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Expression of UDP-N-Acetyl--D-Galactosamine-Polypeptide N-Acetylgalactosaminyltransferase Isozyme 3 in the Subserosal Layer Correlates with Postsurgical Survival of Pathological Tumor Stage 2 Carcinoma of the Gallbladder

¹ Department of Cancer Biology and Molecular Immunology, Faculty of Pharmaceutical Sciences, The University of Tokyo, Tokyo; ² Departments of Gastroenterology and ³ Gastrointestinal Surgery, Institute of Clinical Medicine, The University of Tsukuba, Ibaraki; ⁴ Second Department of Surgery, Nagasaki Central National Hospital, Nagasaki; ⁵ Department of Pharmaceutical Research, Mitsubishi Kagaku Bio-Clinical Laboratories, Inc., Tokyo; ⁶ Hanno Research Center, Taiho Pharmaceutical Company, Ltd., Saitama; and ⁷ Department of Molecular Biology, University of Occupational and Environmental Health, School of Medicine, Kita Kyusyu, Japan

Purpose and Experimental Design: Little is known about the molecular events leading to the development and progression of pathological tumor stage 2 (pT₂) gallbladder carcinoma. An alteration in the site of O-glycosylation may be associated with malignant behavior of carcinoma cells by modulation of the biological properties of the target mucin. The UDP-N-acetyl--D-galactosamine-polypeptide N-acetylgalactosaminyltransferase isozyme 3 (GalNAc-T3) has the epithelial gland-specific expression and catalyzes mucin-type O-glycosylation. In this study, immunohistochemistry was performed to determine the expression level of GalNAc-T3 in 34 cases of pT₂ gallbladder carcinoma to determine the correlation of the GalNAc-T3 expression level with mode of recurrence and postsurgical survival.

Results: The expression levels of GalNAc-T3 protein and mRNA were increased in gallbladder carcinomas compared with the levels in adjacent noncancerous tissues and in intact gallbladders. Immunostaining of GalNAc-T3 was recognized in the cancerous epithelia, and the subcellular localization was classified into granular and diffuse types. In the 34 cases of pT₂ carcinoma, the localization of GalNAc-T3 was granular type in 50% and diffuse type in 50% of the cases at the deepest invading sites in the subserosal layer. Postsurgical recurrence was significantly more frequent in cases showing diffuse-type localization of GalNAc-T3 at the deepest invading sites (65%) than in those showing granular-type localization (23%; P < 0.05). Postsurgical survival was significantly poorer in cases showing diffuse-type localization than in those showing granular-type localization (P = 0.033)

Conclusions: In pT₂ gallbladder carcinoma, the presence of diffuse-type localization of GalNAc-T3 in the subserosal layer is correlated with aggressiveness of the disease. This phenotype may serve as a unique biological feature associated with the malignant behavior.

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