Department and Graduate Institute of Medical Microbiology, National Taiwan University, 100 Taipei, Taiwan.
Graduate Institute of Clinical Oncology, National Taiwan University, 100 Taipei, Taiwan.
Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6717-6725. doi: 10.1073/pnas.1918028117. Epub 2020 Mar 5.
Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin-depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.
大多数肝细胞癌 (HCC) 发生在慢性肝炎患者中，这为门脉周围区域肝祖细胞 (HPC) 的生长和随后 HCC 的发展创造了一个微环境。我们在肝条件性β-catenin 敲除小鼠模型中研究了炎症肝脏对这一发病过程的信号。老年小鼠中衰老的β-catenin 耗尽的肝细胞会产生炎症微环境，刺激门脉周围 HPC 扩增，但阻止其分化，使小鼠易发生肝肿瘤。从炎症龛位中的巨噬细胞中释放的补体 C1q 被确定为激活门脉周围 HPC 中β-catenin 途径的非常规信号，负责其扩增和去分化。C1q 抑制剂阻断了扩增的 HPC 中和肝肿瘤中的β-catenin 途径，但在中央周围正常肝细胞中保留了其经典途径。这一机制已在慢性肝炎患者的人类肝标本中得到验证。总之，这些结果表明，C1q 介导的门脉周围 HPC 中β-catenin 途径的激活是在炎症肝脏中补充肝细胞的先前未被认识的机制，如果不加控制，可能会促进肝癌的发生。C1q 可能成为阻断慢性肝炎患者癌变的新靶点。
