ROR? modulates the extracellular matrix to facilitate hepatocellular carcinoma growth and metastasis

Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), predicting an essential role of abnormal matrix in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor ROR? is highly expressed and amplified in HCC tumors. ROR? functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. The elevated ROR? increased Fibronectin-1 deposition, cell-matrix adhesion, collagen production and cross-linkling, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, ROR? antagonists effectively inhibit tumor growth and metastasis via ECM remodeling in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, the elevated ROR? expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify ROR? as a key player in HCC progression by remodeling ECM and as an attractive therapeutic target for advanced HCC. Overall design: RNA-Seq in two conditions were investigated: (1) control HepG2 cells, (2) HepG2 cells treated with ROR? antagonists GSK805 (10µM).