Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma

• Determination of AGR3 expression in liver cancer
• AGR3 is specific and sensitive marker of intrahepatic cholangiocarcinoma.
• AGR3 is associated with acid mucopolysaccharides in intrahepatic cholangiocarcinoma.
• Combined detection of AGR3 and GPC3 improves diagnostics of liver cancer.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer next to hepatocellular carcinoma (HCC). Despite the significant difference of the therapeutic strategy for both diseases, their histological appearance may be very similar. Thus the correct diagnosis is crucial for treatment choice but is often difficult to achieve. The aim of our study was to evaluate anterior gradient 3 (AGR3) as a new diagnostic marker helping to distinguish between ICC and HCC. AGR3 is a putative transmembrane protein implicated in breast, prostate and ovary tumorigenesis and belongs to the family of protein disulfide isomerases.Since there is little information on how AGR3 is expressed in normal and diseased tissues and what its exact function is, we analyzed its expression pattern in normal liver and tumor tissue of ICC and HCC. The immunohistochemical analysis in normal tissue revealed specific AGR3 expression in intrahepatic bile duct cholangiocytes which was not present in liver hepatocytes. Consequently we analyzed AGR3 expression in 74 representative samples of puncture biopsies, tissue excisions and resection specimens from which 48 samples were diagnosed as HCC and 26 as ICC. Our results showed AGR3 expression negative and weakly positive respectively in hepatocellular carcinomas compared to stronger AGR3 positivity in cholangiocellular carcinomas. AGR3 expression statistically significantly correlated to acid mucopolysaccharide expression and negatively correlated to glypican-3 expression. We conclude that according to receiver operating characteristics (ROC) analysis AGR3 expression is relatively specific for ICC and is potentially linked to mucosecretion, which may indicate potential implication in treatment resistance.