Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The HBV encoded oncoprotein, HBx, alters the expression of host genes and the activity of multiple signal transduction pathways that contribute to the pathogenesis of HCC by multiple mechanisms independent of HBV replication. However, it is not clear which pathways are the most relevant therapeutic targets in hepatocarcinogenesis. Short chain fatty acids (SCFAs) have strong anti-inflammatory and anti-neoplastic properties, suggesting that they may block the progression of chronic liver disease (CLD) to HCC, thereby identifying the mechanisms relevant to HCC development. This hypothesis was tested in HBx transgenic (HBxTg) mice fed SCFAs. Groups of HBxTg mice were fed with SCFAs or vehicle from 6 to 9 months of age and then assessed for dysplasia, and from 9 to 12 months of age and then assessed for HCC. Livers from 12 month old mice were then analyzed for changes in gene expression by mass spectrometry-based proteomics. SCFA-fed mice had significantly fewer dysplastic and HCC nodules compared to controls at 9 and 12 months, respectively. Pathway analysis of SCFA-fed mice showed down-regulation of signaling pathways altered by HBx in human CLD and HCC, including those involved in inflammation, phosphatidylinositol 3-kinase, epidermal growth factor, and Ras. SCFA treatment promoted increased expression of the tumor suppressor, disabled homolog 2 (DAB2). DAB2 depresses Ras pathway activity, which is constitutively activated by HBx. SCFAs also reduced cell viability in HBx-transfected cell lines in a dose-dependent manner while the viability of primary human hepatocytes was unaffected. These unique findings demonstrate that SCFAs delay the pathogenesis of CLD and development of HCC, and provide insight into some of the underlying mechanisms that are relevant to pathogenesis in that they are responsive to treatment.

慢性乙型肝炎病毒 (HBV) 感染是肝细胞癌 (HCC) 发展的主要危险因素。HBV 编码的癌蛋白 HBx 通过独立于 HBV 复制的多种机制改变宿主基因的表达和多种信号转导途径的活性，这些信号转导途径有助于 HCC 的发病机制。然而，尚不清楚哪些途径是肝癌发生中最相关的治疗靶点。短链脂肪酸 (SCFA) 具有很强的抗炎和抗肿瘤特性，表明它们可能会阻止慢性肝病 (CLD) 向 HCC 的进展，从而确定与 HCC 发展相关的机制。这一假设在喂食 SCFA 的 HBx 转基因 (HBxTg) 小鼠中得到了测试。HBxTg 小鼠组在 6 至 9 个月大时喂食 SCFA 或载体，然后评估发育不良，然后在 9 至 12 个月大时评估 HCC。然后通过基于质谱的蛋白质组学分析来自 12 个月大小鼠的肝脏的基因表达变化。与对照组相比，SCFA 喂养的小鼠分别在 9 个月和 12 个月时具有显着更少的发育不良和 HCC 结节。对 SCFA 喂养小鼠的通路分析显示，HBx 在人类 CLD 和 HCC 中改变的信号通路下调，包括与炎症、磷脂酰肌醇 3-激酶、表皮生长因子和 Ras 相关的信号通路。SCFA 治疗促进了肿瘤抑制因子、禁用同源物 2 (DAB2) 的表达增加。DAB2 抑制由 HBx 组成性激活的 Ras 通路活性。SCFA 还以剂量依赖性方式降低 HBx 转染细胞系中的细胞活力，而原代人肝细胞的活力不受影响。这些独特的发现表明 SCFA 延迟了 CLD 的发病机制和 HCC 的发展，并提供了对与发病机制相关的一些潜在机制的洞察，因为它们对治疗有反应。