Liu Qianqian, Wang Junhua, Sun Huizi, Zhang Zhenhua, Wang Hong, Ma Shuai, Zhang Chenxi, Wang Qianqian, Cai Guodi, Zheng Jianwei, Nie Yichu, Liu Peiqing, Wang Junjian
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China.
Clinical Research Institute, The First People's Hospital of Foshan, Foshan 528000, China.
Mol Ther. 2024 Mar 6;32(3):749-765. doi: 10.1016/j.ymthe.2024.01.032. Epub 2024 Feb 3.
Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), highlighting an essential role of ECM in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. Elevated RORγ increases fibronectin-1 deposition, cell-matrix adhesion, and collagen production, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player of ECM remodeling in HCC and as an attractive therapeutic target for advanced HCC.
大约80%-90%的肝细胞癌（HCC）发生在纤维化和细胞外基质（ECM）异常的癌前环境中，这突出了ECM在HCC肿瘤发生和进展中的重要作用。然而，HCC中ECM的决定因素尚不清楚。在此，我们表明核受体RORγ在HCC肿瘤中高表达且扩增。RORγ通过直接驱动HCC细胞中主要ECM基因的表达，作为基质程序的关键激活因子发挥作用。RORγ升高会增加纤连蛋白-1沉积、细胞-基质黏附以及胶原蛋白生成，从而创造一个有利于促进肝癌转移的微环境。此外，RORγ拮抗剂在多种HCC异种移植模型和免疫健全模型中有效抑制肿瘤生长和转移，并且它们能有效使HCC肿瘤对小鼠的索拉非尼治疗敏感。值得注意的是，RORγ表达升高与HCC患者的ECM重塑和转移相关。综上所述，我们确定RORγ是HCC中ECM重塑的关键因素，也是晚期HCC的一个有吸引力的治疗靶点。
