Role of caveolin-1 in hepatocellular carcinoma arising from non-alcoholic fatty liver disease

The molecular features of hepatocellular carcinoma arising from non-alcoholic fatty liver disease (NAFLD-HCC) are not well known. In this study, we investigated the mechanism by which NAFLD-HCC survives in a fat-rich environment. We found that caveolin (CAV)-1 was overexpressed in clinical specimens from NAFLD-HCC patients. HepG2, HLE, and HuH-7 HCC cell lines showed decreased proliferation in the presence of the saturated fatty acids palmitic acid and stearic acid, although only HLE cells expressed high levels of CAV-1. HLE cells treated with oleic acid (OA) showed robust proliferation, whereas CAV-null HepG2 cells showed reduced proliferation and increased apoptosis. CAV-1 knockdown in HLE cells attenuated the OA-induced increase in proliferation and enhanced apoptosis. Liquid chromatography-tandem mass spectrometry analysis revealed that the levels of OA-containing ceramide, a pro-apoptotic factor, were higher in HepG2 and CAV-1-deficient HLE cells than in HLE cells, suggesting that CAV-1 inhibits apoptosis by decreasing the level of OA-containing ceramide. These results indicate that CAV-1 is important for NAFLD-HCC survival in fatty acid-rich environments and is a potential therapeutic target. The aim of this study is to identify an important factor in HCC developing from NAFLD (NAFLD-HCC) and to elucidate its function. Human HCC tissues and the adjacent non-HCC tissues were separately excised from the resected specimens from 3 NAFLD-HCC patients and 3 patients with HCC arising from hepatitis C (HCV-HCC). Samples were snap-frozen with RNA later (Applied Biosystems, Grand Island, NY) in liquid nitrogen and stored at -80℃. Total RNA was extracted from the frozen resected sample using an RNeasy Mini Kit (Quiagen, Valencia, CA, USA). The intensity and quantity of total RNA was assessed with a Nanodrop ND-1000 spectrometer (Nanodrop Technologies, Wilmington, DE, USA). The gene expression profile of HCV-HCC and NAFLD-HCC was determined by Affymetrix Gene Chip Human Gene 2.0 ST array.