Gene Summary

Gene:MUC2; mucin 2, oligomeric mucus/gel-forming
Aliases: MLP, SMUC, MUC-2
Summary:This gene encodes a member of the mucin protein family. Mucins are high molecular weight glycoproteins produced by many epithelial tissues. The protein encoded by this gene is secreted and forms an insoluble mucous barrier that protects the gut lumen. The protein polymerizes into a gel of which 80% is composed of oligosaccharide side chains by weight. The protein features a central domain containing tandem repeats rich in threonine and proline that varies between 50 and 115 copies in different individuals. Alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Promoter Regions
  • Prostate Cancer
  • Nuclear Proteins
  • Pancreatitis
  • Stomach Cancer
  • Staging
  • Polymerase Chain Reaction
  • Precancerous Conditions
  • Xenograft Models
  • MUC1
  • Cancer RNA
  • Messenger RNA
  • Transcription
  • Sialomucins
  • Up-Regulation
  • Immunohistochemistry
  • Mucinous Adenocarcinoma
  • Tandem Repeat Sequences
  • Uterine Diseases
  • Chromosome 11
  • Base Sequence
  • Colonic Neoplasms
  • Mutation
  • Receptors, Interleukin-4
  • Tumor Markers
  • Neoplasm Proteins
  • Survival Rate
  • alpha-Fetoproteins
  • Cancer DNA
  • Adenocarcinoma
  • Mucins
  • Homeodomain Proteins
  • Mucin 5AC
  • p53 Protein
  • Gene Expression
  • Protein Binding
  • Colorectal Cancer
  • Cancer Gene Expression Regulation
  • MUC2
  • Phenotype
  • Mucin-2
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MUC2 (cancer-related)

Shibahara H, Higashi M, Koriyama C, et al.
Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer.
PLoS One. 2014; 9(4):e86111 [PubMed] Free Access to Full Article Related Publications
Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p<0.001), lymph node metastasis (p<0.001), lymphatic invasion (p = 0.026), venous invasion (p<0.001) and curative resection (p<0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p<0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8-17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.

Yokoyama S, Kitamoto S, Higashi M, et al.
Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice.
PLoS One. 2014; 9(4):e93760 [PubMed] Free Access to Full Article Related Publications
Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel 'methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.

Wang CX, Liu B, Wang YF, et al.
Pulmonary enteric adenocarcinoma: a study of the clinicopathologic and molecular status of nine cases.
Int J Clin Exp Pathol. 2014; 7(3):1266-74 [PubMed] Free Access to Full Article Related Publications
Pulmonary enteric adenocarcinoma (PEAC), a extremely rare variant of primary invasive adenocarcinoma of the lung, was recognized by the international multidisciplinary classification of lung adenocarcinoma which was proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) published in early 2011. Histologically, PEAC is considered to be mainly composed of tall columnar cells arranged in an irregular glandular cavity or cribriform pattern with extensive central necrosis which show high resemblance to that of intestinal epithelia and colorectal carcinomas. Immunohistochemically, PEAC can not only expresses typical proteins common to lung primaries but is positive for at least one intestinal markers, such as CDX2, cytokeratin (CK) 20, MUC2, therefore, the differentiation of primary PEACs from metastatic colorectal cancers can be challenging. In this study, we report 9 cases of PEAC and a panel of immunohistochemical protein markers of CK7, CK20, thyroid transcription factor 1 (TTF-1), Napsin A, MUC2 and villin was analyzed with the comparison of 20 metastatic colorectal carcinomas (MCRs), and 20 typical primary adenocarcinomas (tPACs). As was expected, CK7 expression was documented in all 9 PEACs and 20 tPCAs while CK20 was significantly more prevalent in adenocarcinoma that originated from colorectal. Additionally, we evaluate the classical mutations of EGFR, KRAS in the 9 cases of PEACs, it turned out that all tumors were EGFR-wild and KRAS-wild types, which confirmed that PEAC has a separate phenotype from usual pulmonary adenocarcinoma.

Komatsu H, Tanji E, Sakata N, et al.
A GNAS mutation found in pancreatic intraductal papillary mucinous neoplasms induces drastic alterations of gene expression profiles with upregulation of mucin genes.
PLoS One. 2014; 9(2):e87875 [PubMed] Free Access to Full Article Related Publications
GNAS, a gene encoding G protein stimulating α subunit, is frequently mutated in intraductal papillary mucinous neoplasms (IPMNs), which are indolent and slow-growing pancreatic tumors that secrete abundant mucin. The GNAS mutation is not observed in conventional ductal adenocarcinomas of the pancreas. To determine the functional significance of the GNAS mutation in pancreatic ductal lineage cells, we examined in vitro phenotypes of cells of pancreatic ductal lineage, HPDE, PK-8, PCI-35, and MIA PaCa-2, with exogenous expression of either wild-type or mutated (R201H) GNAS. We found that exogenous GNAS upregulated intracellular cyclic adenine monophosphate (cAMP), particularly in mutated GNAS transfectants, and upregulated expression of MUC2 and MUC5AC in HPDE and PK-8 cells. By contrast, exogenous GNAS inhibited expression of mucin genes in PCI-35 and MIA PaCa-2 cells, despite upregulation of cAMP. We examined global gene expression profiles of some of the cells transfected with exogenous mutated GNAS (PK-8, PCI-35, and MIA PaCa-2), and found that PK-8 cells exhibited drastic alterations of the gene expression profile, which contrasted with modest alterations in PCI-35 and MIA PaCa-2 cells. To identify a cause of these different effects of exogenous mutated GNAS on phenotypes of the cells, we examined effects of interactions of the signaling pathways of G protein-coupled receptor (GPCR), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) on expression of mucin genes. The MAPK and PI3K pathways significantly influenced the expression of mucin genes. Exogenous GNAS did not promote cell growth but suppressed it in some of the cells. In conclusion, mutated GNAS found in IPMNs may extensively alter gene expression profiles, including expression of mucin genes, through the interaction with MAPK and PI3K pathways in pancreatic ductal cells; these changes may determine the characteristic phenotype of IPMN. PK-8 cells expressing exogenous mutated GNAS may be an ideal in vitro model of IPMN.

Debunne H, Ceelen W
Mucinous differentiation in colorectal cancer: molecular, histological and clinical aspects.
Acta Chir Belg. 2013 Nov-Dec; 113(6):385-90 [PubMed] Related Publications
BACKGROUND: Mucinous colorectal carcinoma represents a subtype of colorectal carcinoma (CRC), which is characterized by abundant amount of extracellular mucin. We reviewed the molecular, histological and clinical aspects of mucinous CRC as compared to the non-mucinous type.
METHODS: A systematic web-based research was performed using Web of Knowledge. The combination of the Boolean search terms "COLO" AND "MUC" was used. The literature was searched until July 2013.
RESULTS: Patients with mucinous CRC have distinct clinical and pathological features. Mucinous CRC tends to occur in younger patients, are often seen in the proximal colon, are more diagnosed at an advanced stage and are more frequently associated with hereditary non-polyposis colorectal cancer (HNPCC) and young-age sporadic colorectal cancer. The prognostic significance of mucinous differentiation remains uncertain; some studies have shown a poor response to oxaliplatin and/or irinotecan based chemotherapy. Mucinous CRC is associated with a higher expression of MUC2 and MUC5AC, but a lower expression of MUC1. The differential expression of mucins has been related to altered risk of metastasis and death. Recently, mucins have been used as targets for molecular therapy and as a source of immune therapy. Mucinous differentiation is associated with other specific genetic and molecular features such as increased BRAF mutation rate and microsatellite instability.
CONCLUSION: Mucinous CRC is a distinct clinical, pathological, and molecular entity. The implications of mucinous differentiation for treatment response and outcome are not fully elucidated, but the available data suggest an adverse effect. The use of mucins as immunotargets may show therapeutic promise for mucinous CRC.

Zwenger A, Rabassa M, Demichelis S, et al.
High expression of sLex associated with poor survival in Argentinian colorectal cancer patients.
Int J Biol Markers. 2014 Jan-Mar; 29(1):e30-9 [PubMed] Related Publications
AIM: Colorectal cancer (CRC) is one of the most prevalent malignancies in Argentina with 11,043 new cases and 6,596 deaths estimated to have occurred in 2008. The present study was developed to clarify the differential expression of MUC1, MUC2, sLex, and sLea in colorectal cancer patients and their relationship with survival and clinical and histological features.
METHODS: Ninety primary tumor samples and 43 metastatic lymph nodes from CRC patients were studied; follow-up was documented. Twenty-six adenoma and 68 histological normal mucosa specimens were analyzed. An immunohistochemical approach was applied and statistical analysis was performed.
RESULTS: In tumor samples, MUC1, sLea, and sLex were highly expressed (94%, 67%, and 91%, respectively); also, we found a significantly increased expression of the 3 antigens in primary tumors and metastatic lymph nodes compared with normal mucosa and adenomas. MUC2 was expressed in 52% of both normal mucosa and CRC samples; this reactivity significantly decreased in metastatic lymph nodes (p<0.05). A multiple comparison analysis showed that MUC1 and sLex discriminated among 3 groups: normal, adenoma, and CRC tissues. The increase of sLex expression showed an association with recurrence, and survival analysis showed that a high sLex staining was significantly associated with a poor survival. By multivariate analysis MUC1 inmunoreactivity correlated positively and significantly with tumor size, while MUC2 expression showed the opposite correlation.
CONCLUSIONS: The correlation of sLex overexpression in primary tumors and metastatic lymph nodes, the discrimination among the normal, adenoma, and CRC groups based on sLex expression, as well as its association with recurrence and survival, all suggest a prognostic role of sLex in Argentinian CRC patients.

He YF, Zhang MY, Wu X, et al.
High MUC2 expression in ovarian cancer is inversely associated with the M1/M2 ratio of tumor-associated macrophages and patient survival time.
PLoS One. 2013; 8(12):e79769 [PubMed] Free Access to Full Article Related Publications
Mucin 2 (MUC2) is a mucin molecule aberrantly expressed by ovarian cancer cells. Previous in vitro studies have indicated that MUC2 promotes cancer growth and metastasis through a tumor-associated macrophage (TAM)-dependent mechanism. However, this mechanism has never been linked to clinical oncology, and its prognostic significance needed to be clarified. Here, we collected 102 consecutive ovarian cancer specimens and used the multiple immuno-histo-chemical/-fluorescent technique to determine the correlations between the MUC2 expression status, the ratio of M1/M2 TAMs and the densities of cyclooxygenase-2 (COX-2)(+) TAMs and COX-2(+) cancer cells. The Kaplan-Meier survival analysis and multivariate Cox regression analysis were used to evaluate the prognostic influences of these parameters. As a result, we found that the MUC2 overexpression (immunostaining ++/+++) was significantly correlated with a reduced ratio of M1/M2 TAMs (p<0.001), an increased density of COX-2(+) TAMs (p<0.001) and an increased density of COX-2(+) cancer cells (p=0.017). Moreover, most of the M2 TAMs (93%-100%) and COX-2(+) TAMs (63%-89%) overlapped; and the COX-2(+) cancer cells were frequently observed near the COX-2(+) TAMs. In the Cox regression analysis, MUC2 overexpression was found to be an independent prognostic factor for ovarian cancer patients, of which the hazard ratio (HR) was 2.354 (95% confidence interval (CI): 1.031-10.707, p=0.005). Also, the reduced ratio of M1/M2 TAMs and the increased densities of COX-2(+) TAMs and COX-2(+) cancer cells were demonstrated to be the predictors of poor prognosis, among which the reduced M1/M2 ratio possessed the highest HR (1.767, 95% CI: 1.061-6.957, p=0.019). All these findings revealed that MUC2 can concurrently exert M2-polarizing and COX-2-inducing effects on TAMs, by which it causes an imbalanced TAM M1-/M2-polarization pattern and induces local PGE2 synthesis (in both TAMs and cancer cells). The positive feedback between local PGE2 synthesis and TAM M2-polarization accelerates ovarian cancer progression.

Melson J, Li Y, Cassinotti E, et al.
Commonality and differences of methylation signatures in the plasma of patients with pancreatic cancer and colorectal cancer.
Int J Cancer. 2014; 134(11):2656-62 [PubMed] Related Publications
Profiling of DNA methylation status of specific genes is a way to screen for colorectal cancer (CRC) and pancreatic cancer (PC) in blood. The commonality of methylation status of cancer-related tumor suppressor genes between CRC and PC is largely unknown. Methylation status of 56 cancer-related genes was compared in plasma of patients in the following cohorts: CRC, PC and healthy controls. Cross validation determined the best model by area under ROC curve (AUC) to differentiate cancer methylation profiles from controls. Optimal preferential gene methylation signatures were derived to differentiate either cancer (CRC or PC) from controls. For CRC alone, a three gene signature (CYCD2, HIC and VHL) had an AUC 0.9310, sensitivity (Sens) = 0.826, specificity (Spec) = 0.9383. For PC alone, an optimal signature consisted of five genes (VHL, MYF3, TMS, GPC3 and SRBC), AUC 0.848; Sens = 0.807, Spec = 0.666. Combined PC and CRC signature or "combined cancer signature" was derived to differentiate either CRC and PC from controls (MDR1, SRBC, VHL, MUC2, RB1, SYK and GPC3) AUC = 0.8177, Sens = 0.6316 Spec = 0.840. In a validation cohort, N = 10 CRC patients, the optimal CRC signature (CYCD2, HIC and VHL) had AUC 0.900. In all derived signatures (CRC, PC and combined cancer signature) the optimal panel used preferential VHL methylation. In conclusion, CRC and PC differ in specific genes methylated in plasma other than VHL. Preferential methylation of VHL is shared in the optimal signature for CRC alone, PC alone and combined PC and CRC. Future investigations may identify additional methylation markers informative for the presence of both CRC and PC.

Ushijima M, Ogata Y, Tsuda H, et al.
Demethylation effect of the antineoplaston AS2-1 on genes in colon cancer cells.
Oncol Rep. 2014; 31(1):19-26 [PubMed] Free Access to Full Article Related Publications
Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. antineoplastons have been shown to control neoplastic growth. In the present study, we investigated demethylation effect of the antineoplaston AS2-1 (a mixture of phenylacetylglutamine and phenylacetate in the ratio of 1:4) on various genes in colon cancer cells. An HpaII-MspI methylation microarray was used to investigate the methylation status of 51 genes at the promoter region in HCT116 and KM12SM human colon cancer cells before and after treatment of AS2-1. The expression of protein and mRNA of the demethylated genes by AS2-1 in HCT116 cells was evaluated. In 19 of the 34 methylated genes in HCT116 and in 7 of the 8 methylated genes in KM12SM, the methylation status was downregulated after treatment with 2 mg/ml of AS2-1 for 24 h. AS2-1 dramatically downregulated the methylation status of p15 and ESR1 in HCT116 cells and of MTHFR and MUC2 in KM12SM cells. Both mRNA and protein expression of p15 increased in a dose- and time-dependent manner after treatment with AS2-1. The antineoplaston AS2-1 may normalize the hypermethylation status at the promoter region in various genes including tumor suppressor genes, resulting in activation of the transcription and translation in colon cancer.

Kusy M, Obrzut B, Kluska J
Application of gene expression programming and neural networks to predict adverse events of radical hysterectomy in cervical cancer patients.
Med Biol Eng Comput. 2013; 51(12):1357-65 [PubMed] Free Access to Full Article Related Publications
The aim of this article was to compare gene expression programming (GEP) method with three types of neural networks in the prediction of adverse events of radical hysterectomy in cervical cancer patients. One-hundred and seven patients treated by radical hysterectomy were analyzed. Each record representing a single patient consisted of 10 parameters. The occurrence and lack of perioperative complications imposed a two-class classification problem. In the simulations, GEP algorithm was compared to a multilayer perceptron (MLP), a radial basis function network neural, and a probabilistic neural network. The generalization ability of the models was assessed on the basis of their accuracy, the sensitivity, the specificity, and the area under the receiver operating characteristic curve (AUROC). The GEP classifier provided best results in the prediction of the adverse events with the accuracy of 71.96 %. Comparable but slightly worse outcomes were obtained using MLP, i.e., 71.87 %. For each of measured indices: accuracy, sensitivity, specificity, and the AUROC, the standard deviation was the smallest for the models generated by GEP classifier.

Than BL, Goos JA, Sarver AL, et al.
The role of KCNQ1 in mouse and human gastrointestinal cancers.
Oncogene. 2014; 33(29):3861-8 [PubMed] Free Access to Full Article Related Publications
Kcnq1, which encodes for the pore-forming α-subunit of a voltage-gated potassium channel, was identified as a gastrointestinal (GI) tract cancer susceptibility gene in multiple Sleeping Beauty DNA transposon-based forward genetic screens in mice. To confirm that Kcnq1 has a functional role in GI tract cancer, we created Apc(Min) mice that carried a targeted deletion mutation in Kcnq1. Results demonstrated that Kcnq1 is a tumor suppressor gene as Kcnq1 mutant mice developed significantly more intestinal tumors, especially in the proximal small intestine and colon, and some of these tumors progressed to become aggressive adenocarcinomas. Gross tissue abnormalities were also observed in the rectum, pancreas and stomach. Colon organoid formation was significantly increased in organoids created from Kcnq1 mutant mice compared with wild-type littermate controls, suggesting a role for Kcnq1 in the regulation of the intestinal crypt stem cell compartment. To identify gene expression changes due to loss of Kcnq1, we carried out microarray studies in the colon and proximal small intestine. We identified altered genes involved in innate immune responses, goblet and Paneth cell function, ion channels, intestinal stem cells, epidermal growth factor receptor and other growth regulatory signaling pathways. We also found genes implicated in inflammation and in cellular detoxification. Pathway analysis using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis confirmed the importance of these gene clusters and further identified significant overlap with genes regulated by MUC2 and CFTR, two important regulators of intestinal homeostasis. To investigate the role of KCNQ1 in human colorectal cancer (CRC), we measured protein levels of KCNQ1 by immunohistochemistry in tissue microarrays containing samples from CRC patients with liver metastases who had undergone hepatic resection. Results showed that low expression of KCNQ1 expression was significantly associated with poor overall survival.

Bengtsson AM, Jönsson G, Magnusson C, et al.
The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-induced differentiation of colon cancer cells.
BMC Cancer. 2013; 13:336 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT(1)R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT(2)R) is lost. Further, our previous data indicate that patients with high CysLT(1)R and low CysLT(2)R expression have a poor prognosis. In this study, we examined whether the balance between CysLT(1)R and CysLT(2)R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).
METHODS: To determine the effect of ATRA on CysLT(2)R promoter activation, mRNA level, and protein level, we performed luciferase gene reporter assays, real-time polymerase chain reactions, and Western blots in colon cancer cell lines under various conditions.
RESULTS: ATRA treatment induces CysLT(2)R mRNA and protein expression without affecting CysLT(1)R levels. Experiments using siRNA and mutant cell lines indicate that the up-regulation is retinoic acid receptor (RAR) dependent. Interestingly, ATRA also up-regulates mRNA expression of leukotriene C4 synthase, the enzyme responsible for the production of the ligand for CysLT(2)R. Importantly, ATRA-induced differentiation of colorectal cancer cells as shown by increased expression of MUC-2 and production of alkaline phosphatase, both of which could be reduced by a CysLT(2)R-specific inhibitor.
CONCLUSIONS: This study identifies a novel mechanism of action for ATRA in colorectal cancer cell differentiation and demonstrates that retinoids can have anti-tumorigenic effects through their action on the cysteinyl leukotriene pathway.

Walsh MD, Clendenning M, Williamson E, et al.
Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.
Mod Pathol. 2013; 26(12):1642-56 [PubMed] Related Publications
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.

Perrais M, Rousseaux C, Ducourouble MP, et al.
Helicobacter pylori urease and flagellin alter mucin gene expression in human gastric cancer cells.
Gastric Cancer. 2014; 17(2):235-46 [PubMed] Related Publications
BACKGROUND: Helicobacter pylori (Hp), which is one of the causative agents in human gastric adenocarcinoma, is known to interact with mucous gel and alter mucin gene expression. The aim of this work was to study, using an in vitro model of cell infection, the effects of urease, flagellin, and CagA virulence factors on the regulation of the four 11p15 mucin genes (MUC2, MUC5AC, MUC5B, and MUC6).
METHODS: KATO-III and AGS gastric cancer cells were infected for 1, 3 or 6 h with Hp wild-type strains (ATCC 43504, N6, and SS1) or corresponding isogenic mutants deficient for urease subunit B, flagellin subunit A, and CagA. mRNA levels of MUC2, MUC5B, MUC5AC and MUC6 were assessed by RT-PCR, and functional activity of their promoters was measured by transient transfection assays.
RESULTS: Infection of KATO-III cells with Hp wild-type strains resulted in an early (at 1 h) transient expression of MUC2, MUC5AC, and MUC6 mRNA concomitant with those of interleukin (IL)-1β, IL-8, and TNF-α cytokines. In these cells, the UreB(-) isogenic mutant induced strong activation of MUC5AC expression, and UreB-responsive elements were located in the -486/-1 region of the promoter. FlaA(-) and CagA(-) mutants had no effect on mucin gene mRNA levels in KATO-III cells. In AGS cells, Hp-responsive elements were identified in all promoters, and overexpression of NF-κB induced upregulation of MUC5AC promoter activity when infected with the UreB(-) isogenic mutant.
CONCLUSION: These results indicate that Hp infection of gastric cancer cells alters 11p15 mucin gene transcription and that MUC5AC downregulation is mediated by urease virulence factor.

Terada T
Primary cutaneous small cell carcinoma; a case report with differential diagnosis.
Int J Clin Exp Pathol. 2013; 6(6):1164-8 [PubMed] Free Access to Full Article Related Publications
Primary cutaneous small cell carcinoma (PC-SmCC) is extremely rare; only two cases have been reported in the world literatures. A 79-year-old woman presented a small cutaneous tumor in the face. Physical examination showed a tumor measuring 1.0x.08x0.6 cm in the shallow skin of the face. Excisional skin biopsy was performed. The biopsy showed complete excision of the tumor. The tumor was located in the shallow dermis and no connections to epidermis were seen. The tumor was invasive into subcutaneous tissue and surrounding dermis. The tumor was very hypercellular tumor composed of small cells with scant cytoplasm, hyperchromatic nu lei, negative nucleoli, and molded nuclei. The shapes of tumor cells are round, ovoid or spindle. The histological appearances fulfilled the criteria of SmCC of WHO. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CD5, CD6, CK8, p63, NSE, NCAM, synaptophysin (focal), chromogranin (focal), p53, KIT, PDGFRA and Ki-67 (labeling index (LI)=86%). They were negative for CK7, CK19, CK20, EMA, vimentin, CEA, S100 protein, CA19-9, TTF-1, MUC1, MUC2, MUC5AC and MUC6. Mucin histochemistry revealed no mucins. A molecular genetic analysis of PCR-direct sequencing identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The author diagnosed this cutaneous tumor as SmCC. Post-diagnosis whole body examination using various imaging and endoscopic techniques revealed no tumors. This may confirm that the skin tumor was primary. The cutaneous tumor was completely resected with wide margins. The patient is now followed up without therapy 8 months after the diagnosis. No recurrence or metastasis is seen. The differential diagnosis from Merkel cell carcinoma and basal cell carcinoma is very difficult and herein discussed.

Terada T
Urinary bladder urothelial carcinoma with expression of KIT and PDGFRA and showing diverse differentiations into plasmacytoid, clear cell, acantholytic, nested, and spindle variants, and into adenocarcinoma, signet-ring cell carcinoma, small cell carcinoma, large cell carcinoma, and pleomorphic carcinoma.
Int J Clin Exp Pathol. 2013; 6(6):1150-6 [PubMed] Free Access to Full Article Related Publications
Various tumors can arise in the urinary bladder (UB); most common is urothelial carcinoma (UC). UC of the UB have many variants. Other types of carcinomas such as adenocarcinoma (AC) and small cell carcinoma (SmCC) can occur in UB carcinomas. Expression of KIT and PDGFRA has not been reported. A 66-year-old man admitted to our hospital because of hematuria. Cystoscopy revealed papillary invasive tumor and a transurethral bladder tumorectomy (TUR-BT) was performed. The TUR-BT showed UC, AC, SmCC, large cell carcinoma (LCC), and pleomorphic carcinoma (PC). The UC component showed plasmacytoid, spindle, nested, clear cell, acantholytic variants. The AC element showed tubular adenocarcinoma and signet-ring cell carcinoma (Sig). Immunohistochemically, all of these subtypes were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CK5, CK6, CK7, CK8, CK18, CK19, CK20, EMA, CEA, p63, CA19-9, p53 (positive 45%), MUC1, NSE, NCAM, KIT, PDGFRA, and Ki-67 (87%). They were negative for vimentin, chromogranin, synaptophysin, S100 protein, CD34, CD14, α-smooth muscle actin, CD31, caldesmon, CD138, CD45, κ-chain, λ-chain, MUC2, MUC5AC and MUC6. Mucin histochemistry revealed mucins in AC element including Sig. A molecular genetic analysis using PCR-direct sequencing method identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The carcinoma was highly aggressive and invaded into muscular layer. The nuclear grade was very high, and there were numerous lymphovascular permeations were seen. The surface showed carcinoma in situ involving von-Brunn's nests. This case shows that carcinoma of UB can show diverse differentiations into numerous histological types and variants, and can express KIT and PDGFRA. The both genes showed no mutations in the present case.

Hata H, Abe R, Hoshina D, et al.
MUC5AC expression correlates with invasiveness and progression of extramammary Paget's disease.
J Eur Acad Dermatol Venereol. 2014; 28(6):727-32 [PubMed] Related Publications
BACKGROUND: Patients with in situ extramammary Paget's disease (EMPD) tend to have a good prognosis, although dermal invasion and metastasis are associated with significantly increased morbidity and mortality. Previous studies have addressed mechanisms underlying the EMPD pathogenesis; however, no molecular markers that reflect invasiveness or progression have been established.
OBJECTIVE: This study aims to identify a reliable marker for predicting the risk of invasion and metastasis in EMPD.
METHODS: We performed an initial microarray screening for in situ, invasive or metastatic lymph node lesions of EMPD. We analysed 44 specimens from 38 primary EMPD cases by immunohistochemical staining.
RESULTS: We found that expressions of MUC5AC directly correlate with invasion and prognosis. Labelling rates of tumour cells were scored by staining intensity on a four-tiered scale (- to 3+) to investigate the correlation between the expression score of these molecular markers and the type of EMPD lesion. All the specimens scored positive (3+) for MUC1 and negative (-) for MUC6. MUC5AC expression was detected in 19 of 44 (43.2%) specimens. Invasive lesions and metastatic lymph nodes tended to express MUC5AC significantly higher than in situ lesions (P < 0.01). MUC2 was positive in 10 specimens (22.7%). There was no significant difference between the degree of MUC2 expression and invasiveness.
CONCLUSION: The degree of MUC5AC expression may correlate with the invasiveness and progression of EMPD, and may be a useful marker for identifying high-risk EMPD cases.

Terada T
Primary cutaneous neuroendocrine tumor (atypical carcinoid) expressing KIT and PDGFRA with myoepithelial differentiation: a case report with immunohistochemical and molecular genetic studies.
Int J Clin Exp Pathol. 2013; 6(4):802-9 [PubMed] Free Access to Full Article Related Publications
Primary cutaneous neuroendocrine tumors (NET) except for Merkel cell carcinoma have rarely been reported. Herein reported is a very unique case of primary cutaneous NET with immunohistochemical markers of myoepitheliomas. A 47-year-old woman presented a tumor measuring 0.8x0.9x0.6 cm of the face. The tumor was excised completely with wide margins. Morphologically, the tumor was located in the dermis, and the tumor was composed of epithelioid cells arranged in trabecular, sinusoidal, rosette, ribbon-like, and cord-like patterns. Focal areas show tubular formations. The tumor cells were homogenous, and their nuclei showed hyperchromasia but no apparent histological features of malignancy were seen. The stroma was very scant. No invasive features were seen. Immunohistochemically, the tumor cells were strongly positive for cytokeratin (CK) 34BE12, CD5/6, CK14, NCAM (CD56), p63, and KIT (CD117), and moderately positive for CK AE1/3, p53, chromogranin, synaptophysin, neuron-specific enolase (NSE), PDGFRA, CA19-9, and Ki-67 antigen (labeling index=23%). The tumor cells were negative for CK CAM5.2, CK7, CK8, CK18,CK19,CK20, EMA, vimentin, CEA, HMB45, S100 protein, α-smooth muscle antigen, desmin, CD34, GFAP, neurofilaments, CD99 (MIC2), CD45, CD57, ErbB2, TTF-1, MUC1, MUC2, MUC5AC, and MUC6. Mucins examined by d-PAS and Alcian blue techniques were negative. A genetic analysis using PCR-direct sequencing method in paraffin sections identified no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. Imaging modalities including CT and MRI identified no tumor in the body. The clinicians thought that the tumor was cured. She was a sailor and immediately visited other countries; therefore the follow-up could not be done.

Ideno N, Ohtsuka T, Kono H, et al.
Intraductal papillary mucinous neoplasms of the pancreas with distinct pancreatic ductal adenocarcinomas are frequently of gastric subtype.
Ann Surg. 2013; 258(1):141-51 [PubMed] Related Publications
OBJECTIVE: To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes.
BACKGROUND: Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types.
METHODS: Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with and without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs.
RESULTS: Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC.
CONCLUSIONS: Mucin expression patterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.

Yin H, Liang Y, Yan Z, et al.
Mutation spectrum in human colorectal cancers and potential functional relevance.
BMC Med Genet. 2013; 14:32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatic variants, which occur in the genome of all cells, are well accepted to play a critical role in cancer development, as their accumulation in genes could affect cell proliferations and cell cycle.
METHODS: In order to understand the role of somatic mutations in human colorectal cancers, we characterized the mutation spectrum in two colorectal tumor tissues and their matched normal tissues, by analyzing deep-sequenced transcriptome data.
RESULTS: We found a higher mutation rate of somatic variants in tumor tissues in comparison with normal tissues, but no trend was observed for mutation properties. By applying a series of stringent filters, we identified 418 genes with tumor specific disruptive somatic variants. Of these genes, three genes in mucin protein family (MUC2, MUC4, and MU12) are of particular interests. It has been reported that the expression of mucin proteins was correlated with the progression of colorectal cancer therefore somatic variants within those genes can interrupt their normal expression and thus contribute to the tumorigenesis.
CONCLUSIONS: Our findings provide evidence of the utility of RNA-Seq in mutation screening in cancer studies, and suggest a list of candidate genes for future colorectal cancer diagnosis and treatment.

Saxena A, Baliga MS, Ponemone V, et al.
Mucus and adiponectin deficiency: role in chronic inflammation-induced colon cancer.
Int J Colorectal Dis. 2013; 28(9):1267-79 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study aims to define the role of adiponectin (APN) in preventing goblet cell apoptosis and in differentiation of epithelial cells to goblet cell lineage resulting in greater mucus production and hence greater protection from chronic inflammation-induced colon cancer (CICC).
METHODS: Six- to eight-week-old male APNKO and C57BL/6 (WT) mice were randomly distributed to three treatment groups: DSS, DMH, DSS + DMH and control. Chronic inflammation was induced in DSS and DSS + DMH group by administrating 2 % DSS in drinking water for 5 days followed by 5 days of normal drinking water and this constitutes one DSS cycle. Three cycles of DSS were administered to induce chronic inflammation. Cancer was induced in both APNKO and WT mice in DMH and DSS + DMH groups by intraperitoneal injections of DMH (20 mg/kg body weight) once for DSS + DMH group and once per week for 12 weeks for DMH group. On day 129, the colon tissue was dissected for mucus thickness measurements and for genomic studies. HT29-C1.16E and Ls174T cells were used for several genomic and siRNA studies.
RESULTS: APNKO mice have more tumors and tumor area in DSS + DMH group than WT mice. APN deficiency downregulated goblet to epithelial cell ratio and enhanced the colonic mucosal erosion with reduced mucus thickness. APN increases Muc2 production with no affect on Muc1 production. APN abated goblet cell apoptosis, while APN deficiency reduced epithelial to goblet cell differentiation.
CONCLUSION: APN may be involved in reducing the severity of CICC by preventing goblet cell apoptosis and increasing epithelial to goblet cell differentiation.

Souazé F, Bou-Hanna C, Kandel C, et al.
Differential roles of Hath1, MUC2 and P27Kip1 in relation with gamma-secretase inhibition in human colonic carcinomas: a translational study.
PLoS One. 2013; 8(2):e55904 [PubMed] Free Access to Full Article Related Publications
Hath1, a bHLH transcription factor negatively regulated by the γ-secretase-dependent Notch pathway, is required for intestinal secretory cell differentiation. Our aim was fourfold: 1) determine whether Hath1 is able to alter the phenotype of colon cancer cells that are committed to a differentiated phenotype, 2) determine whether the Hath1-dependent alteration of differentiation is coupled to a restriction of anchorage-dependent growth, 3) decipher the respective roles of three putative tumor suppressor genes Hath1, MUC2 and P27kip1 in this coupling and, 4) examine how our findings translate to primary tumors. Human colon carcinoma cell lines that differentiate along a mucin secreting (MUC2/MUC5AC) and/or enterocytic (DPPIV) lineages were maintained on inserts with or without a γ-secretase inhibitor (DBZ). Then the cells were detached and their ability to survive/proliferate in the absence of substratum was assessed. γ-secretase inhibition led to a Hath1-mediated preferential induction of MUC2 over MUC5AC, without DPPIV modification, in association with a decrease in anchorage-independent growth. While P27kip1 silencing relieved the cells from the Hath1-induced decrease of anchorage-independent growth, MUC2 silencing did not modify this parameter. Hath1 ectopic expression in the Hath1 negative enterocytic Caco2 cells led to a decreased anchorage-independent growth in a P27kip1-independent manner. In cultured primary human colon carcinomas, Hath1 was up-regulated in 7 out of 10 tumors upon DBZ treatment. Parallel MUC2 up-regulation occurred in 4 (4/7) and P27kip1 in only 2 (2/7) tumors. Interestingly, the response patterns of primary tumors to DBZ fitted with the hierarchical model of divergent signalling derived from our findings on cell lines.

Kwon MJ, Min BH, Lee SM, et al.
Serrated adenoma of the stomach: a clinicopathologic, immunohistochemical, and molecular study of nine cases.
Histol Histopathol. 2013; 28(4):453-62 [PubMed] Related Publications
Gastric serrated adenoma is a recently recognized entity that has been rarely described and poorly characterized. To examine whether gastric serrated adenoma shares the same immunophenotypic and molecular features of its colorectal traditional serrated adenoma, the clinicopathologic features, expression of mucin proteins (MUC2, MUC5AC, CD10, MUC6) and mismatch repair protein (MLH1), and mutations of BRAF and KRAS genes were studied. The nine serrated adenomas were obtained from five men and four women, with a mean age of 67 years. Seven (78%) serrated adenomas were located in the body of the stomach. The endoscopic findings were not sufficiently characteristic to diagnose serrated adenoma or serrated adenocarcinoma; however, most were elevated lesions. The initial biopsy material was available in all cases and the serrated features were evident in 6 cases diagnosed as adenoma. Among the nine cases, seven (78%) were associated with invasive adenocarcinoma within the serrated adenoma. MUC5AC was expressed in 6 serrated adenomas (67%). Expression of MUC5AC was observed in all tumors located in the lower third of the stomach. Focal MUC6 expression was observed in the basal part of two serrated adenomas. MLH1 expression was lost in two cases (22%). KRAS mutations were observed in three cases (33%) while BRAF mutations were not detected in any of the cases. Gastric serrated adenoma does not completely share the same immunophenotypic and molecular features of its colorectal counterpart. Gastric serrated adenomas are frequently associated with adenocarcinoma. When serrated adenoma is encountered in a gastric biopsy specimen, the possibility of associated adenocarcinoma should be considered in the adjacent stomach.

Nishikawa G, Sekine S, Ogawa R, et al.
Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms.
Br J Cancer. 2013; 108(4):951-8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The molecular basis for the development of appendiceal mucinous tumours, which can be a cause of pseudomyxoma peritonei, remains largely unknown.
METHODS: Thirty-five appendiceal mucinous neoplasms were analysed for GNAS and KRAS mutations. A functional analysis of mutant GNAS was performed using a colorectal cancer cell line.
RESULTS: A mutational analysis identified activating GNAS mutations in 16 of 32 low-grade appendiceal mucinous neoplasms (LAMNs) but in none of three mucinous adenocarcinomas (MACs). KRAS mutations were found in 30 LAMNs and in all MACs. We additionally analysed a total of 186 extra-appendiceal mucinous tumours and found that GNAS mutations were highly prevalent in intraductal papillary mucinous tumours of the pancreas (88%) but were rare or absent in mucinous tumours of the colorectum, ovary, lung and breast (0-9%). The prevalence of KRAS mutations was quite variable among the tumours. The introduction of the mutant GNAS into a colorectal cancer cell line markedly induced MUC2 and MUC5AC expression, but did not promote cell growth either in vitro or in vivo.
CONCLUSION: Activating GNAS mutations are a frequent and characteristic genetic abnormality of LAMN. Mutant GNAS might play a direct role in the prominent mucin production that is a hallmark of LAMN.

Makita K, Kitazawa R, Semba S, et al.
Cdx2 expression and its promoter methylation during metaplasia-dysplasia-carcinoma sequence in Barrett's esophagus.
World J Gastroenterol. 2013; 19(4):536-41 [PubMed] Free Access to Full Article Related Publications
AIM: To examine how the expression of caudal type homebox transcription factor 2 (Cdx2) is regulated in the development of malignancy in Barrett's esophagus.
METHODS: Cdx2, mucin (MUC) series (MUC2, MUC5AC and MUC6), p53 and E-cadherin expression in Barrett's esophagus and adenocarcinoma specimens were examined by immunostaining. Isolated clusters of cells from (1) MUC2 and Cdx2-positive intestinal metaplastic mucosa; (2) MUC5AC and MUC6-positive, and MUC2 and Cdx2-negative high-grade dysplasia (HD), or intramucosal adenocarcinoma (IMC); and (3) MUC5AC, MUC6 and Cdx2-positive poorly-differentiated invasive adenocarcinoma (PDA) were analyzed by methylation-specific polymerase chain reaction using sets of primers for detecting methylation status of the Cdx2 gene.
RESULTS: Most of the non-neoplastic Barrett's esophageal mucosa showing intestinal-type metaplasia with or without low-grade dysplasia was positive for E-cadherin, MUC series and Cdx2, but negative for p53. A portion of the low-grade to HD was positive for E-cadherin, MUC5AC, MUC6 and p53, but negative for MUC2 and Cdx2. The definite IMC area was strongly positive for MUC5AC, MUC6 and p53, but negative for MUC2 and Cdx2. Methylation of the Cdx2 promoter was not observed in intestinal metaplasia, while hypermethylation of part of its promoter was observed in hot dipped and IMC. Hypermethylation of a large fraction of the Cdx2 promoter was observed in PDA.
CONCLUSION: Cdx2 expression is restored irrespective of the methylation status of its promoter. Apparent positive immunohistochemical results can be a molecular mark for gene silencing memory.

Walsh MD, Cummings MC, Pearson SA, et al.
Lynch syndrome-associated breast cancers do not overexpress chromosome 11-encoded mucins.
Mod Pathol. 2013; 26(7):944-54 [PubMed] Free Access to Full Article Related Publications
Mismatch repair-deficient breast cancers may be identified in Lynch syndrome mutation carriers, and have clinicopathological features in common with mismatch repair-deficient colorectal and endometrial cancers such as tumour-infiltrating lymphocytes and poor differentiation. Mismatch repair-deficient colorectal cancers frequently show mucinous differentiation associated with upregulation of chromosome 11 mucins. The aim of this study was to compare the protein expression of these mucins in mismatch repair-deficient and -proficient breast cancers. Cases of breast cancer (n=100) were identified from families where (1) both breast and colon cancer co-occurred and (2) families met either modified Amsterdam criteria or had at least one early-onset (<50 years) colorectal cancer. Tumour sections were stained for the epithelial mucins, MUC2, MUC5AC, MUC5B and MUC6, and the homeobox protein CDX2, a regulator of MUC2 expression. In all, 16 mismatch repair-deficient Lynch syndrome breast cancers and 84 non-Lynch breast cancers were assessed for altered mucin expression. No significant difference in the expression of MUC2, MUC5AC or MUC6 was observed between the mismatch repair-deficient and mismatch repair-proficient breast cancers; however, there was a trend for mismatch repair-deficient tumours to express high levels of MUC5B less frequently (P=0.07, OR=0.2 (0.0-1.0)). Co-expression of two or more gel-forming mucins was common. Ectopic expression of CDX2 was associated with expression of MUC2 (P=0.035, OR=8.7 (1.3-58.4)). Mismatch repair-deficient breast cancers do not show differential expression of the mucins genes on chromosome 11 when compared with mismatch repair-proficient breast cancers, in contrast with mismatch repair-deficient colorectal and endometrial cancers, which frequently have increased mucin protein expression when compared with their mismatch repair-proficient counterparts. In addition, ectopic CDX2 expression is positively associated with de novo MUC2 expression.

Ling Y, Zhu J, Gao L, et al.
The silence of MUC2 mRNA induced by promoter hypermethylation associated with HBV in Hepatocellular Carcinoma.
BMC Med Genet. 2013; 14:14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: To evaluate the promoter methylation status of MUC2 gene and mRNA expression in patients with hepatocellular carcinoma.
METHODS: We analyzed MUC2 methylation by MSP, and MUC2 mRNA by real-time PCR in 74 HCC.
RESULTS: MUC2 mRNA were lower in HCC tissues (Mean -ΔCt = -4.70) than that in Non-HCC tissues (Mean -ΔCt = -2.98). Expression of MUC2 was elevated in only 23 (31.08%) of the 74 HCC patients. MUC2 promoter was hypermethylated in 62.2% (46/74) of HCCs, and in only 18.9% (14/74) of non-tumor samples. MUC2 mRNA were lower in HCC patients with hypermethylation (Mean -ΔΔCt = -2.25) than those with demethylation (Mean -ΔΔCt = -0.22), and there is a decreased tendency for MUC2 mRNA in HCC patients with promoter hypermethylation (p = 0.011). There was a significantly correlation found between MUC2 mRNA and HBV and AFP in HCC. The loss of MUC2 mRNA and hypermethylation could be poor prognostic factors. After treated by 5-Aza-CdR and TSA, we found that MUC2 mRNA induced significantly in 7721, Huh7 and HepG2 cells.
CONCLUSION: The results suggested that MUC2 mRNA silenced by promoter hypermethylation is associated with high levels HBV in HCC.

Inagaki-Ohara K, Mayuzumi H, Kato S, et al.
Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.
Oncogene. 2014; 33(1):74-84 [PubMed] Related Publications
Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.

Nakae K, Mitomi H, Saito T, et al.
MUC5AC/β-catenin expression and KRAS gene alteration in laterally spreading colorectal tumors.
World J Gastroenterol. 2012; 18(39):5551-9 [PubMed] Free Access to Full Article Related Publications
AIM: To clarify differences in mucin phenotype, proliferative activity and oncogenetic alteration among subtypes of colorectal laterally spreading tumor (LST).
METHODS: LSTs, defined as superficial elevated lesions greater than 10 mm in diameter with a low vertical axis, were macroscopically classified into two subtypes: (1) a granular type (Gr-LST) composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface; and (2) a non-granular type (NGr-LST) with a flat smooth surface and an absence of granulonodular formation. A total of 69 LSTs, comprising 36 Gr-LSTs and 33 NGr-LSTs, were immunohistochemically stained with MUC2, MUC5AC, MUC6, CD10 (markers of gastrointestinal cell lineage), p53, β-catenin and Ki-67 antibodies, and examined for alteration in exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and exon 15 of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) by polymerase chain reaction followed by direct sequencing.
RESULTS: Histologically, 15 Gr-LST samples were adenomas with low-grade dysplasia (LGD), 12 were high-grade dysplasia (HGD) and 9 were adenocarcinomas invading the submucosa (INV), while 12 NGr-LSTs demonstrated LGD, 14 HGD and 7 INV. In the proximal colon, MUC5AC expression was significantly higher in the Gr-type than the NGr-type. MUC6 was expressed only in NGr-LST. MUC2 or CD10 did not differ. P53 expression demonstrated a significant stepwise increment in progression through LGD-HGD-INV with both types of LST. Nuclear β-catenin expression was significantly higher in the NGr-type. Ki-67 expression was significantly higher in the Gr-type in the lower one third zone of the tumor. In proximal, but not distal colon tumors, the incidence of KRAS provided mutation was significantly higher in the Gr-type harboring a specific mutational pattern (G12V). BRAF mutations (V600E) were detected only in two Gr-LSTs.
CONCLUSION: The two subtypes of LST, especially in the proximal colon, have differing phenotypes of gastrointestinal cell lineage, proliferation and activation of Wnt/β-catenin or RAS/RAF/extracellular signal-regulated kinase signaling.

Kawashima H
Roles of the gel-forming MUC2 mucin and its O-glycosylation in the protection against colitis and colorectal cancer.
Biol Pharm Bull. 2012; 35(10):1637-41 [PubMed] Related Publications
MUC2 is the major gel-forming colonic mucin that forms the two mucus layers. Recent studies using gene-targeted mice have revealed the physiological functions of Muc2, the mouse counterpart of human MUC2, and its O-glycosylation in the colon. Muc2-deficient mice spontaneously developed colitis and colorectal cancer. As for the O-glycosylation of Muc2, conditional core 1-derived O-glycan-deficient mice in the intestines exhibited a breached inner mucus layer and spontaneously developed colitis. Similarly, core 3-derived O-glycan-deficient mice exhibited an increased susceptibility to colitis and colorectal cancer, suggesting that both core 1- and core 3-derived O-glycans on Muc2 are required for colonic protection. Mice deficient in core 2-branched O-glycans synthesized after the formation of core 1 O-glycans also exhibited increased experimental colitis. Furthermore, our recent studies using gene-targeted mice deficient in N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-2 revealed that sulfation of the core 2-branched O-glycans of the colonic mucins by GlcNAc6ST-2 is required for the protection against experimental colitis. Taken together, these findings demonstrate the critical roles of the MUC2 mucin and its various O-glycans in the protection against colitis and colorectal cancer. Consistently, various alterations in the expression of mucins and their O-glycosylation have been noted in clinical samples of colorectal cancer. This review focuses on the roles of the MUC2 core protein and its O-glycosylation in health and disease.

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