Objective

Hepatitis B virus (HBV) infection causes liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC) development, but the underlying mechanism remains poorly understood. This study aimed to investigate the roles and molecular mechanisms of Dystrobrevin-α (DTNA) in HBV-induced liver cirrhosis and HCC pathogenesis.

Methods

DTNA expression was bioinformatically analyzed using the GEO database. DTNA expression was silenced by transfection with shRNAs. Cell proliferation and apoptosis were evaluated by MTT and flow cytometry respectively. The expression of genes in mRNA or protein levels was assessed by quantitative RT-PCR and western blotting. The interaction between proteins was predicted with the String and GCBI online softwares, and then confirmed by co-immunoprecipitation. Animal models were established by injecting nude mice with AVV8-HBV1.3 vector.

Results

Bioinformatics analysis showed a significantly increase in DTNA expression in HBV-positive liver cirrhosis and HCC patients. HBV infection caused a significantly increase in DTNA expression in HCC cell lines HepAD38 and HepG2.2.15. DTNA knockdown suppressed proliferation and promoted apoptosis of HBV-infected HepAD38 and HepG2.2.15 cells. HBV induced elevated expression of fibrosis-related genes Collagen II and TGFβ1 in LO-2 cells, which were suppressed by DTNA knockdown. DTNA directly binded with STAT3 protein to promote STAT3 phosphorylation and TGFβ1 expression and repress P53 expression in HBV-infected HepAD38 and LO-2 cells. The DTNA/STAT3 axis was activated during HBV-induced fibrosis, cirrhosis and HCC development in mouse model.

Conclusion

DTNA binds with and further activates STAT3 to induce TGFβ1 expression and repress P53 expression, thus promoting HBV-induced liver fibrosis, cirrhosis and hepatocellular carcinoma progression.

中文翻译：

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DTNA通过激活STAT3并调节TGFβ1和P53信号传导来促进HBV诱导的肝癌进展。

目的

乙型肝炎病毒（HBV）感染可导致肝纤维化，肝硬化和肝细胞癌（HCC）的发展，但其潜在机制仍知之甚少。本研究旨在探讨dystrobrevin-α（DTNA）在HBV诱导的肝硬化和HCC发病机理中的作用和分子机制。

方法

使用GEO数据库对DTNA表达进行生物信息学分析。通过shRNA转染使DTNA表达沉默。通过MTT和流式细胞术分别评估细胞增殖和凋亡。通过定量RT-PCR和蛋白质印迹法评估mRNA或蛋白质水平中基因的表达。用String和GCBI在线软件预测蛋白质之间的相互作用，然后通过共免疫沉淀法进行确认。通过向裸鼠注射AVV8-HBV1.3载体建立动物模型。

结果

生物信息学分析显示，在HBV阳性肝硬化和HCC患者中，DTNA的表达显着增加。HBV感染导致HCC细胞系HepAD38和HepG2.2.15中DTNA的表达显着增加。DTNA组合体抑制HBV感染的HepAD38和HepG2.2.15细胞的增殖并促进其凋亡。HBV诱导LO-2细胞中与纤维化相关的胶原II和TGFβ1基因的表达升高，这被DTNA抑制所抑制。DTNA直接与STAT3蛋白结合，从而促进HBV感染的HepAD38和LO-2细胞中STAT3磷酸化和TGFβ1表达，并抑制P53表达。DTNA / STAT3轴在小鼠模型中由HBV诱导的纤维化，肝硬化和HCC形成过程中被激活。

结论

DTNA与STAT3结合并进一步激活STAT3以诱导TGFβ1表达并抑制P53表达，从而促进HBV诱导的肝纤维化，肝硬化和肝细胞癌的进展。