Matrix stiffness-related extracellular matrix signatures and the DYNLL1 protein promote hepatocellular carcinoma progression through the Wnt/β-catenin pathway

Abstract

Abstract Background In hepatocellular carcinoma (HCC) treatment, first-line targeted therapy in combination with immune checkpoint inhibitors (ICIs) has improved patient prognosis, but the 5-year survival rate is far from satisfactory. Studies have shown that the extracellular matrix (ECM) is an essential part of the tumour microenvironment (TME) and participates in the progression of malignant tumours. ECM remodelling can enhance matrix stiffness in cirrhosis patients, induce an immunosuppressive microenvironment network, and affect the efficacy of targeted therapies and ICIs for treating HCC. However, the exact mechanism is still unclear. Methods We downloaded data from public databases, selected differentially expressed ECM proteins associated with matrix stiffness, constructed and validated a prognostic model of HCC using Lasso Cox regression, and investigated the roles and mechanism of one of the ECM proteins, dynein light chain LC8-type 1 (DYNLL1), in HCC proliferation, migration, and apoptosis via in vitro experiments. Results In this study, the risk score of the matrix stiffness-related ECM protein model effectively predicted the prognosis of HCC patients. The high- and low-risk subgroups of the model also showed differences in immune cells, immune functions, and drug sensitivity. DYNLL1 promoted HCC cell progression and migration and inhibited HCC cell apoptosis through the Wnt/β-catenin pathway in vitro. Conclusion The expression of matrix stiffness-related ECM proteins could be an independent predictor of HCC prognosis. DYNLL1, an oncogenic gene in HCC, has the potential to be a new target for HCC treatment.

Keywords

• Hepatocellular carcinoma
• Matrix stiffness
• Extracellular matrix proteins
• Prognostic model
• DYNLL1
• Wnt/β-catenin pathway