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MUC13 mucin augments pancreatic tumorigenesis.

ABSTRACT: The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic cancer was investigated using a recently generated monoclonal antibody (clone PPZ0020) and pancreatic tissue microarrays. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with normal/nonneoplastic pancreatic tissues. For functional analyses, full-length MUC13 was expressed in MUC13 null pancreatic cancer cell lines, MiaPaca and Panc1. MUC13 overexpression caused a significant (P < 0.05) increase in cell motility, invasion, proliferation, and anchorage-dependent or -independent clonogenicity while decreasing cell-cell and cell-substratum adhesion. Exogenous MUC13 expression significantly (P < 0.05) enhanced pancreatic tumor growth and reduced animal survival in a xenograft mouse model. These tumorigenic characteristics correlated with the upregulation/phosphorylation of HER2, p21-activated kinase 1 (PAK1), extracellular signal-regulated kinase (ERK), Akt, and metastasin (S100A4), and the suppression of p53. Conversely, suppression of MUC13 in HPAFII pancreatic cancer cells by short hairpin RNA resulted in suppression of tumorigenic characteristics, repression of HER2, PAK1, ERK, and S100A4, and upregulation of p53. MUC13 suppression also significantly (P < 0.05) reduced tumor growth and increased animal survival. These results imply a role of MUC13 in pancreatic cancer and suggest its potential use as a diagnostic and therapeutic target.

SUBMITTER: Chauhan SC

PROVIDER: S-EPMC4100478 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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MUC13 mucin augments pancreatic tumorigenesis.

Chauhan Subhash C SC Ebeling Mara C MC Maher Diane M DM Koch Michael D MD Watanabe Akira A Aburatani Hiroyuki H Lio Yuhlong Y Jaggi Meena M

Molecular cancer therapeutics 20111025 1

The high death rate of pancreatic cancer is attributed to the lack of reliable methods for early detection and underlying molecular mechanisms of its aggressive pathogenesis. Although MUC13, a newly identified transmembrane mucin, is known to be aberrantly expressed in ovarian and gastro-intestinal cancers, its role in pancreatic cancer is unknown. Herein, we investigated the expression profile and functions of MUC13 in pancreatic cancer progression. The expression profile of MUC13 in pancreatic ...[more]

PMID: 22027689

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Project description:BACKGROUND:Mucins are large glycoproteins that cover epithelial surfaces of the body. All mucins contain at least one PTS domain, a region rich in proline, threonine and serine. Mucins are also characterized by von Willebrand D (VWD) domains or SEA domains. We have developed computational methods to identify mucin genes and proteins based on these properties of the proteins. Using such methods we are able to characterize different organisms where genome sequence is available with respect to their mucin repertoire. RESULTS:We have here made a comprehensive analysis of potential mucins encoded by the chicken (Gallus gallus) genome. Three transmembrane mucins (Muc4, Muc13, and Muc16) and four gel-forming mucins (Muc6, Muc2, Muc5ac, and Muc5b) were identified. The gel-forming mucins are encoded within a locus similar to the corresponding human mucins. However, the chicken has an additional gene inserted between Muc2 and Muc5ac that encodes the the alpha-subunit of ovomucin, a protein similar to Muc2, but it is lacking a PTS domain. We also show that the beta-subunit of ovomucin is the orthologue of human MUC6. The transmembrane Muc13 gene is in chicken as well as in mammals adjacent to the HEG (heart of glass) gene. HEG has PTS, EGF and transmembrane domains like Muc13, suggesting that these two proteins are evolutionary related. Unlike previously known mucins, the PTS domain of Muc13 is encoded by multiple exons, where each exon encodes a repeat unit of the PTS domain. CONCLUSION:We report new mucin homologues in chicken and this information will aid in understanding the evolution of mucins in vertebrates. The fact that ovomucin, a protein not found in mammals, was located in the same locus as other gel-forming mucins provides strong support that these proteins are evolutionary related. Furthermore, a relationship of HEG and the transmembrane Muc13 is suggested on the basis of their biochemical properties and their presence in the same locus. Finally, our finding that the chicken Muc13 is distributed between multiple exons raises the interesting possibility that the length of the PTS domain could be controlled by alternative splicing.

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MUC13 mucin augments pancreatic tumorigenesis.

Publications

MUC13 mucin augments pancreatic tumorigenesis.

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