Abstract
Mucin-type O-glycans are involved in cancer initiation and progression, although details of their biological and clinicopathological roles remain unclear. The aim of this study was to investigate the clinicopathological significance of β1,3-N-acetylglucosaminyltransferase 6 (β3Gn-T6), an essential enzyme for the synthesis of core 3 O-glycan and several other O-glycans in pancreatic ductal adenocarcinoma (PDAC). We performed immunohistochemical and lectin-histochemical analyses to detect the expression of β3Gn-T6 and several O-glycans in 156 cases of PDAC with pancreatic intraepithelial neoplasias (PanINs) and corresponding normal tissue samples. The T antigen, Tn antigen, sialyl Lewis X (sLeX) antigen, and sLeX on core 2 O-glycan were more highly expressed in PDAC cells than in normal pancreatic duct epithelial cells (NPDEs). Conversely, the expression of 6-sulfo N-acetyllactosamine on extended core 1 O-glycan was found in NPDEs and was low in PDAC cells. These glycan expression levels were not associated with patient outcomes. β3Gn-T6 was expressed in ~20% of PDAC cases and 30–40% of PanINs but not in NPDEs. Higher expression of β3Gn-T6 was found in PDAC cells in more differentiated adenocarcinoma cases showing significantly longer disease-free survival in both univariate and multivariate analyses. In addition, the expression of β3Gn-T6 in PDAC cells and PanINs significantly correlated with the expression of MUC5AC in these cells, suggesting that β3Gn-T6 expression is related to cellular differentiation status of the gastric foveolar phenotype. Thus, it is likely that β3Gn-T6 expression in PDAC cells is a favorable prognostic factor in PDAC patients, and that the expression of β3Gn-T6 correlates with the gastric foveolar phenotype in pancreatic carcinogenesis.
Highlights
Mucin-type O-glycans play roles in various biological functions, including lymphocyte homing and gastric mucosal defense against Helicobacter pylori [1,2,3]
Representative immunohistochemical and lectin-histochemical features are shown in Fig 2 and S1 Fig. pancreatic ductal adenocarcinoma (PDAC) is usually composed of variously differentiated cancer cells, with varied frequency and intensity of glycan expression in PDAC cells in the same case
Higher β3Gn-T6 expression was noted in more differentiated adenocarcinoma in PDAC patients
Summary
Mucin-type O-glycans play roles in various biological functions, including lymphocyte homing and gastric mucosal defense against Helicobacter pylori [1,2,3]. Cancer cells express unique and characteristic glycan structures [4], some of which are involved in cancer initiation, progression, and metastasis, mainly through cellular recognition and/or cell adhesion [5]. These unique characteristics have the potential to be used for diagnostic and therapeutic research and development, limited information is currently available regarding the biological roles and clinicopathological significance of O-glycans in cancer. Based on the Tn antigen, core 1 (T antigen) or core 3 structures are formed, which are branched to give rise to core 2 or core 4 structures, sequentially These core structures can be further extended resulting in complex glycans, such as several blood type antigens (Fig 1). It has been reported that both core and peripheral modified glycans are expressed in some types of cancer and are related to biological characteristics of the cancer cells, thereby representing tumor markers and prognostic markers [7,8,9,10]
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