Decreased alpha‐1,4‐linked N‐acetylglucosamine glycosylation in biliary tract cancer progression from biliary intraepithelial neoplasia to invasive adenocarcinoma

Abstract

Biliary tract cancer (BTC) is typically lethal due to the difficulty of early stage diagnosis. Thus, novel biomarkers of BTC precursors are necessary. Biliary intraepithelial neoplasia (BilIN) is a major precursor of BTC and is classified as low or 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 that 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 have remained unclear. Here, we analyzed MUC5AC, MUC6, and αGlcNAc expression status in 51 BTC cases and compared the 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’s expression level with tumor progression, we found that the MUC6 expression score in IAC was significantly lower than in low‐grade 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‐grade 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.

Decreased Gastric Gland Mucin-specific <i>O</i>-glycans Are Involved in the Progression of Ovarian Primary Mucinous Tumours

“…Because decreased αGlcNAc expression was also observed in benign lesions, such a decrease may occur during the very early stage of tumour progression. This phenomenon was also observed in IPMN-IPMNAIC, PanIN-IDAC, BilIN-IAC, and LEGH-GAS sequences [10,11,17]. We have previously reported that gastric adenocarcinoma develops spontaneously in A4gnt-deficient mice [5].…”

“…MUC6 and αGlcNAc expression was reduced with OPMT progression. The phenomenon was also observed in IPMN-IPMNAIC and PanIN-IDCA sequences in pancreatic tumours [10], the BilIN-IAC sequence in biliary tract tumours [11], and the LEGH-GAS sequence in uter-Expression scores of MUC6 and αGlcNAc at each grade of OPMTs. The expression score of αGlcNAc is significantly lower than that of MUC6 at all tumour grades.…”

“…Moreover, the decreased expression of αGlcNAc was more remarkable than that of MUC6. A decrease in αGlcNAc has been observed in IPMN-IPMNAIC, PanIN-IDAC, BilIN-IAC, and LEGH-GAS sequences [10,11,17]. Semiquantitative analysis of αGlcNAc and MUC6 immunoreactivity showed that αGlcNAc expression relative to MUC6 expression was significantly decreased at all grades.…”

“…In fact, αGlcNAc expression is frequently lost in MUC6-positive human differentiated type gastric carcinoma [14]. Additionally, αGlcNAc expression is reduced with the progression of tumours that express the gastrictype phenotype, which include pyloric gland adenoma of the stomach, pancreatic lesions [pancreatic intraepithelial neoplasia and invasive ductal adenocarcinoma (PanIN-IDCA) sequence, and intraductal papillary mucinous neoplasms and those with associated invasive carcinoma (IPMN-IPMNAIC) sequence], bile duct lesions [biliary intraepithelial neoplasia and invasive adenocarcinomas (BilIN-IAC) sequence], and uterus cervical lesions [lobular endocervical glandular hyperplasia and gastric-type mucinous carcinoma (LEGH-GAS) sequence] [10,11,16,19].…”

The Abnormal Glycopatterns of Salivary Glycoproteins in Esophageal Squamous Cell Carcinoma Patients

“…Decades of research have demonstrated that aberrant protein glycosylation often occurs in the development of tumors, and it has been shown that specific tumor-associated glycans are expressed in the precursor lesions of different types of cancer, which makes them potentially powerful early diagnosis markers ( Oliveira-Ferrer et al, 2017 ; Liu et al, 2018 ; Okumura et al, 2020 ; Schedin-Weiss et al, 2020 ; Zhang et al, 2020 ). Glycomic and glycoproteomic analysis of blood samples have shown that glycans or glycan profiles could be used as candidate biomarkers to distinguish EC from controls and potential predictors of disease progression ( Yehia et al, 2009 ; Hammoud et al, 2010 ; Mohanty et al, 2012 ; Song et al, 2014 ).…”