Immunohistochemical expression of HIK1083 and MUC6 in endometrial carcinomas.

AIMS: Gastric-type endocervical adenocarcinoma (EA) is characterised by aggressive behaviour and pathogenesis independent of human papillomavirus infection. Because of its morphology and frequent mutation-pattern expression of p53, gastric-type EA may be confused with several types of endometrial carcinoma, particularly in biopsy and curettage specimens. HIK1083 and MUC6 are immunohistochemical markers used to support a diagnosis of gastric-type EA; however, the rates of expression of these markers in endometrial tumours are largely unknown. We therefore aimed to assess the expression of HIK1083 and MUC6 in a cohort of different types of endometrial carcinoma. METHODS AND RESULTS: Ninety-one endometrial carcinomas (56 endometrioid, 16 clear cell, and 19 serous) from 91 patients treated with hysterectomy were included. A representative tumour block from each case was used for immunohistochemical staining with HIK1083 and MUC6. The percentage of stained cells (0-100%) and average staining intensity (weak, moderate, and strong) were recorded for both markers. None of 91 cases expressed HIK1083. In contrast, 66% (60/91) of cases showed at least focal expression of MUC6; importantly, 54 of 60 (90%) positive cases showed moderate or strong staining. Five of 60 (8%) cases showed MUC6 staining in ≥50% of tumour cells. Endometrioid tumours (49/56, 88%) were more likely to express MUC6 than cases of clear cell (1/16, 6%) or serous (10/19, 53%) carcinoma. DISCUSSION: Endometrial carcinoma often expresses MUC6. In contrast, HIK1083 is consistently negative, and thus, when positive, is a more reliable marker for distinguishing gastric-type EA from some of its endometrial mimics.

Prognostic significance of CDX2 and mucin expression in small intestinal adenocarcinoma.

The clinicopathological and prognostic significance of CDX2 and mucin expression have not been comprehensively evaluated in small intestinal adenocarcinoma. Immunohistochemical microarray analyses of CDX2, MUC1, MUC5AC, and MUC6 protein expressions in 189 surgically resected small intestinal adenocarcinoma cases were examined and compared with various clinicopathologic variables, including survival. CDX2, MUC1, MUC5AC, and MUC6 expressions were observed in 43.4% (82 patients), 37.6% (71), 31.7% (60), and 21.7% (41) of patients, respectively. Whereas CDX2 expression was found to be associated with low-grade tumors (P=0.034), fewer nodal metastases (P=0.019), and less perineural invasion (P=0.049) in small intestinal adenocarcinoma patients, patients expressing MUC1 tended to demonstrate high-grade (P=0.021) and nodular or infiltrative (P=0.020) tumors. On the basis of the combined CDX2, MUC1, MUC5AC, and MUC6 expression patterns, small intestinal adenocarcinoma patients were further classified as intestinal (CDX2+/MUC1-; 29.6%), pancreatobiliary (CDX2-/MUC1+; 23.8%), mixed (CDX2+/MUC1+; 13.8%), gastric (CDX2-/MUC1-/MUC5AC+ or MUC6+; 13.8%), or null (CDX2-/MUC1-/MUC5AC-/MUC6-; 19.0%). Among these immunophenotypes, intestinal-type patients demonstrated more frequent distal (jejunal or ileal; P=0.033), tubular (P=0.039), and low-grade tumors (P=0.004) and significantly better survival according to univariate (P<0.0001) and multivariate (P=0.001) analyses. In summary, intestinal immunophenotype adenocarcinomas are associated with distal (jejunal or ileal), tubular, and low-grade tumors and better survival outcomes. Hence, CDX2 and mucin immunohistochemical staining may provide better estimations of survival after surgical resection and intestinal immunophenotype could therefore be used as a better prognostic indicator of small intestinal adenocarcinoma.

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.

Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.

Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct.

AIMS: Intraductal papillary neoplasm of the bile duct (IPNB) usually has a favourable prognosis, but occasionally is associated with invasive carcinoma. Overexpression of the polycomb group protein enhancer of zeste homolog 2 (EZH2) is involved in the progression of malignant tumours. In this study, we examined the significance of EZH2 expression in IPNB and its association with clinicopathological features and the expression of p16(INK4a) , p53 and mucin core proteins. METHODS AND RESULTS: We examined immunohistochemically the expression of EZH2, p16(INK4a) , MUC mucin core proteins and p53 in 15 patients with IPNB without invasion, including the cystic variant [male/female ratio (M/F) = 9/6], and in 19 with IPNB associated with invasive carcinoma (M/F = 13/6). The expression levels of EZH2, p53 and MUC1 were significantly lower (P < 0.01), and of MUC6 were significantly higher (P < 0.05), in IPNB without invasion than in IPNB with invasion. Expression of EZH2 was significantly correlated with expression of MUC1 (P < 0.01) and inversely correlated with expression of MUC6 (P < 0.05). In cholangiocarcinoma cells (HuCTT-1 and TFK-1), knockdown of EZH2 and MUC1 by small interfering RNA decreased invasion and proliferation, whereas knockdown of MUC6 increased invasion. CONCLUSIONS: Overexpression of EZH2 may be associated with malignant behaviour in IPNB in parallel with up-regulated MUC1 expression and down-regulated MUC6 expression.

Expression of gastric pyloric mucin, MUC6, in colorectal serrated polyps.

Serrated polyps of the colorectal mucosa represent a heterogeneous and controversial taxonomic category with variation in histopathological, molecular, and immunohistochemical characteristics and with an incomplete understanding of pathogenesis. A previous study reported that the expression of gastric pyloric-type mucin, MUC6, characterized sessile serrated adenomas. We therefore evaluated the expression of MUC6 in serrated polyps identified among 2502 participants in a Phase III chemoprevention trial within the Arizona Cancer Center Colorectal Cancer Prevention Trials Program and characterized the associated histopathological features and location. We carried out immunohistochemistry for MUC6 on 146 serrated lesions and 87 conventional tubular adenomas, and assessed the percentage of cells with expression and the grade of staining intensity. In all 92 hyperplastic polyps, 43 sessile serrated adenomas, and 11 traditional serrated adenomas were included. Polyps ranged in size from 1-150 mm. The association of MUC6 staining with serrated polyp category was evaluated using classification and regression tree (CART) analysis and two-sided Fisher's exact test. A total of 53% of sessile serrated adenomas (n=23), 17% of hyperplastic polyps (n=16), and 18% of traditional serrated adenomas (n=2), but none of 87 tubular adenomas, expressed MUC6. Expression was limited to the lower crypts in all serrated polyps. The extent of positive staining ranged from 2-100% of crypt cells and was independent of the histopathological type. MUC6 expression had relatively high specificity for sessile serrated adenoma (82%) but low sensitivity (54%). In CART analysis, proximal location was found to be the best partitioning factor for MUC6, followed by classification as sessile serrated adenoma. We conclude that MUC6 expression is strongly associated with proximal location of serrated polyps, but only has modest utility as a tissue biomarker for sessile serrated adenoma.

Mucins in neoplastic spectrum of colorectal polyps: can they provide predictions?

BACKGROUND: The significance of expression of different mucins in succession of malignant transformation of colorectal polyps is not determined yet. The aim of the present study was to determine the pattern of expression of MUC1, MUC2, MUC5AC and MUC6 in colorectal polyps and to evaluate the applicability of using mucin expression in predicting the extent of malignant transformation in colorectal polyps. METHODS: A total of 454 polyp specimens comprising 36 hyperplastic polyps, 15 serrated adenomas, 258 tubular adenomas, 114 tubulovillous adenomas, and 31 villous adenomas were included in this study, and were immunostained for MUC1, MUC2, MUC5AC and MUC6 by using mucin specific antibodies. RESULTS: MUC1 and MUC6 were absent in all hyperplastic polyps and their expression was higher in serrated and traditional adenomas. Only 5 cases including 2 serrated adenomas, 1 tubulovillous adenoma, and 2 villous adenomas stained negative for MUC2. The highest expression of MUC5AC was observed in serrated adenomas followed by tubular adenomas. Binary logistic regression analysis indicated that positive staining for MUC1, and MUC6, and negative staining for MUC2 would increase the risk of invasion to mucosa or the muscularis mucosae in colorectal polyps. Ordinal regression analysis demonstrated a positive association between the level of staining for MUC1 and risk of being of high configuration/grade in colorectal polyps. CONCLUSIONS: MUC1, MUC2, MUC5AC, and MUC6 have the potential to be used as predictors of malignant transformation and invasion to mucosa or the muscularis mucosae in colorectal polyps. The most reliable predictions can be achieved by determining the level of expression of MUC1.

Colloid carcinoma of the intestinal type in the uterine cervix: mucin immunohistochemistry.

A case of colloid carcinoma (gelatinous carcinoma) of the intestinal type in the uterine cervix is reported along with the findings of an immunohistochemical study of intracytoplasmic mucus of the neoplastic cells. The patient was a 69-year-old woman with a circumferential uterine cervical tumor measuring about 4 cm. Histopathological examination of the hysterectomy specimen demonstrated typical features of colloid carcinoma. The tumor consisted of numerous mucous nodules, and low-columnar or cuboidal cells with intracytoplasmic mucus lined the margins of the mucous nodules or floated within them. The cytoplasm of neoplastic cells was immunoreactive for both cytokeratins 7 and 20, and the intracytoplasmic mucus was immunoreactive for MUC2 but negative for MUC5AC and MUC6. Nuclei of tumor cells were immunoreactive for CDX2. Colloid carcinoma is a very rare variant of mucus-producing adenocarcinoma of the uterine cervix and probably a heterogeneous group that consists of neoplasms of different histogeneses, that is, neoplasms of endocervical, gastric, and intestinal origins. Results of the immunohistochemical studies in the present case showed that neoplastic cells produced mucus of the large intestine type, thus verifying the presence of a distinct subtype of colloid carcinoma of the cervix that shows the intestinal phenotype.

Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in ALK-positive lung cancer: Comparison with EGFR-mutated lung cancer.

ALK-positive (ALK+) lung adenocarcinoma usually shows a more advanced-staged disease with frequent nodal metastasis and highly aggressive outcomes compared with EGFR-mutated lung cancers. The aim of this study was to investigate the expression profiles of several mucins in ALK + lung cancers to gain insight into the relationship between the more aggressive biological nature of ALK + lung cancers and the role of mucins. We examined the immunohistochemical profiles of mucins MUC1, MUC2, MUC5AC, and MUC6 in 19 ALK + lung cancers compared with 42 EGFR-mutated lung cancers. ALK + cancers were found to occur in younger patients and were characterized by a solid-predominant histologic subtype with frequent signet ring cells and peritumoral muciphages. By contrast, EGFR-mutated cancers lacked ALK-specific histological patterns. Although all MUC1 and MUC5AC were expressed in both subtypes, MUC1 expression in ALK + cancers was visualized exclusively through cytoplasmic staining, whereas those in EGFR-mutated cancers were predominantly membranous staining in apical area (92.9%) and focally in cytoplasmic staining (7.1%). MUC5AC expression in ALK + cancers was exclusively visualized through cytoplasmic staining (100%), whereas EGFR-mutated cancers showed predominantly perinuclear dot-like patterns (90.5%) and focal cytoplasmic staining (9.5%). MUC2 and MUC6 expression was not detected in either type of lung cancer. CONCLUSIONS: The high frequency of both MUC1 and MUC5AC cytoplasmic expression, coupled with a lack of MUC2 and MUC6 expression in ALK + lung cancer may contribute to the biologically aggressive behavior of ALK + cancer. Inhibitors to these types of mucins may thus act as a barrier to cancerous extension reducing their aggressive behavior.

Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase.

In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

Effects of the Helicobacter pylori Virulence Factor CagA and Ammonium Ion on Mucins in AGS Cells.

PURPOSE: To investigate the effects of Helicobacter pylori (H. pylori)-CagA and the urease metabolite NH4⁺ on mucin expression in AGS cells. MATERIALS AND METHODS: AGS cells were transfected with CagA and/or treated with different concentrations of NH4CL. Mucin gene and protein expression was assessed by qPCR and immunofluorescence assays, respectively. RESULTS: CagA significantly upregulated MUC5AC, MUC2, and MUC5B expression in AGS cells, but did not affect E-cadherin and MUC6 expression. MUC5AC, MUC6, and MUC2 expression in AGS cells increased with increasing NH4⁺ concentrations until reaching a peak level at 15 mM. MUC5B mRNA expression in AGS cells (NH4⁺ concentration of 15 mM) was significantly higher than that at 0, 5, and 10 mM NH4⁺. No changes in E-cadherin expression in AGS cells treated with NH4⁺ were noted, except at 20 mM. The expression of MUC5AC, MUC2, and MUC6 mRNA in CagA-transfected AGS cells at an NH4⁺ concentration of 15 mM was significantly higher than that at 0 mM, and decreased at higher concentrations. The expression of MUC5B mRNA increased with increases in NH4⁺ concentration, and was significantly higher compared to that in untreated cells. No significant change in the expression of E-cadherin mRNA in CagA-transfected AGS cells was observed. Immunofluorescence assays confirmed the observed changes. CONCLUSION: H. pylori may affect the expression of MUC5AC, MUC2, MUC5B, and MUC6 in AGS cells via CagA and/or NH4⁺, but not E-cadherin.

Correlation between magnifying narrow-band imaging endoscopy results and organoid differentiation indicated by cancer cell differentiation and its distribution in depressed- type early gastric carcinoma.

BACKGROUND: A close association between patterns identified by magnifying narrow-band imaging (M-NBI) and histological type has been described. M-NBI patterns were also recently reported to be related to the mucin phenotype; however, detials remain unclear. MATERIALS AND METHODS: We investigated the cellular differentiation of gastric cancer lesions, along with their mucosal distribution observed by M-NBI. Ninety-seven depressed-type early gastric cancer lesions (74 differentiated and 23 undifferentiated adenocarcinomas) were visualized by M-NBI. Findings were divided into 4 patterns based on abnormal microvascular architecture: a chain loop pattern (CLP), a fine network pattern (FNP), a corkscrew pattern (CSP), and an unclassified pattern. Mucin phenotypes were judged as gastric (G-type), intestinal (I-type), mixed gastric and intestinal (M-type), and null (N-type) based on 4 markers (MAC5AC, MUC6, MUC2, and CD10). The relationship of each pattern of microvascular architecture with organoid differentiation indicated by cancer cell differentiation and its distribution in each histological type of early gastric cancer was investigated. RESULTS: All CLP and FNP lesions were differentiated. The cancer cell distribution showed organoid differentiation in 84.2% (16/19) and 61.1% (22/36) of the two types of lesions, respectively, and there was a significant difference from the unclassified pattern with organoid differentiation (p<0.001). Almost all (94.7%; 18/19) CSP lesions were undifferentiated, and organoid differentiation was observed in 72.2% (13/18). There was a significant difference from the unclassified pattern with organoid differentiation (p<0.05). CONCLUSIONS: Cellular differentiation and distribution are associated with microvascular architecture observed by M-NBI.

Intraductal neoplasm of the intrahepatic bile duct: clinicopathological study of 24 cases.

AIM: To investigate the clinicopathological features of intraductal neoplasm of the intrahepatic bile duct (INihB). METHODS: Clinicopathological features of 24 cases of INihB, which were previously diagnosed as biliary papillomatosis or intraductal growth of intrahepatic biliary neoplasm, were reviewed. Mucin immunohistochemistry was performed for mucin (MUC)1, MUC2, MUC5AC and MUC6. Ki-67, P53 and ß-catenin immunoreactivity were also examined. We categorized each tumor as adenoma (low grade), borderline (intermediate grade), and malignant (carcinoma in situ, high grade including tumors with microinvasion). RESULTS: Among 24 cases of INihB, we identified 24 tumors. Twenty of 24 tumors (83%) were composed of a papillary structure; the same feature observed in intraductal papillary neoplasm of the bile duct (IPNB). In contrast, the remaining four tumors (17%) showed both tubular and papillary structures. In three of the four tumors (75%), macroscopic mucin secretion was limited but microscopic intracellular mucin was evident. Histologically, 16 tumors (67%) were malignant, three (12%) were borderline, and five (21%) were adenoma. Microinvasion was found in four cases (17%). Immunohistochemical analysis revealed that MUC1 was not expressed in the borderline/adenoma group but was expressed only in malignant lesions (P = 0.0095). Ki-67 labeling index (LI) was significantly higher in the malignant group than in the borderline/adenoma group (22.2 ± 15.5 vs 7.5 ± 6.3, P < 0.01). In the 16 malignant cases, expression of MUC5AC showed borderline significant association with high Ki-67 LI (P = 0.0622). Nuclear expression of ß-catenin was observed in two (8%) of the 24 tumors, and these two tumors also showed MUC1 expression. P53 was negative in all tumors. CONCLUSION: Some cases of INihB have a tubular structure, and are subcategorized as IPNB with tubular structure. MUC1 expression in INihB correlates positively with degree of malignancy.

MUC expression in hyperplastic and serrated colonic polyps: lack of specificity of MUC6.

Previous studies have shown that hyperplastic and serrated polyps of the colon show variable degrees of gastric and intestinal differentiation. MUCs are a class of approximately 20 genes that encode high-molecular-weight glycoproteins, or mucopolysaccharides, that are widely expressed in epithelial cells and show organ specificity. The role of MUC in serrated carcinogenesis is unknown. One previously published study suggested that expression of MUC6 is specific for sessile serrated adenoma/polyps (SSA/Ps) and thus can be used to distinguish these lesions from hyperplastic polyps (HPs). However, data from our group suggest that MUC antibodies are not reliable in this differential diagnosis. The aims of this study were to systematically evaluate the expression of MUCs in serrated colon polyps and to determine the efficacy of MUC expression in differentiating HPs from SSA/Ps specifically. Routinely processed specimens from 182 serrated polyps [58 HPs, 46 SSA/Ps, 59 SSA/Ps with dysplasia (SSA/P-D), 19 traditional serrated adenomas, and 38 conventional tubular or tubulovillous adenomas (CAs)] were immunohistochemically stained with MUC1, MUC2, MUC5AC, and MUC6, and scored for extent, intensity, and location of staining within the polyps. HPs were further subclassified into goblet cell type (N=18), microvesicular type (N=21), and mucin-depleted type (N=19). The data were compared between the different polyp groups and between polyps from different anatomic locations in the colon. MUC1, MUC2, MUC5AC, and MUC6 were expressed in 27%, 100%, 100%, and 72% of serrated polyps overall. These antibodies were positive in 32%, 100%, 100%, and 43% of CAs. Expression levels of MUC1, MUC2, and MUC5AC were not significantly different between any of the polyp subgroups or between serrated polyps and CAs. Both SSA/P and SSA/P-D showed a significantly higher percentage of polyps that stained with MUC6, and a greater degree and intensity of staining for this peptide in comparison with HPs. Overall, 91% of SSA/Ps and 84% of SSA/P-Ds were positive for MUC6 in comparison with 60% of HPs (P<0.001 and P=0.02, respectively). Although polyps from both the left and right colon from each polyp group showed positivity for MUC6, a significantly higher proportion of SSA/P-Ds and traditional serrated adenomas from the right colon showed MUC6 positivity compared with those from the left. No differences were noted in MUC6 staining between each of the 3 HP subgroups. On the basis of these data, we conclude that SSA/P and SSA/P-D show increased expression of MUC6 compared with HPs; however, because of overlap in the presence, degree, and intensity of staining, use of MUC6 to differentiate HPs from SSA/P or SSA/P-D in individual cases is not reliable because of a lack of specificity. Differences in MUC6 expression between right-sided and left-sided colonic polyps supports the theory that there may be biological differences in the progression of malignancy in different portions of the colon with regard to the serrated pathway of carcinogenesis.

Aberrant expression of TFF1, TFF2, and PDX1 and their diagnostic value in lobular endocervical glandular hyperplasia.

Lobular endocervical glandular hyperplasia (LEGH) is a distinct benign glandular lesion expressing gastric gland mucous cell-type mucin (N-acetylglucosaminα1 → 4galactose → R [GlcNAcα1 → 4Gal → R]). To investigate histogenesis and diagnostic markers of LEGH, we examined the immunohistochemical expression profile of gastric surface mucous cell (MUC5AC and TFF1), gastric gland mucous cell (MUC6, TFF2, and GlcNAcα1 → 4Gal → R), gastric pyloric epithelial cell (PDX1), and endocervical cell (keratan sulfate) markers in normal endocervix samples and benign glandular lesions (nabothian cysts, tunnel clusters, and LEGHs). MUC5AC and MUC6 were expressed in normal endocervical mucosa and benign glandular lesions. TFF1, TFF2, GlcNAcα1 → 4Gal → R, and PDX1 were expressed only in LEGH. Keratan sulfate was expressed in normal endocervical mucosa and benign glandular lesions. In LEGH, gastric surface mucous cell and gastric gland mucous cell differentiation were demonstrated, and transdifferentiation from endocervical mucosa into gastric pyloric mucosa was suggested. In addition to GlcNAcα1 → 4Gal → R, TFF1, TFF2, and PDX1 are additional useful markers for LEGH.

RUNX3 expression correlates with chief cell differentiation in human gastric cancers.

RUNX3 is a novel tumor suppressor in gastric carcinogenesis and an important factor for differentiation of chief cells in the normal gastric fundic mucosa. In this study, we confirmed RUNX3 immunolocalization in the fundic gland (bottom part) but minimum in surface mucous cell epithelium (top part) in the isolated gland from fundic mucosa. We also analyzed RUNX3 expression by immunohistochemistry in 102 gastric cancers and made a histological assessment of the expression of differentiation markers to evaluate interrelations. Among them, 45 and 57 cases were judged to be RUNX3 positive and negative, respectively, and 33 and 69 cases were pepsinogen I positive and negative, with no link to histological types. RUNX3 expression was significantly associated with that of pepsinogen I (P<0.001), but not mucins, including MUC5AC and MUC6, or the parietal or intestinal phenotypes. In conclusion, the present study showed, for the first time to our knowledge, a relation between RUNX3 and pepsinogen I expression in human gastric cancers. RUNX3 is strongly associated with chief cell phenotypic expression in human gastric cancers, as well as in normal gastric mucosa, and could be considered to play an important role in maintaining the chief cell phenotype.