Battling IL-17, the troublemaker in alcohol-induced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide.1 The primary risk factors for HCC include chronic hepatitis B and C viral infections, non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver diseases (ALD). While recent clinical advances have considerably improved the management of HBV/HCV-driven liver diseases, both NAFLD and ALD are expected to increase the global burden of HCC significantly.1 Though NAFLD and ALD share similar histological features, ALD is the main cause of liver-related mortality worldwide.2 A recent large epidemiological study published in the Lancet and the clinical practice guidelines of the Latin American Association of the Study of the Liver (ALEH) have suggested that light-to-moderate consumption of alcohol, also by patients with NAFLD, increases all-cause mortality, most likely because of HCC development.3,4

Alcohol is metabolized in hepatocytes by 2 enzymes – alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH2) – whereby ADH metabolizes alcohol into highly toxic and carcinogenic acetaldehyde which is further metabolized by ALDH2 into acetate and then into carbon dioxide and water. A deficiency or polymorphism in ALDH2 has been shown to associate with an increasing risk of alcohol-associated HCC development. This results from the secretion of oxidized mitochondrial DNA-enriched extracellular vesicles by hepatocytes; these vesicles subsequently promote reactive oxygen species production and trigger multiple oncogenic pathways.5 Furthermore, exome sequencing analysis of liver tissues from patients with alcohol-induced HCC revealed alcohol-specific mutational signatures driving HCC.6 Intriguingly, acetaldehyde interferes with transcription factors – sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors that are also involved in lipid metabolism. Particularly, it has been shown that SREBP1/2 is activated by S1P, which is triggered by increased endoplasmic reticulum (ER)-stress and tumor necrosis factor (TNF) signaling.7 Consequently, SREBP1/2 activation leads to the augmented production and accumulation of fatty acids and cholesterol in hepatocytes: a hallmark of steatosis and the high energy demands of tumor progression.

Best Regards
Sarah Jhonson
Managing Editor
International Journal of Case Reports
Email: caserep@emedicalsci.org