Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125)

Chauhan, Subhash C.; Singh, Ajay P.; Ruiz, Fernanda; Johansson, Sonny L.; Jain, Maneesh; Smith, Lynette M.; Moniaux, Nicolas; Batra, Surinder K.

doi:10.1038/modpathol.3800646

Cited by 136 publications

(124 citation statements)

References 28 publications

(41 reference statements)

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“…Although there is a substantial literature that expression of mucins in epithelial ovarian cancer have diagnostic and prognostic value (22,23) and may represent therapeutic targets (24), the basis for their altered expression remains unknown. There is now emerging evidence that glycans in general (25), and MUC1 in particular (22) may play a role in host defense against pathogenic molecules.…”

Section: Discussionmentioning

confidence: 99%

Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Sellers

Huang

Cunningham³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Studies suggest that underglycosylation of the cell membrane mucin MUC1 may be associated with epithelial ovarian cancer. We identified 26 genes involved in glycosylation and examined 93 single nucleotide polymorphisms (SNP) with a minor allele frequency of z0.05 in relation to incident ovarian cancer. Cases were ascertained at the Mayo Clinic, Rochester, MN (n = 396) or a 48-county region in North Carolina (Duke University; n = 534). Ovarian cancerfree controls (n = 1,037) were frequency matched to the cases on age, race, and residence. Subjects were interviewed to obtain data on risk factors and a sample of blood for DNA and genotyped using the Illumina GoldenGate assay. We excluded subjects and individual SNPs with genotype call rates of <90%. Data were analyzed using logistic regression, with adjustment for age and residence. We fitted dominant, log additive, and recessive genetic models. Among Caucasians, nine SNPs in eight genes were associated with risk at P < 0.05 under at least one genetic model before adjusting for multiple testing. A SNP in GALNT1 (rs17647532) was the only one that remained statistically significant after Bonferroni adjustment for multiple testing but was not statistically significant in Hardy-Weinberg equilibrium among controls. Haplotype analyses revealed a global association of GALNT1 with risk (P = 0.038, under a recessive genetic model), which largely reflected a decreased risk of one haplotype (0.10 frequency; odds ratio, 0.07; P = 0.01) compared with the most common haplotype (0.39 frequency). These results suggest that genetic polymorphisms in the glycoslyation process may be novel risk factors for ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(2):397 -404)

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Section: Discussionmentioning

confidence: 99%

Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Sellers

Huang

Cunningham³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…The TMA slides were stained with antihuman MUC13 mAb (17) by heat-induced epitope retrieval immunohistochemistry technique using a Vector ABC kit (Vector Laboratories), as described earlier (13,22). Briefly, the TMA slides were deparaffinized, rehydrated, and incubated in 0.3% H 2 O 2 .…”

Section: Methodsmentioning

confidence: 99%

“…However, alterations in the expression of mucins and/or their glycosylation patterns are often associated with the development of cancer via influencing cellular growth, differentiation, transformation, adhesion, invasion, and immune surveillance (6,(9)(10)(11)(12)(13). The aberrant expression of certain membrane-anchored mucins in different histologic types and grades of ovarian tumors has recently been shown (13).…”

Section: Introductionmentioning

confidence: 99%

Expression and Functions of Transmembrane Mucin MUC13 in Ovarian Cancer

et al. 2009

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MUC13, a transmembrane mucin, is normally expressed in gastrointestinal and airway epithelium. Its aberrant expression has been correlated with gastric colon and cancer. However, the expression and functions of MUC13 in ovarian cancer are unknown. In the present study, the expression profile and functions of MUC13 were analyzed to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. A recently generated monoclonal antibody (clone PPZ0020) was used to determine the expression profile of MUC13 by immunohistochemistry using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was specifically present in EOC. For the functional analyses, a full-length MUC13 gene cloned in pcDNA3.1 was expressed in a MUC13 null ovarian cancer cell line, SKOV-3. Here, we show that the exogenous MUC13 expression induced morphologic changes, including scattering of cells. These changes were abrogated through c-Jun NH 2 kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Additionally, a marked reduction in cell-cell adhesion and significant (P < 0.05) increases in cell motility, proliferation, and tumorigenesis in a xenograft mouse model system were observed upon exogenous MUC13 expression. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase 1, and p38 protein expression. Our findings show the aberrant expression of MUC13 in ovarian cancer and that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer.

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“…3 Molecular changes, such as protein alterations, which may correspond with the biologic behavior of tumors, are helpful in classifying tumors and predicting clinical outcome. Following examination of the existing literature for immunoexpression data on proteins in mucinous neoplasms of various organs, including colorectum, [13][14][15][16][17][18] pancreas, 19,20 ovary, [21][22][23] and appendix, [24][25][26] we focused on 24 proteins. The immunoexpression profiles of different functional proteins in three groups-mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma of the appendix-were analyzed.…”

mentioning

confidence: 99%

Differential protein immunoexpression profiles in appendiceal mucinous neoplasms: a special reference to classification and predictive factors

et al. 2009

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Appendiceal mucinous neoplasms have been the focus of considerable debate in recent years. We histologically classified 70 appendiceal mucinous neoplasms into three categories: 32 mucinous adenoma, 23 mucinous neoplasm of uncertain malignant potential, and 15 mucinous adenocarcinomas. Immunohistochemistry was performed for 24 proteins in different functional categories, specifically, oncogenic proteins (bcl-2, b-catenin, CEA, C-erbB2, c-kit, Cox-2, Cyclin D1, EGFR, Ki-67, NF-jB, VEGF), tumor suppressors (E-cadherin, FHIT, hMLH1, p53, p63, smad4), cell-cycle regulators (p21, p27, p16), and mucin proteins (MUC1, MUC2, MUC5AC, MUC6). Our data showed that 9 out of the 24 proteins were more frequently altered in the mucinous adenocarcinoma group than in the mucinous adenoma group (Po0.05), including b-catenin (13% in mucinous adenoma vs 60% in mucinous adenocarcinoma), CyclinD1 (44 vs 87%), Ki-67 (high labeling index: 31 vs 67%), NF-jB (19 vs 60%), VEGF (16 vs 87%), E-cadherin (0 vs 47%), p53 (6 vs 40%), MUC2 (9 vs 67%), and MUC5AC (3 vs 40%). The distinct immunoexpression profile of mucinous neoplasm of uncertain malignant potential was placed between those of mucinous adenoma and mucinous adenocarcinoma (Po0.05). Moreover, the mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma categories displayed differences in terms of the number of altered markers among the nine proteins (Po0.05; mean 1.4 vs 2.6 vs 5.5, respectively). In mucinous adenocarcinoma, the p53 status was related to disease-free survival and overall survival of patients (Po0.05, both). NF-jB status and the number of altered protein markers made statistically marginal impacts on disease-free survival; also b-catenin loss, on overall survival of patients. In conclusion, protein immunoexpression profiles may facilitate the classification of appendiceal mucinous neoplasms. In our study, the three tumor categories of mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma exhibited distinct immunoexpression profiles. Five and more altered protein markers, p53 overexpression, NF-jB positivity, and b-catenin loss were predictive factors of adverse clinical outcomes in appendiceal mucinous adenocarcinomas.

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Aberrant expression of MUC4 in ovarian carcinoma: diagnostic significance alone and in combination with MUC1 and MUC16 (CA125)

Cited by 136 publications

References 28 publications

Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Association of Single Nucleotide Polymorphisms in Glycosylation Genes with Risk of Epithelial Ovarian Cancer

Expression and Functions of Transmembrane Mucin MUC13 in Ovarian Cancer

Differential protein immunoexpression profiles in appendiceal mucinous neoplasms: a special reference to classification and predictive factors

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