Emerging Roles of MUC4 in Cancer: A Novel Target for Diagnosis and Therapy

Singh, Ajay P.; Chaturvedi, Pallavi; Batra, Surinder K.

doi:10.1158/0008-5472.can-06-3114

Cited by 133 publications

(122 citation statements)

References 21 publications

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“…Profiling of ductal differentiation markers, such as mucins and cytokeratins, may aid in tumor characterization and monitoring passage-derived deviations. Regarding to mucins, MUC1 and MUC4 seem to play a key role in the progression of the disease and have been proposed as markers of poor prognosis whereas MUC2 plays usually a tumor suppressor role and is rarely detectable in aggressive pancreatic tumors [20][21][22][23] .In our study, MUC1 and MUC4 were present in 100% and 80% tumors, respectively, whereas only 20% of primary tumors were positive for MUC2. With respect to cytokeratins, although the expression of a single CK is of little diagnostic value, the expression pattern of CK7/CK20 in epithelial tumors has been proposed as useful in distinguishing primary from metastatic carcinomas of varied origins [24,25].…”

Section: Discussionmentioning

confidence: 46%

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

et al. 2011

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Background Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. Methods An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability.Results Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. Conclusions This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses.

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Section: Discussionmentioning

confidence: 46%

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

et al. 2011

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“…Therapeutic blockade of ErbB2 with the monoclonal antibody trastuzumab improves the effectiveness of chemotherapy and survival in breast cancer (Vogel et al, 2002). In human mammary epithelial cells, MUC4 has an antiadhesive effect and appears to promote tumour growth and progression (Pino et al, 2006;Singh et al, 2007). In human pancreatic intraepithelial neoplasia, MUC4 expression increases progressively with advanced dysplasia (Swartz et al, 2002), and inhibition of MUC4 by antisense RNA suppresses cell growth and metastases in pancreatic cancer cells (Singh et al, 2004;Moniaux et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

MUC4 and MUC5AC are highly specific tumour-associated mucins in biliary tract cancer

et al. 2008

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Alterations in epithelial mucin expression are associated with carcinogenesis, but there are few data in biliary tract cancer (BTC). In pancreatic malignancy, MUC4 is a diagnostic and prognostic tumour marker, whereas MUC5AC has been proposed as a sensitive serological marker for BTC. We assessed MUC4 and MUC5AC expression in (i) prospectively collected bile and serum specimens from 72 patients with biliary obstruction (39 BTC) by real-time reverse transcriptase -PCR (qPCR) and western blot analysis, and (ii) 79 archived biliary tissues (69 BTC) by immunohistochemistry. In bile, MUC4 protein was detected in 27% of BTC and 29% of primary sclerosing cholangitis (PSC) cases, but not in other benign and malignant biliary diseases (Po0.01 and P ¼ 0.06). qPCR revealed a 1.9-fold increased MUC4 mRNA expression in BTC patients' bile compared with benign disease. In archived tissues, MUC4 protein was detected in 37% of BTC but in none of the benign samples (P ¼ 0.03). In serum, MUC5AC was found exclusively in BTC and PSC sera (44% and 13%, respectively; Po0.001 for BTC vs non-BTC) and correlated negatively with BTC survival. Biliary MUC4 and serum MUC5AC are highly specific tumour-associated mucins that may be useful in the diagnosis and formulation of therapeutic strategies in BTC.

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“…Recent studies have provided compelling evidence implicating the MUC4 mucin in the pathogenesis of pancreatic cancer (Singh et al, 2007). Comparative expression analyses have revealed a positive correlation between MUC4 levels, the differentiation status of pancreatic tumour cell lines (Andrianifahanana et al, 2001) and tumour grading (Swartz et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

IFN-γ-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-γ response

et al. 2007

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MUC4 is a transmembrane mucin, which is aberrantly expressed in pancreatic adenocarcinoma with no detectable expression in the normal pancreas. Here, we present a novel mechanism of IFN-c-induced expression of MUC4 in pancreatic cancer cells. Our studies highlight the upregulation of STAT-1 as a basis for MUC4 induction and demonstrate that its activation and upregulation by IFN-c are two distinct, albeit temporally integrated, signalling events that drive the selective induction of IRF-1 and MUC4, respectively, within a single cell system. The profile of interferon regulatory factor (IRF)-1 gene induction by IFN-c is consistent with its rapid transactivation by phospho-Y701-STAT-1. In contrast, the induction of the MUC4 mucin gene expression is relatively delayed, and occurs only in response to an increase in STAT-1 expression. A progressive binding of STAT-1 to various c-interferon-activated sequences (GAS) in the MUC4 promoter is observed in chromatin immunoprecipitation assay, indicating its direct association. Stimulation of STAT-1 expression by double-stranded polynucleotides or ectopic expression is shown to induce MUC4 expression, without Y701 phosphorylation of STAT-1. This effect is abrogated by short interfering RNA (siRNA)-mediated inhibition of STAT-1 expression, supporting further the relevance of STAT-1 in MUC4 regulation. In conclusion, our findings identify a novel mechanism for MUC4 regulation in pancreatic cancer cells and unfold new perspectives on the foundation of IFN-c-dependent gene regulation.

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Emerging Roles of MUC4 in Cancer: A Novel Target for Diagnosis and Therapy

Cited by 133 publications

References 21 publications

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening

MUC4 and MUC5AC are highly specific tumour-associated mucins in biliary tract cancer

IFN-γ-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-γ response

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