Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China.
Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China.
Virol Sin. 2023 Oct;38(5):680-689. doi: 10.1016/j.virs.2023.06.004. Epub 2023 Jun 17.
Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.
慢性乙型肝炎病毒（HBV）感染是肝细胞癌（HCC）的主要病因之一。HBV 基因组容易发生突变，几种变异与肝病的恶性转化密切相关。G1896A 突变（核苷酸 1896 处的 G 突变为 A）是 HBV 前核心区最常见的突变之一，可阻止 HBeAg 的表达，并与 HCC 强烈相关。然而，这种突变导致 HCC 的机制尚不清楚。在这里，我们探讨了 G1896A 突变在 HBV 相关 HCC 中的功能和分子机制。G1896A 突变显著增强了 HBV 在体外的复制。此外，它增加了肿瘤的形成并抑制了肝癌细胞的凋亡，降低了 HCC 对索拉非尼的敏感性。从机制上讲，G1896A 突变可以激活 ERK/MAPK 通路，增强 HCC 细胞对索拉非尼的耐药性，并增强细胞的存活和生长。总之，我们的研究首次表明，G1896A 突变在加剧 HCC 严重程度方面具有双重调节作用，并为治疗 G1896A 突变相关 HCC 患者提供了一些思路。
