Reciprocal Interaction of Wnt and RXR-α Pathways in Hepatocyte Development and Hepatocellular Carcinoma

Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal development. We found a major shift in expression of Wnt and RXR-α pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-α gene signature categorized HCCs into two subtypes (high Wnt, low RXR-α and low Wnt, high RXR-α), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-α levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-α achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-α, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.

人类肝细胞癌（hepatocellular carcinoma, HCC）的基因组分析往往会受到起源肝细胞分化状态的混杂干扰。本研究整合了具有明确起源细胞的小鼠HCC基因组分析数据与正常发育过程的相关组学数据，发现肝母细胞向肝细胞转化的过程中，Wnt通路与视黄醇X受体α（RXR-α）通路基因的表达发生显著改变——Wnt通路基因表达上调，而RXR-α通路基因表达下调，该变化与细胞转化过程同步发生。结合Wnt与RXR-α的基因特征，可将HCC划分为两个亚型：高Wnt、低RXR-α亚型，以及低Wnt、高RXR-α亚型，这两类亚型分别匹配小鼠模型中的起源细胞特征与人类HCC的分化状态。在肝细胞中抑制RXR-α的表达水平，可增强Wnt信号通路活性并提升致瘤性；而通过配体激活RXR-α则会产生相反的效应。本研究结果证实，HCC存在两种主要亚型，其与肝细胞分化程度密切相关；RXR-α可通过部分调控Wnt信号通路，在肝细胞样亚型中发挥关键功能，有望成为选择性治疗靶点。