Gene Summary

Gene:MUC5AC; mucin 5AC, oligomeric mucus/gel-forming
Aliases: TBM, leB, MUC5
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 27 February, 2015


What does this gene/protein do?
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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.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: MUC5AC (cancer-related)

Liszka L
Ductal adenocarcinoma of the pancreas usually retained SMAD4 and p53 protein status as well as expression of epithelial-to-mesenchymal transition markers and cell cycle regulators at the stage of liver metastasis.
Pol J Pathol. 2014; 65(2):100-12 [PubMed] Related Publications
There are limited data on the biology of metastatic pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to compare the expression of immunohistochemical markers that may be involved in the development of metastatic disease in primary PDAC and in synchronous liver metastatic tissues. Thirty-two stains (corresponding to proteins encoded by 31 genes: SMAD4, TP53, ACTA2, CDH1, CDKN1A, CLDN1, CLDN4, CLDN7, CTNNB1, EGFR, ERBB2, FN1, KRT19, MAPK1/MAPK3, MAPK14, MKI67, MMP2, MMP9, MUC1 (3 antibodies), MUC5AC, MUC6, MTOR, MYC, NES, PTGS2, RPS6, RPS6KB1, TGFB1, TGFBR1, VIM) were evaluated using tissue microarray of 26 pairs of primary PDACs and their liver metastases. There were no significant differences in expression levels of examined proteins between primary and secondary lesions. In particular, metastatic PDAC retained the primary tumour's SMAD4 protein status in all and p53 protein status in all but one case. This surprising homogeneity also involved expression levels of markers of epithelial-to-mesenchymal transition as well as cell cycle regulators studied. In conclusion, the biological profiles of primary PDACs and their liver metastases seemed to be similar. Molecular alterations of PDAC related to a set of immunohistochemical markers examined in the present study were already present at the stage of localized disease.

Musrap N, Karagiannis GS, Saraon P, et al.
Proteomic analysis of cancer and mesothelial cells reveals an increase in Mucin 5AC during ovarian cancer and peritoneal interaction.
J Proteomics. 2014; 103:204-15 [PubMed] Related Publications
UNLABELLED: Ovarian cancer is a highly metastatic disease that is often characterized by widespread abdominal dissemination. A hallmark of ovarian cancer progression is the attachment of malignant cells to the mesothelium and the formation of invasive peritoneal implants. Therefore, delineating factors involved in cancer-peritoneal cell interaction is critical to improving patient survival, as it may lead to the discovery of novel therapeutic targets. As such, we aimed to identify proteins that participate in this interaction by comparing the secreted proteome of a co-culture model containing ovarian cancer (OVCAR-5) and mesothelial cells (LP-9), to their respective monoculture secretomes. In total, 49 proteins were differentially secreted during cancer and mesothelial cell contact. Relative mRNA expression of candidates was performed, which revealed a significant increase in MUC5AC gene expression in cancer cells cultured in three different co-culture models (OVCAR-5 and LP-9; BG-1 and LP-9; OV-90 and LP-9). An increased expression was also observed in LP-9 cells that were co-cultured with OVCAR-5 and OV-90 cancer cells. Further immunocytochemistry analysis also confirmed increased expression of MUC5AC in ovarian cancer and peritoneal co-cultures. Overall, our analysis uncovers novel molecular markers of peritoneal metastasis, which may have potential roles in regulating the progression of the disease.
BIOLOGICAL SIGNIFICANCE: In this study, our objective was to focus on identifying novel mediators of ovarian cancer and peritoneal interaction using a mass spectrometry-based approach. Our analysis resulted in the discovery of both previously known and novel factors involved this interaction, and as such, these newly discovered proteins might have potential roles in cancer progression, such as invasion and adhesion. We believe that these findings add to our current knowledge and understanding of ovarian cancer progression, and will aid researchers in their future attempts in finding new targets of the disease.

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.

Ono H, Motoi N, Nagano H, et al.
Long noncoding RNA HOTAIR is relevant to cellular proliferation, invasiveness, and clinical relapse in small-cell lung cancer.
Cancer Med. 2014; 3(3):632-42 [PubMed] Free Access to Full Article Related Publications
Small-cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis. To identify accurate predictive biomarkers and effective therapeutic modalities, we focus on a long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR), and investigated its expression, cellular functions, and clinical relevance in SCLC. In this study, HOTAIR expression was assessed in 35 surgical SCLC samples and 10 SCLC cell lines. The efficacy of knockdown of HOTAIR by siRNA transfection was evaluated in SBC-3 cells in vitro, and the gene expression was analyzed using microarray. HOTAIR was expressed highly in pure, rather than combined, SCLC (P = 0.012), that the subgroup with high expression had significantly more pure SCLC (P = 0.04), more lymphatic invasion (P = 0.03) and more relapse (P = 0.04) than the low-expression subgroup. The knockdown of HOTAIR in SBC-3 cells led to decreased proliferation activity and decreased invasiveness in vitro. Gene expression analysis indicated that depletion of HOTAIR resulted in upregulation of cell adhesion-related genes such as ASTN1, PCDHA1, and mucin production-related genes such as MUC5AC, and downregulation of genes involved in neuronal growth and signal transduction including NTM and PTK2B. Our results suggest that HOTAIR has an oncogenic role in SCLC and could be a prognostic biomarker and therapeutic target.

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.

Chen Y, Garvin LM, Nickola TJ, et al.
IL-1β induction of MUC5AC gene expression is mediated by CREB and NF-κB and repressed by dexamethasone.
Am J Physiol Lung Cell Mol Physiol. 2014; 306(8):L797-807 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Chronic airway diseases are characterized by inflammation and mucus overproduction. The MUC5AC mucin gene is upregulated by the proinflammatory cytokine interleukin-1 β (IL-1β) via activation of cAMP response element-binding protein (CREB) in the NCI-H292 cancer cell line and nuclear factor-κB (NF-κB) in the HBE1 transformed cell line, with each transcription factor binding to a cognate cis site in the proximal or distal region, respectively, of the MUC5AC promoter. We utilized primary differentiated human bronchial epithelial (HBE) and A549 lung adenocarcinoma cells to further investigate the contributions of CREB and NF-κB subunits to the IL-1β-induced upregulation of MUC5AC. Data show that ligand binding of IL-1β to the IL-1β receptor is required to increase MUC5AC mRNA abundance. Chromatin immunoprecipitation analyses show direct binding of CREB to the previously identified cAMP response element site and binding of p65 and p50 subunits to a novel NF-κB site in a mucin-regulatory domain in the proximal promoter and to a previously identified NF-κB site in the distal promoter. P50 binds to both NF-κB sites at 1 h following IL-1β exposure, but is replaced at 2 h by p65 in A549 cells and by a p50/p65 heterodimer in HBE cells. Thus IL-1β activates multiple domains in the MUC5AC promoter but exhibits some cell-specific responses, highlighting the complexity of MUC5AC transcriptional regulation. Data show that dexamethasone, a glucocorticoid that transcriptionally represses MUC5AC gene expression under constitutive conditions, also represses IL-1β-mediated upregulation of MUC5AC gene expression. A further understanding of mechanisms mediating MUC5AC regulation should lead to a honing of therapeutic approaches for the treatment of mucus overproduction in inflammatory lung diseases.

Pan S, Chen R, Tamura Y, et al.
Quantitative glycoproteomics analysis reveals changes in N-glycosylation level associated with pancreatic ductal adenocarcinoma.
J Proteome Res. 2014; 13(3):1293-306 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
Glycosylation plays an important role in epithelial cancers, including pancreatic ductal adenocarcinoma. However, little is known about the glycoproteome of the human pancreas or its alterations associated with pancreatic tumorigenesis. Using quantitative glycoproteomics approach, we investigated protein N-glycosylation in pancreatic tumor tissue in comparison with normal pancreas and chronic pancreatitis tissue. The study lead to the discovery of a roster of glycoproteins with aberrant N-glycosylation level associated with pancreatic cancer, including mucin-5AC (MUC5AC), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), insulin-like growth factor binding protein (IGFBP3), and galectin-3-binding protein (LGALS3BP). Pathway analysis of cancer-associated aberrant glycoproteins revealed an emerging phenomenon that increased activity of N-glycosylation was implicated in several pancreatic cancer pathways, including TGF-β, TNF, NF-kappa-B, and TFEB-related lysosomal changes. In addition, the study provided evidence that specific N-glycosylation sites within certain individual proteins can have significantly altered glycosylation occupancy in pancreatic cancer, reflecting the complexity of the molecular mechanisms underlying cancer-associated glycosylation events.

Aissi S, Buisine MP, Zerimech F, et al.
Somatic molecular changes and histo-pathological features of colorectal cancer in Tunisia.
World J Gastroenterol. 2013; 19(32):5286-94 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
AIM: To determine correlations between family history, clinical features and mutational status of genes involved in the progression of colorectal cancer (CRC).
METHODS: Histo-pathological features and molecular changes [KRAS, BRAF and CTNNB1 genes mutations, microsatellite instability (MSI) phenotype, expression of mismatch repair (MMR) and mucin (MUC) 5AC proteins, mutation and expression analysis of TP53, MLH1 promoter hypermethylation analysis] were examined in a series of 51 unselected Tunisian CRC patients, 10 of them had a proven or probable hereditary disease, on the track of new tumoral markers for CRC susceptibility in Tunisian patients.
RESULTS: As expected, MSI and MMR expression loss were associated to the presence of familial CRC (75% vs 9%, P < 0.001). However, no significant associations have been detected between personal or familial cancer history and KRAS (codons 12 and 13) or TP53 (exons 4-9) alterations. A significant inverse relationship has been observed between the presence of MSI and TP53 accumulation (10.0% vs 48.8%, P = 0.0335) in CRC tumors, suggesting different molecular pathways to CRC that in turn may reflect different environmental exposures. Interestingly, MUC5AC expression was significantly associated to the presence of MSI (46.7% vs 8.3%, P = 0.0039), MMR expression loss (46.7% vs 8.3%, P = 0.0039) and the presence of familial CRC (63% vs 23%, P = 0.039).
CONCLUSION: These findings suggest that MUC5AC expression analysis may be useful in the screening of Tunisian patients with high risk of CRC.

Hao Y, Kuang Z, Xu Y, et al.
Pyocyanin-induced mucin production is associated with redox modification of FOXA2.
Respir Res. 2013; 14:82 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: The redox-active pyocyanin (PCN) is a toxic, secondary metabolite secreted by the respiratory pathogen Pseudomonas aeruginosa (PA). Previously, we have shown that mouse lungs chronically exposed to PCN develop goblet cell hyperplasia and metaplasia (GCHM) and mucus hypersecretion, fibrosis and emphysema. These pathological features are commonly found in the airways of several chronic lung diseases, including cystic fibrosis (CF), as well as in mouse airways deficient in the forkhead box A2 (FOXA2), a transcriptional repressor of goblet GCHM and mucus biosynthesis. Furthermore, PCN inhibits FOXA2 by activating the pro-GCHM signaling pathways Stat6 and EGFR. However, it is not known whether PCN-generated reactive oxygen (ROS) and nitrogen (RNS) species posttranslationally modify and inactivate FOXA2.
METHODS: We examined the posttranslational modifications of FOXA2 by PCN using specific antibodies against oxidation, nitrosylation, acetylation and ubiquitination. Electrophoretic mobility shift assay (EMSA) was used to examine the ability of modified FOXA2 to bind the promoter of MUC5B mucin gene. In addition, we used quantitative real time PCR, ELISA, immunofluorescence and mouse lung infection to assess whether the loss of FOXA2 function caused GCHM and mucin overexpression. Finally, we examined the restoration of FOXA2 function by the antioxidant glutathione (GSH).
RESULTS: We found that PCN-generated ROS/RNS caused nitrosylation, acetylation, ubiquitination and degradation of FOXA2. Modified FOXA2 had reduced ability to bind the promoter of the MUC5B gene. The antioxidant GSH alleviated the modification of FOXA2 by PCN, and inhibited the overexpression of MUC5AC and MUC5B mucins.
CONCLUSION: These results suggest that PCN-mediated posttranslational modifications of FOXA2 are positively correlated with GCHM and overexpression of airway mucins. Furthermore, antioxidant treatment restores the function of FOXA2 to attenuate GCHM and mucus hypersecretion.

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.

Kim SM, Kwon CH, Shin N, et al.
Decreased Muc5AC expression is associated with poor prognosis in gastric cancer.
Int J Cancer. 2014; 134(1):114-24 [PubMed] Related Publications
Mucins reportedly play numerous key roles in carcinogenesis, including in tumor invasion, regulation of differentiation and tumor cell proliferation. We investigated the effect of Muc5AC, a secreted mucin, on the invasiveness/migratory capability of gastric cancer cells and the prognostic significance of Muc5AC in gastric cancer patients. The clinicopathological and prognostic significance of Muc5AC expression was validated using immunohistochemical analysis in 412 gastric cancer patients. Differential gene expression was investigated using complementary DNA microarray analysis of 48 fresh tumor tissue samples. Silencing of Muc5AC by using a small hairpin RNA-containing lentivirus increased the invasion and migration of SNU216 and AGS cells as well as Akt phosphorylation and the expression of vascular endothelial growth factor and matrix metalloproteinase-7, which were blocked by inhibitors of the phosphatidylinositol 3-kinase/Akt pathway. Loss of Muc5AC expression was significantly associated with tumor progression (advanced T stage; p = 0.004), lymph node metastases (p = 0.001), lymphovascular invasion (p < 0.0001), and increased tumor size (p = 0.027). Lower MUC5AC expression was identified as an independent poor prognostic factor in diffuse-type gastric cancer by using the Cox regression proportional hazard model (hazard ratio, 2.39; p = 0.043). Complementary DNA microarray analysis revealed 86 differentially expressed genes, including genes related to metastasis and invasion, in gastric cancer tissues with high (≥25%) and low (<25%) Muc5AC expression levels. Low Muc5AC expression increased the invasion and migration of gastric cancer cells and could be a useful biomarker of poor prognosis in gastric cancer.

Haslene-Hox H, Oveland E, Woie K, et al.
Increased WD-repeat containing protein 1 in interstitial fluid from ovarian carcinomas shown by comparative proteomic analysis of malignant and healthy gynecological tissue.
Biochim Biophys Acta. 2013; 1834(11):2347-59 [PubMed] Related Publications
We aimed to identify differentially expressed proteins in interstitial fluid from ovarian cancer employing multiple fractioning and high resolution mass spectrometry-based proteomic analysis, and asked whether specific proteins that may serve as biomarker candidates or therapeutic targets could be identified. High throughput proteomics was conducted on immunodepleted and fractioned interstitial fluid from pooled samples of ovarian carcinomas, using endometrial carcinomas and healthy ovarian tissue as controls. Differential analysis revealed the up-regulation of extracellular proteasomes in tumor interstitial fluid compared to the healthy control. Moreover, a number of differentially expressed proteins in interstitial fluid from ovarian carcinomas compared with control tissues were identified. Detection of proteasome 20S related proteins in TIF compared to IF from healthy tissue indicates that the 20S proteasome can have a role in the tumor microenvironment. Six selected proteins, CEACAM5, FREM2, MUC5AC, TFF3, PYCARD and WDR1, were independently validated in individual tumor lysates from ovarian carcinomas by multiple reaction monitoring initiated detection and sequence analysis, Western blot and/or selected reaction monitoring. Quantification of specific proteins revealed substantial heterogeneity between individual samples. Nevertheless, WD repeat-containing protein 1 was confirmed as being significantly overexpressed in interstitial fluid from ovarian carcinomas compared to healthy ovarian tissue by Orbitrap analysis of individual native interstitial fluid from ovarian and endometrial carcinomas and healthy ovarian tissue. We suggest that this protein should be explored as a therapeutic target in ovarian carcinomas. This article is part of a Special Issue entitled: An Updated Secretome.

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] Article available free on PMC after 15/04/2015 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] Article available free on PMC after 15/04/2015 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.

Skrzypek K, Tertil M, Golda S, et al.
Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis.
Antioxid Redox Signal. 2013; 19(7):644-60 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
AIMS: Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development.
RESULTS: Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated, and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors.
INNOVATION AND CONCLUSION: In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16, 293-296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason, and Yasufumi Sato.

Song KS, Choi JK, Ahn DW
Src homology 2-containing protein tyrosine phosphatase-2 acts as a negative regulator for MUC5AC transcription via the inhibition of the ERK1/2 MAPK signalling pathway in the airway.
Acta Physiol (Oxf). 2013; 208(3):245-50 [PubMed] Related Publications
AIMS: Mucus hypersecretion has been frequently observed in inflammation respiratory diseases. However, the negative regulators for mucus overproduction have not been readily identified. Our work focused on identifying novel negative regulator that modulates mucus overproduction in the human respiratory system. Herein, we examined whether H2 O2 could induce MUC5AC transcription in a dose-dependent manner and activate tyrosine phosphatase (SHP)-2 in human airway epithelial cells.
METHODS: We performed qRT-PCR to detect the changes in MUC5AC transcription and dot-blotting analysis to investigate MUC5AC secretion as regulated by SHP-2.
RESULTS: H2 O2 induced MUC5AC transcription in a dose-dependent manner and dramatically activated SHP-2. In addition, whereas wild-type SHP-2 completely inhibited H2 O2 -induced MUC5AC transcription, siRNA-SHP-2 restored it interestingly, suggesting that SHP-2 may act as a negative regulator for mucus overproduction and hypersecretion in the human respiratory tract. Moreover, SHP-2 inhibited the ERK1/2 MAPK pathway, thus abolishing the signalling for MUC5AC transcription.
CONCLUSION: We found that H2 O2 induced SHP-2 activation, which acted as a suppressor in H2 O2 signalling to regulate MUC5AC transcription in the airway.

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] Article available free on PMC after 15/04/2015 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.

Seibold MA, Smith RW, Urbanek C, et al.
The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium.
PLoS One. 2013; 8(3):e58658 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: We previously identified a MUC5B gene promoter-variant that is a risk allele for sporadic and familial Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia (IPF/UIP). This allele was strongly associated with increased MUC5B gene expression in lung tissue from unaffected subjects. Despite the strong association of this airway epithelial marker with disease, little is known of mucin expressing structures or of airway involvement in IPF/UIP.
METHODS: Immunofluorescence was used to subtype mucus cells according to MUC5B and MUC5AC expression and to identify ciliated, basal, and alveolar type II (ATII) cells in tissue sections from control and IPF/UIP subjects. Staining patterns were quantified for distal airways (Control and IPF/UIP) and in honeycomb cysts (HC).
RESULTS: MUC5B-expressing cells (EC) were detected in the majority of control distal airways. MUC5AC-EC were identified in half of these airways and only in airways that contained MUC5B-EC. The frequency of MUC5B+ and MUC5AC+ distal airways was increased in IPF/UIP subjects. MUC5B-EC were the dominant mucus cell type in the HC epithelium. The distal airway epithelium from control and IPF/UIP subjects and HC was populated by basal and ciliated cells. Most honeycombing regions were distinct from ATII hyperplasic regions. ATII cells were undetectable in the overwhelming majority of HC.
CONCLUSIONS: The distal airway contains a pseudostratified mucocilary epithelium that is defined by basal epithelial cells and mucus cells that express MUC5B predominantly. These data suggest that the HC is derived from the distal airway.

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] Article available free on PMC after 15/04/2015 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] Article available free on PMC after 15/04/2015 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] Article available free on PMC after 15/04/2015 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] Article available free on PMC after 15/04/2015 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.

Hoshi H, Sawada T, Uchida M, et al.
MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways.
Int J Oncol. 2013; 42(3):887-93 [PubMed] Related Publications
We have previously reported that a specific siRNA transfected MUC5AC could knockdown MUC5AC expression and suppress in vivo tumor growth and metastasis, although it had no effects on in vitro cell growth, cell survival, proliferation and morphology. In the present study, we investigated which host immune cells induced these effects and how the effects were induced using immunocyte-depleted animal models. The tumor growth of SW1990/si-MUC5AC cells, which show no tumor growth when implanted subcutaneously into a nude mouse, was recovered when neutrophils were removed by anti-Gr-1 mAb administration. This result suggests that MUC5AC may suppress the antitumor effects of neutrophils by allowing tumor cells to escape the host immune system. Subsequently, we investigated the effects of MUC5AC on apoptosis induction mediated by TNF-related apoptosis-inducing ligand (TRAIL), one of the antitumor mechanisms of neutrophils. SW1990/si-MUC5AC cells showed significantly increased active caspase 3 expression after the addition of TRAIL. On the other hand, SW1990/si-mock cells showed no such changes. Our results indicate that MUC5AC inhibits TRAIL‑induced apoptosis in human pancreatic cancer and may serve as an important indicator in diagnosis and prognosis.

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] Article available free on PMC after 15/04/2015 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.

Rachagani S, Torres MP, Kumar S, et al.
Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model: potential implications for diagnosis and therapy.
J Hematol Oncol. 2012; 5:68 [PubMed] Article available free on PMC after 15/04/2015 Related Publications
BACKGROUND: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients.
METHODS: In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (Kras(G12D);Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR.
RESULTS: In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN-γ (p < 0.0062), CXCL1 (p < 0.00014) and CXCL2 (p < 0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC.
CONCLUSIONS: Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC.

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