Matrix Stiffness Promotes Invasion and Metastasis of Hepatocellular Carcinoma via a New Mechanoresponsive SCD1/HMMR Pathway

ABSTRACT Hepatocellular carcinoma (HCC) almost exclusively develops in the context of liver fibrosis or cirrhosis, both of which are characterized by increased matrix stiffness. Matrix stiffness promotes HCC invasion and metastasis via upregulation of stearoyl‐CoA desaturase 1 (SCD1). However, the downstream effector of the SCD1‐dependent mechanoresponsive pathway remains unclear. HCC cells were grown on mechanically tunable polyacrylamide gels in 2% Matrigel‐supplemented culture media and subjected to the in vitro invasion assay. The key molecule that responded to matrix stiffness was identified. The underlying mechanism by which the molecule participated in in vitro matrix stiffness‐induced invasion and in vivo metastasis was explored. High matrix stiffness caused an increase in hyaluronan‐mediated motility receptor (HMMR) expression, which enhanced the invasion of HCC cells in vitro and augmented the response of HCC cells to the HMMR ligand hyaluronic acid. Stiffness‐dependent HMMR upregulation occurred through integrin β1 and a positive feedback loop that included focal adhesion kinase (FAK)/SCD1/oleic acid (OA)/CCAAT‐enhancer binding protein α (C/EBPα). HMMR knockdown significantly inhibited high matrix stiffness‐induced HCC cell invasion in vitro and suppressed HCC metastasis in vivo. In human HCC samples, the combination of collagen content, a surrogate for increased matrix stiffness, and increased HMMR expression predicted poor survival of HCC patients. We define a new mechanotransduction axis of SCD1/HMMR that enhances HCC invasion and metastasis in response to increased matrix stiffness, providing a new therapeutic target against stiffness‐driven HCC invasion and metastasis.