Comparative membrane lipidomics of hepatocellular carcinoma cells reveals diacylglycerol and ceramide as key regulators of Wnt/β-catenin signaling and tumor growth

Abstract

Hepatocellular carcinoma (HCC) is largely associated with aberrant activation of Wnt/{beta}-catenin signaling. Nevertheless, how membrane lipid composition is altered in HCC cells with abnormal Wnt signaling remains elusive. Here, by exploiting comprehensive lipidome profiling, we unravel membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/{beta}-catenin signaling, leading to differences in their endogenous signaling activity. Among the differentially regulated lipids are diacylglycerol (DAG) and ceramide, which were downregulated at the membrane of HCC cells after Wnt3a stimulation. DAG and ceramide enhanced Wnt/{beta}-catenin signaling in SNU475 and HepG2 cells. In contrast, depletion of DAG and ceramide suppressed Wnt/{beta}-catenin signaling and significantly impeded the proliferation, tumor growth and in vivo migration capacity of SNU475 and HepG2 cells. This study, by pioneering plasma membrane lipidome profiling in HCC cells, exhibits the remarkable potential of lipids to correct dysregulated signaling pathways in cancer and stop abnormal tumor growth.