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Abstract
Hepatocellular carcinoma (HCC) is the second-leading cause of cancer-related death worldwide, and the factors influencing HCC progression are poorly understood. Here we reveal that HCC progression via induction of epithelial-mesenchymal transition (EMT) is closely associated with the expression of CD36/fatty acid translocase and elevated free fatty acid (FFA) levels. Although obesity is manifested as elevated FFA levels, the degree of EMT was not associated with the body mass index of the patients, highlighting the specific roles of CD36 and FFA uptake. Treatment of human liver cancer cell lines with FFAs exacerbated the EMT phenotype, whereas chemical inhibition of CD36 mitigated these effects. Furthermore, the Wnt and TGF-β signaling pathways were activated upon FFA treatment, potentially acting as upstream activators of the EMT program. These results provide the first direct evidence associating CD36 and elevated FFAs with HCC progression.
Highlights
Expression is increased in hepatocytes from rodent models of diet-induced obesity, which correlated with elevated fatty acid uptake[12,13]
We investigated the association between patient BMI, expression levels of hepatic fatty acid uptake proteins and epithelial-mesenchymal transition (EMT) progression in the TCGA liver cancer dataset
We found that the pair-wise correlations between EMT scores with CD36 (p = 10−4) and FABP4 (p = 10−6) were statistically significant (Fig. 1D, Supplementary Table 2)
Summary
Expression is increased in hepatocytes from rodent models of diet-induced obesity, which correlated with elevated fatty acid uptake[12,13]. In a previous study exploring the lipotoxic pathways activated by saturated FFAs, we reported a synergistic association between abrogation of insulin signaling and loss of desmoplakin protein[14], an obligate component of the desmosomal cell adhesion complex. We investigated the association between obesity and elevated uptake of FFAs with the induction of EMT program in human HCC. Our data suggests that elevated expression of fatty acid uptake proteins including CD36, and not BMI, was associated with EMT progression. Inhibition of CD36 resulted in reduced migration in liver cancer cells, confirming a critical role of the fatty acid uptake protein in the progression of the EMT program
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