HBx-FXR signaling相关LncRNA在原发性肝癌中的作用及机制研究

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with high prevalence and lethality. Chronic hepatitis B virus (HBV) infection is a major risk factor for HCC in China. The underlying mechanism for HBV(+) HCC has not been entirely elucidated. Recent our study showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR-responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx–FXR interaction was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down assays, and the FXR activation function 1 domain was mapped to bind to the third a helix in the C terminus of HBx. We also found that the C-terminally truncated variants of HBx, which were found in clinical HCC,were not effective at transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis. However, how HBV/HBx-FXR signaling impacts hepatocarcinogenesis remains unclear. Long non-coding RNAs (lncRNA) are critical regulators of gene expression, and modulators of cellular processes involved in cellular growth and differentiation, and thereby contribute to tumorigenesis. So, we propose that C-terminal truncated HBx can regulated HBx-FXR signaling, and (HBx-FXR signaling) related lncRNAs-miRNA-mRNA(CeRNA) may provide potential novel mechanism to find some new HCC susceptibility genes in hepatocarcinogenesis.

HBV病毒感染是我国原发性肝细胞癌(Hepatocellular Carcinoma,HCC)发生的主要危险因素。我们最新发现，HBx是FXR的Co-Factor；HBx与FXR的AF1 结构域结合并调控 FXR signaling。In vivo水平，FXR缺失促进HBx诱导HCC发生。我们提出HBx-FXR signaling与HBV(+)HCC相关； HCC中，HBx-FXR signaling如何发挥FXR的保护功能？机制不清。我们通过RNA Seq初步发现自发HCC小鼠肝组织中HBx-FXR signaling相关LncRNA表达异常。综上，本课题拟以HBx截短体-(HBx-FXR signaling)-(LncRNA-miRNA-mRNA)-HCC易感基因-HCC为主线，深入探讨HBx在HBV（+）HCC的分子机制，以期在乙肝病毒致HCC“非DNA整合、重组”理论方面取得进展。

HBV病毒感染是我国原发性肝细胞癌(Hepatocellular Carcinoma,HCC)发生的主要危险因素。我们前期提出全长HBx可通激活FXR signaling参与HCC发生，但考虑到截短HBx的存在以及HCC中FXR低表达或缺失表达，在肝组织失去FXR signaling保护下，全长HBx及截短HBx在HCC中功能如何？是否有LncRNA参与，均不得而知。我们的细胞、动物模型等结果提示截短HBx可影响HBx-FXR signaling、干扰机体代谢，并通过影响病毒等过程参与HCC发生、发展。