Decreased αGlcNAc glycosylation in biliary tract cancer progression from BilIN to invasive adenocarcinoma

Decreased αGlcNAc glycosylation in biliary tract cancer progression from BilIN to invasive adenocarcinoma:

Abstract

Biliary tract cancer (BTC) is lethal due to difficulty of diagnosis at an early stage. Thus novel biomarkers of BTC precursors are necessary. Biliary intraepithelial neoplasia (BilIN) is a major precursor of BTC and is classified as low and high grade based on cell atypia. In normal gastric mucosa, gastric gland mucin specific O‐glycans are unique in having α1,4‐linked N‐acetylglucosamine (αGlcNAc) attached to MUC6. Previously, we reported that αGlcNAc functions as a tumor suppressor of differentiated‐type gastric adenocarcinoma and decreased αGlcNAc glycosylation on MUC6 in gastric, pancreatic and uterine cervical neoplasms occurs in cancer as well as in their precursor lesions. However, αGlcNAc and MUC6 expression patterns in biliary tract neoplasms remained unclear. Here we analysed MUC5AC, MUC6 and αGlcNAc expression status in 51 BTC cases and compared expression of each with progression from low‐grade BilIN to invasive adenocarcinoma (IAC). The frequency of αGlcNAc‐positive and MUC6‐positive lesions decreased with tumor progression. When we compared each marker expression levels with tumor progression, we found that the MUC6 expression score in IAC was significantly lower than in low‐ or high‐grade BilIN (P < 0.001 or P < 0.01, respectively). However, the αGlcNAc expression score was low irrespective of histological grade, and also lower than that of MUC6 across all histological grades (P < 0.001 for low‐ and high‐grade BilIN, and P < 0.01 for IAC). These results suggest that decreased expression of αGlcNAc relative to MUC6 marks the initiation of BTC progression.