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/β‐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 the membrane lipid composition of six different HCC cell lines with mutations in components of Wnt/β‐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 treatment. DAG and ceramide enhanced Wnt/β‐catenin signaling by inducing caveolin‐mediated endocytosis of the canonical Wnt‐receptor complex, while their depletion suppressed the signaling activity along with a reduction of caveolin‐mediated endocytosis in SNU475 and HepG2 cells. Moreover, depletion of DAG and ceramide 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.

Causal Relationship Between Plasma Lipidome and Six Types of Cancer: A Mendelian Randomization Study

“…Following Wnt3a treatment, diacylglycerol and ceramide are downregulated on the membrane of hepatic cancer cells. Both can influence the Wnt signaling pathway, and their significant depletion can impede tumor cell growth and proliferation [21]. Phosphatidylethanolamine (34:2), phosphatidylcholine (34:0), phosphatidylcholine (37:1), and triacylglycerol (56:4) play intermediary roles in the relationship between bisphenol A and colorectal cancer, offering better insights into the causative factors of colorectal cancer development [22].…”

Early monitoring values of oncogenic signalling molecules for hepatocellular carcinoma

“…The over-expression of some members in the Wingless (Wnt)/β-catenin pathway is related to HCC occurrence or progression[ 46 , 47 ]. Cancer-associated Wnt molecules regulate a variety of cellular events, such as cell proliferation, apoptosis, differentiation and HCC growth, via β-catenin-dependent classical or non-classical pathways[ 48 , 49 ].…”