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

Abstract

Purpose and Experimental Design:Little is known about the molecular events leading to the development and progression of pathological tumor stage 2 (pT 2 ) 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 mucintype O-glycosylation. In this study, immunohistochemistry was performed to determine the expression level of GalNAc-T3 in 34 cases of pT 2 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 pT 2 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 diffusetype localization than in those showing granular-type localization (P ‫؍‬ 0.033) Conclusions: In pT 2 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.

Expression of GalNAc-T3 and its relationships with clinicopathological factors in 61 extrahepatic bile duct carcinomas analyzed using stepwise sections—Special reference to its association with lymph node metastases—

“…We also found that the immunohistochemical staining of GalNAc-T3 in EBDCs showed granulartype and diffuse-type expression patterns, and these features of EBDCs were similar to those reported for gallbladder adenocarcinomas. 29 Furthermore, our observations that all the noninvasive or minimally invasive carcinomas showed only the granular type and that the proportion of diffuse-type expression was increased at the invasive front of advanced EBDCs were also similar to the findings for gallbladder adenocarcinomas. The GalNAc-T family enzymes normally reside in the Golgi apparatus of cells, 19 and alterations in the subcellular localization of GalNAc-T3 may be associated with the status of the morphological and functional differentiation of the carcinoma cells.…”

“…In the adenocarcinomas of some organs, including the pancreas and gallbladder, the presence of weak expression or diffuse-type GalNAc-T3 expression in EBDCs T Inoue et al localization of GalNAc-T3 was correlated with tumor aggressiveness. [24][25][26][27][28][29] On the other hand, early-stage gastric carcinomas with submucosal invasion tended to show positive (strong or granular) GalNAc-T3 expression, while early-stage undifferentiated gastric carcinomas showing positive GalNAc-T3 expression were associated with significantly higher frequencies of metastatic lymph node involvement. 30 In addition, GalNAc-T3-positive esophageal squamous cell carcinomas exhibited more aggressive behavior.…”

“…17,18 Furthermore, recent studies have suggested a relationship between GalNAc-T3 expression and the tumor differentiation or progression, including prognosis, of human adenocarcinomas in the colon, lung, stomach, pancreas and gallbladder. [24][25][26][27][28][29][30] Although the GalNAc-T subtypes are usually localized in the Golgi apparatus, their subcellular localization alters following malignant transformation due to reorganization of the Golgi apparatus elements. 8,19,20 Therefore, not only the levels but also the patterns of GalNAc-T3 expression, such as the subcellular distribution, may be associated with the malignant transformation and differentiation of adenocarcinoma cells.…”

UDP-N-Acetyl-d-Galactosamine: Polypeptide N-Acetylgalactosaminyltransferase-6 as a New Immunohistochemical Breast Cancer Marker

“…One reason for the diffuse ppGalNAc-T6 immunostaining could probably be suboptimal tissue fixation, a commonly observed phenomenon in immersion-fixed surgical specimens. However, a similar diffuse cytoplasm (Taatjes et al 1987), for b1,4-galactosyltransferase in endometrial cancer (Kubushiro et al 1999), and for ppGalNAc-T3 in colorectal (Shibao et al 2002) and gallbladder carcinomas (Miyahara et al 2004). Enzyme localization is an important determinant of the carbohydrate repertoire expressed on the cell surface, and their relative positions are known to govern, in part, the structures of glycans produced by the cell (Grabenhorst and Conradt 1999).…”

N-Acetylgalactosaminyltransferase-14 as a potential biomarker for breast cancer by immunohistochemistry

“…Higher expression of GalNAc-T1, GalNAc-T2 and GalNAc-T3 has also been described in colorectal carcinoma when compared with the normal colonic epithelium [27]. Different levels of expression of GalNAc-T3 were detected in patients with colorectal [12], lung [28], pancreatic [29], gastric [30], gallbladder [31], prostate [32] and extrahepatic bile duct carcinomas [33], and it was identified as an independent factor of prognosis. GalNAc-T6, which exhibits a high sequence homology to GalNAc-T3, has been recently described to be expressed in most ductal breast carcinomas but not in normal breast epithelium.…”