one of the most prevalent malignant tumors and a leading cause of cancer-related death, globally [, , ]. Hepatitis B virus (HBV) infection is closely related to the development of liver diseases [, , , ]. More than 350 million people are chronically infected with HBV worldwide, and of these, about one-third develop severe HBV-related complications [, , ]. Upon HBV infection, cccDNA, which harbors a chromatin-like structure, dwells in the nuclei of infected cells. There, cccDNA serves as a template for the transcription of all viral RNAs, and thus, it sustains viral persistence [, , ]. The DNA cytidine deaminases, APOBEC3A (termed A3A) and APOBEC3B (termed A3B), are responsible for the deamination (i.e., destruction) of HBV cccDNA [24,25]. The interactions between HBV and host factors play crucial roles in the development of HCC . However, the effect of lncRNAs on HBV is unclear.
Material and methods
Discussion HULC was the first identified lncRNA that was specifically overexpressed in liver cancer . We previously reported that HULC played pivotal roles in aberrant lipid metabolism and tumor angiogenesis in HCC [8,10]. The interplay between HBV and host factor plays vital roles in the development of hepatoma. However, the significance of HULC in HBV-related HCC is poorly understood. In this study, we investigated the mechanism underlying the HULC enhancement of hepatocarcinogenesis in HBV-related-HCC. We first observed that HULC could activate HBV replication in hepatoma cells. It has been known that the BINA receptor deaminization activity of APOBEC3A or APOBEC3B is essential for inducing cccDNA degradation . Strikingly, we demonstrated that HULC was able to maintain the stability of HBV cccDNA by down-regulating APOBEC3B. We showed that HULC increased miR-539 -expression, which targeted the APOBEC3B mRNA 3′UTR. It was previously reported that HULC might act as an endogenous sponge, which down-regulated the miR-372 and miR-107 [8,9]. Moreover, our previous data showed that HULC suppressed the miR-9 by inducing CpG island methylation of the miR-9 promoter . It has been reported that HBx constitutively enhances tyrosine phosphorylation on STAT3 . Here, our data revealed that HULC elevated HBx, which transcriptionally co-activated STAT3 to activate the miR-539 promoter. Functionally, we demonstrated that HULC could activate HBV replication by HBx/miR-539/APOBEC3B signaling, leading to the growth of hepatoma cell in vitro and in vivo. To better understand the effect of HBV on gene expression, we profiled HBV-modulated genes with cDNA microarrays. Our data showed that HBV globally affected cellular gene expression. HBV is known to be a key driver in hepatocarcinogenesis. However, the deletion of APOBEC3B might promote persistent HBV infection, and therefore, increases the risk of developing HCC . In this study, we found that APOBEC3B reduced the growth of HBV-expressing hepatoma cells in vitro and in vivo. It suggests that APOBEC3B may serve as a potential tumor suppressor in HBV-related HCC. Thus, we conclude that HULC is able to activate HBV by HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related HCC. Previous studies showed that antiviral treatments for viral hepatitis appeared to reduce the risk of HCC in patients chronically infected with HBV [34,35]. In this study, we failed to observe that ETV and LdT could affect the expression of HULC, miR-539 or APOBEC3B in HBV-expressing hepatoma cells. It implies that no-response to the HULC/miR-539/APOBEC3B signaling might contribute to the failure of nucleos(t)ide analogues in eliminating HBV. Therapeutically, HULC may serve as a therapeutic target for HCC. However, the detailed mechanism by which HULC modulates HBV cccDNA is not well documented, largely due to the lack of animal models that reproduce clinical HBV-associated HCC. Overall, our finding suggests that the interaction between host factors and HBV plays a crucial role in hepatocarcinogenesis.