Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases

Abstract

Long-chain fatty acyl CoA synthetases (ACSLs) activate fatty acids by CoA addition thus facilitating their intracellular metabolism. Dysregulated ACSL expression features in several cancers and can affect processes such as ferroptosis, fatty acid β-oxidation, prostaglandin biosynthesis, steroidogenesis and phospholipid acyl chain remodelling. Here we investigate long chain acyl-CoA synthetase 3 (ACSL3) and long chain acyl-CoA synthetase 4 (ACSL4) expression in liver malignancies. The expression and subcellular localisations of the ACSL3 and ACSL4 isoforms in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA) and hepatic metastases were assessed by immunohistochemical analyses of multiple tumour tissue arrays and by subcellular fractionation of cultured HepG2 cells. The expression of both enzymes was increased in HCC compared with normal liver. Expression of ACSL3 was similar in HCC and hepatic metastases but lower in healthy tissue. Increased ACSL3 expression distinguished HCC from CCA with a sensitivity of 87.2% and a specificity of 75%. ACSL4 expression was significantly greater in HCC than in all other tumours and distinguished HCC from normal liver tissue with a sensitivity of 93.8% and specificity of 93.6%. Combined ACSL3 and ACSL4 staining scores distinguished HCC from hepatic metastases with 80.1% sensitivity and 77.1% specificity. These enzymes had partially overlapping intracellular distributions, ACSL4 localised to the plasma membrane and both isoforms associated with lipid droplets and the endoplasmic reticulum (ER). In conclusion, analysis of ACSL3 and ACSL4 expression can distinguish different classes of hepatic tumours.

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

“…Interestingly, ACSL4 and ALOX5 were found to be significantly up-regulated in HCC patients with high CIFI values, even though they facilitate the execution of ferroptosis ( Liu et al, 2015 ; Yuan et al, 2016 ; Doll et al, 2017 ). However, it is worth noting that both ACSL4 and ALOX5 are over-expressed in HCC as compared to normal livers, and promote the progression of the disease ( Xu et al, 2011 ; Chen et al, 2020 ; Ndiaye et al, 2020 ; Wang et al, 2020 ). Thus, the over-expression of ACSL4 and ALOX5 contributes to the proliferation and progression of HCC, but renders the patients more susceptible to ferroptosis inducers.…”

Heat Shock Protein Beta 1 is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma

“… 31 , 32 Studies have shown that ferroptosis participates in tumor immunoregulation. 9 , 33 Ferroptosis plays a vital role in anti-tumor immunotherapy. However, there are few studies on the association between HSPB1 and immunocytes in HCC.…”

Discovery and validation of novel protein markers in mucosa of portal hypertensive gastropathy

“…Other validated proteins, though not enriched in the two pathways mentioned above, also play a role in the process of liver and gastrointestinal diseases. CPT1A and ACSL3, which are responsible for fatty acid oxidation, have been proved to stimulate gastric cancer and hepatocellular carcinoma cell growth and migration [ 34 – 36 ]. MCAM (CD146) involves in actin cytoskeleton rearrangement, blood vessel endothelial cells remodeling and intercellular junction [ 37 ].…”