Pancreatic cancer is lethal, as it is often detected late. Thus, novel biomarkers of precursor lesions are needed to devise timely therapies. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) are major precursors of pancreatic cancer. In normal gastric mucosa, gastric gland mucin‐specific O‐glycans are unique in having α1,4‐linked N‐acetylglucosamine (αGlcNAc) residues attached to MUC6. Recently we reported that αGlcNAc functions as a tumor suppressor for differentiated‐type gastric adenocarcinoma (Karasawa et al., J Clin Invest 122, 923, 2012). MUC6 is also expressed in pancreatic neoplasms, including PanIN and IPMN, but the role of αGlcNAc expression in pancreatic neoplasms remains unknown. Here, we analyze expression patterns of αGlcNAc, MUC6 and MUC5AC in pancreatic neoplasms and compare them with progression from PanIN to invasive ductal adenocarcinoma (IDAC) (the PanIN‐IDAC sequence; 20 cases) and from IPMN to IPMN with associated invasive carcinoma (IPMNAIC) (the IPMN‐IPMNAIC sequence; 20 cases). At both sequences, the frequency of MUC6‐positive and αGlcNAc‐positive lesions decreased with tumor progression. We then compared expression levels of αGlcNAc and MUC6 at each step of the progression. At the PanIN‐IDAC sequence, αGlcNAc expression significantly decreased relative to MUC6 in low‐grade PanIN (P = 0.021), high‐grade PanIN/intraductal spread of IDAC (P = 0.031) and IDAC (P = 0.013). At the IPMN‐IPMNAIC sequence, decreased αGlcNAc expression was also observed in low‐grade IPMN exhibiting gastric‐type morphology (P = 0.020). These results suggest that decreased expression of αGlcNAc relative to MUC6 occurs early and marks the initiation of tumor progression to pancreatic cancer.
SummarySingle-CpG resolution genome-wide DNA methylation analysis indicated that distinct DNA methylation profiles are established during field cancerization in gastric mucosae, and such profiles at the precancerous stage are inherited by gastric cancers, thus determining tumor aggressiveness and patient outcome.
Gastric gland mucin secreted from pyloric gland cells, mucous neck cells, and cardiac gland cells of the gastric mucosa harbors unique O-glycans carrying terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc), which are primarily attached to the scaffold mucin core protein MUC6. αGlcNAc acts as an antibiotic against Helicobacter pylori (H. pylori), a microbe causing gastric cancer. In addition, mice deficient in A4gnt, which encodes the enzyme α1,4-N-acetylglucosaminyltransferase (α4GnT) that catalyzes αGlcNAc biosynthesis, spontaneously develop gastric differentiated-type adenocarcinoma, even if not infected by H. pylori. Thus, αGlcNAc prevents gastric cancer as both an antibiotic and a tumor suppressor (Nakayama in Acta Histochem Cytochem 47:1-9, 2014b). Indeed, in humans αGlcNAc loss on MUC6 in differentiated-type adenocarcinoma is closely associated with poor patient prognosis (Shiratsu et al. in Cancer Sci 105:126-133, 2014). Recently, we reported reduced αGlcNAc expression on MUC6 in both pyloric gland adenoma of the stomach and chronic atrophic gastritis, in Barrett's esophagus, and in pancreatic intraductal papillary-mucinous neoplasm (IPMN)/pancreatic intraepithelial neoplasia (PanIN), all potentially premalignant conditions. This review discusses whether relatively reduced levels of αGlcNAc in these lesions could serve as a biomarker to predict malignant potential and cancer progression.
Gastric gland mucin-specific O-glycans are unique in having α1,4-linked N-acetylglucosamine (αGlcNAc) attached to MUC6. We previously reported decreased expression of αGlcNAc relative to MUC6 in gastric and pancreatic neoplasms, but its significance in cervical glandular lesions remained unclear. Here, we analyzed MUC5AC, MUC6, αGlcNAc, and p16 expression in 9 lesions of mucinous carcinoma, gastric type with minimal deviation adenocarcinoma (GAS-MDA), 5 of GAS with nonMDA (GAS-nonMDA), 14 of typical lobular endocervical gland hyperplasia (LEGH), and 5 of atypical LEGH (33 total lesions). All 33 were MUC5AC-positive. Moreover, all 14 typical LEGH, 5 atypical LEGH, 8 of 9 GAS-MDA, and 3 of 5 GAS-nonMDA were MUC6-positive. All 14 typical LEGH, 2 of 5 atypical LEGH, 3 of 9 GAS-MDA, and 1 of 5 GAS-nonMDA were αGlcNAc-positive. The proportion of αGlcNAc-positive atypical LEGH or GAS-MDA or GAS-nonMDA lesions was significantly smaller than that seen in typical LEGH lesions (P < 0.001 and P < 0.01, respectively). Of 33 lesions, 32 were p16-negative. Furthermore, when we evaluated MUC6 and αGlcNAc immunoreactivity semi-quantitatively in all 33 lesions, in typical LEGH and GAS-MDA, the immunohistochemical score for αGlcNAc was significantly lower than that for MUC6 (P < 0.01). We did not observe significantly decreased αGlcNAc expression relative to MUC6 in typical LEGH lesions. These studies suggest that αGlcNAc expression decreases as typical LEGH progresses to GAS. Given the difficulty in distinguishing MDA and atypical LEGH from typical LEGH in H.E. staining, we propose that immunohistochemical analysis of αGlcNAc and MUC6 could be useful.
Cervical adenocarcinoma, gastric type (GAS) is not associated with human papilloma virus (HPV) infection. GAS patients prognoses are significantly worse compared with cervical adenocarcinoma associated with HPV infection, as their tumors exhibit resistance to conventional chemotherapy and radiotherapy. GAS is often associated with lobular endocervical glandular hyperplasia (LEGH), which is regarded as a precursor to GAS in the latest WHO classification. Recently, we reported that a decrease in expression of terminal α1,4-linked N-acetylglucosamine (αGlcNAc) relative to that of MUC6 was already apparent in atypical LEGH in the LEGH-GAS sequence. Here, we analyzed expression of α1,4-N-acetylglucosaminyltransferase (α4GnT), the sole enzyme catalyzing αGlcNAc biosynthesis, and that of αGlcNAc and MUC6 in cases representing non-neoplastic endocervical gland (NNEG) (11 cases), LEGH (26 cases) and GAS (12 cases). α4GnT protein was detected in a “dot-like” pattern, indicating localization in the Golgi apparatus in all 26 LEGH cases and 5 of 12 GAS cases. α4GnT- and αGlcNAc-positive cells largely overlapped, suggesting that α4GnT gene expression regulates αGlcNAc biosynthesis. Interestingly, all NNEG cases were negative for α4GnT and αGlcNAc expression, but 7 of 11 NNEG and all LEGH cases were MUC6-positive. In GAS cases, patients whose tumors were α4GnT- and αGlcNAc-positive had more favorable prognosis than others. Multivariate analysis revealed that positive expressions of α4GnT and αGlcNAc were independent prognostic indicators. These results indicate that α4GnT and αGlcNAc could serve as useful markers not only to distinguish LEGH from NNEG but to evaluate prognoses of GAS patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.