Abstract
Abnormal expression of dermatan sulfate epimerase (DSE) has been found in many types of cancer, while its expression and biological functions in hepatocellular carcinoma (HCC) progression remains obscure. Here we report that DSE, the enzyme that catalyzes the conversion of chondroitin sulfate (CS) to dermatan sulfate (DS), is a critical mediator of malignant character in HCC, through regulation of CCL5 signaling. DSE mRNA and protein were downregulated frequently in HCC tumors, where these events were associated with advanced tumor stages, metastases, and poor survival. DSE-mediated tumor growth was evaluated in immune-deficient and immune-complement mice models. Restoring DSE expression in HCC cells suppressed tumor growth, as well as decreased IL-1β and CCL5 levels in transplanted tumor tissue. Mechanistic investigations revealed that the expression of DSE altered CCL5 signaling and cell surface binding in HCC cells. Accordingly, DSE suppressed CCL5-induced cell growth, migration, and invasion, whereas silencing of DSE enhanced CCL5-triggered malignant phenotypes. Inhibiting CCR1 activity with BX471 decreased CCL5-induced malignant characters caused by siRNA-mediated knockdown of DSE in HCC cells, establishing the critical role of the CCL5/CCR1 axis in mediating the effects of DSE expression. Taken together, our results suggest that DSE dysregulation contributes to the malignant behavior of HCC cells. This provides novel insight into the significance of DSE in CCL5 signaling and HCC pathogenesis.