Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review MUC13 (mucin 13, cell surface associated) Diane Maher, Brij Gupta, Mara Ebeling, Satoshi Nagata, Meena Jaggi, Subhash C Chauhan Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57105, USA (DM, BG, ME, SN, MJ, SCC); Department of OB/GYN, and Basic Biomedical Science Division, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA (MJ, SCC) Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MUC13ID41454ch3q21.html DOI: 10.4267/2042/44884 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity DNA/RNA Other names: DRCC1; FLJ20063; MUC-13; RECC HGNC (Hugo): MUC13 Location: 3q21.2 Note: MUC13 is a membrane bound mucin exhibiting abundant O- and N-glycosylation. The aberrant expression and localization of MUC13 may be involved in cancer pathobiology and could be a potential diagnostic/prognostic biomarker of cancer as well as a target for antibody guided therapy for cancer treatment. Description Human MUC13 was originally identified as a ortholog of the previously identified murine MUC13 (Williams et al., 2001). Based on fluorescence in situ hybridization, MUC13 was originally identified at location 3q13.3 (Williams et al., 2001); however, MUC13 is now reported to be located on chromosome 3; location 3q21.2, MUC13 is flanked by ITGB5 (beta 5 integrin) and HEG-1 (Heart of Glass), each transcribed from the reverse strand. Schematic diagram of the genomic MUC13 DNA (including neighboring genes) and the transcript of MUC13. MUC13 is located on chromosome 3 between ITGB5 and HEG-1. These 3 genes are transcribed from the reverse strand. The MUC13 transcript contains 12 exons and the final mRNA consists of 2,876 base pairs (Figure modified from Ensembl). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1020 MUC13 (mucin 13, cell surface associated) Maher D, et al. Interestingly, HEG and MUC13 share some molecular features, suggesting they may be evolutionarily related (Lang et al., 2006). invasion of the cancer cells (Hollingsworth and Swanson, 2004). Description Transcription MUC13 is a recently identified membrane bound mucin (Williams et al., 2001). At the N-terminus, a signal peptide shuttles the protein into the secretary pathway. The signal peptide is followed by a large serine-threonine rich tandem repeat domain (TD). Composed of 10 degenerate tandem repeats, the tandem repeat domain provides a scaffold on which cells build oligosaccharide structures. O-glycosylation with complex oligosaccharides is crucial to mucin structure and function. The central region of MUC13 contains three epidermal growth factor (EGF)-like domains (EGF1, EGF2 and EGF3), suggesting that MUC13 may play an important role in a signaling cascade. A sea urchin sperm protein enterokinase arginine (SEA) module is present between EGF1 and EGF2 like domains, providing a cleavage site which separates MUC13 into an extracellular a subunit and a transmembrane beta subunit. It is expected that the SEA domain is cleaved while in transport to the cell surface and that after cleavage, the alpha and beta subunits are covalently bound together. Adjacent to the EGF3-like domain is a short transmembrane domain (TM), followed by a 69 amino acid long cytoplasmic domain (CD) (Williams et al., 2001; Shimamura et al., 2005). The predominate MUC13 transcript (exact match between Ensembl and Havana) contains 12 exons and encodes 511 amino acids. Splice variants have been detected and may alter the length of the tandem repeat domain (Lang et al., 2006); however they have not been well studied for MUC13. Protein Note Members of the mucin family are characterized by a hallmark feature: the presence of a tandem repeat domain, consisting of a protein backbone which acts as a scaffold for a large number of complex O-linked carbohydrate side chains (Williams et al., 2001). In general, mucins have important biological roles in the lubrication and protection of normal epithelial tissues. In normal tissue, mucins are expressed in a tissue type dependent manner; however, for many types of cancer, mucin expression becomes altered (down-regulated, up-regulated or newly expressed). The mucin's ectodomain may protrude more than 200-2000 nm above the cell surface and can effectively block cellcell adhesion. Therefore, the over-expression of mucins may be implicated in the exfoliation, dissemination and Schematic diagram and annotated amino acid sequence of MUC13. Left: a schematic diagram shows the structural features of MUC13, highlighting the signal peptide, mucin repeat domain, SEA module, EGF-like domains, transmembrane region and the cytoplasmic domain. Right: The annotated amino acid sequence shows the extensive post-translation modifications that MUC13 undergoes (O-glycosylation, N-glycosylation and predicted disulfide bonds). The signal peptide, SEA module and Transmembrane sequences are indicated by pink, red and green font, respectively. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1021 MUC13 (mucin 13, cell surface associated) Maher D, et al. Within the cytoplasmic domain of MUC13, there are several potential phosphorylation sites (8 serine and 2 tyrosine residues) and a protein kinase C consensus phosphorylation motif, further supporting the hypothesis that MUC13 may be involved in cell signaling pathways. diagnosed with ovarian cancer and 14600 women will die due to this disease (Jemal et al., 2009). A high percent of women with ovarian cancer are diagnosed at an advanced stage (67%) and have a 5 year survival rate of only 46% (Jemal et al., 2009). Oncogenesis In a recently published report, we analyzed the expression profile and functions of MUC13 to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. We determined 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 to the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was highest in EOC. Exogenous expression of full length MUC13 induced morphological changes, including scattering of cells, marked reduction in cellcell adhesion and significant (p<0.05) increases in cell motility and proliferation. Additionally, we observed increased tumorigenesis in a xenograft mouse model system. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase1 (PAK1) and p38 protein expression. These changes were abrogated through c-jun NH2-terminal kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Our findings demonstrate the aberrant expression of MUC13 in ovarian cancer and show that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer. Expression Among normal tissues, MUC13 mRNA and/or protein has been detected in the large intestine, trachea, kidney, small intestine, gastric epithelium and esophagus (Williams et al., 2001). MUC13 is normally localized to the apical surface of epithelial cells lining the mucosal surface. In ovarian, gastric and colon cancers, MUC13 expression (determined by immunohistochemical analysis) is increased compared to expression levels of non-neoplastic tissues (Shimamura et al., 2005; Walsh et al., 2007; Chauhan et al., 2009). Localisation MUC13 is a transmembrane glycoprotein present at the apical surface in normal cells. In cancer cells, MUC13 is over-expressed and aberrantly located in the cytoplasm and occasionally in the nucleus (Williams et al., 2001; Chauhan et al., unpublished data). Function Under normal physiological conditions, mucins, including MUC13, protect the epithelial surface of mucosal surfaces (gastrointestinal tract, respiratory tract and reproductive tract). Mucins create a physical barrier from the extracellular environment and protect epithelial tissues from noxious and toxic substances. When aberrantly expressed, MUC13 has oncogenic functions which are described below. Colon cancer Disease Colon cancer is the third leading cause of cancer related deaths among men and women worldwide, with an estimated 639000 deaths in 2004 (WHO, 2009). In the United States in 2009, approximately 106000 people were diagnosed with colon cancer and 49900 people died, making colon cancer the second leading cause of deaths among all cancers (Jemal et al., 2009). Colon cancer has an overall survival rate of 49%, which is drastically dependent on the stage of diagnosis (Jemal, et al., 2009). For example, if colon cancer is detected in an early stage, prior to metastasis, survival is 90%; however, if colon cancer is not treated until an advanced stage (with metastasis to distant organs), survival decreases to approximately 10% (Jemal et al., 2009). Oncogenesis Walsh et al studied the expression of MUC13 in various stages of colon cancer (99 samples) (Walsh et al., 2007). Using immunohistochemical analysis, MUC13 was detected predominantly on the apical surface, with some cytoplasmic staining, of glands in normal colon. Scoring of the normal tissue was not done for this study, so it is difficult to state a comparison of MUC13 staining between normal and Homology MUC13 is known to have orthologs in mice, rats, chickens, dogs, cows, chimpanzees and even fish (Williams et al., 2001; Lang et al., 2006; NCBI: homologene). Additional putative orthologs are likely in a variety of different species and can be viewed via Ensembl. Mutations Note While a variety of Single Nucleotide Polymorphisms (SNPs) have been identified, the clinical significance has not yet been determined (NCBI: SNPs). Implicated in Ovarian cancer Disease Ovarian cancer is the most lethal gynecological cancer and the fifth most common cause of cancer mortality in women in the United States (Jemal et al., 2009). In 2009, it is estimated that 21550 women will be Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1022 MUC13 (mucin 13, cell surface associated) Maher D, et al. tissues. However, MUC13 staining in gastric cancer tissue was positive in 64.9% of cases and the cellular localization of MUC13 was dependent upon the histological type of gastric cancer. MUC13 was also detected in 9 out of 10 cases of intestinal metaplasia (precancerous lesions of intestinal type gastric cancer). When correlated with clinicopathological factors, MUC13 expression only correlated significantly with intestinal types of gastric cancer. MUC13 expression did not correlate with the expression of other mucins (MUC2, MUC5AC, MUC6 and CD10), suggesting that MUC13 may be regulated in a different manner then other mucins markers for gastric cancer (Shimamura et al., 2005). cancer cells. However, MUC13 was highly expressed in most of the colon tumors, with 81% of well differentiated adenocarcinomas exhibiting strong MUC13 staining. Interestingly, although the significance is not yet known, this study also found that tumors originating from the left side of the patient's body had a higher proportion of MUC13-positive cancer cells. Mucinous tumors expressed MUC13, but at a lower staining intensity (50% indicating strong staining) compared to adenocarcinomas. While MUC13 was most intense on the apical surface, it was also detected in the cytoplasm. Basolateral staining was detected in 24% of the cases, most frequently in poorly differentiated tumors (55% of poorly differentiated tumors showed basolateral staining). Although not statistically significant, there was a trend toward poorer survival in patients with tumors showing basolateral MUC13 expression. Taken together, these observations suggest aberrant expression of MUC13 may affect colon cancer pathogenesis. In contrast to these results, Packer et al reported that the RNA level of MUC13 was decreased in colon cancer; however this was a small study with only 23 samples of colon cancer and 6 normal colon tissues (Packer et al., 2004). In our own studies, we have observed the over-expression of MUC13 in colon and pancreatic cancer compared to normal colon and pancreas (unpublished data). Taken together, these data suggest that MUC13 may be a potential diagnostic/prognostic biomarker for colon, pancreatic and ovarian cancers. Additionally, due to its cell surface expression, MUC13 may be a suitable target for antibody guided therapy for cancer treatment. References Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, McGuckin MA. Muc13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J Biol Chem. 2001 May 25;276(21):18327-36 Hollingsworth MA, Swanson BJ. Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer. 2004 Jan;4(1):45-60 Packer LM, Williams SJ, Callaghan S, Gotley DC, McGuckin MA. Expression of the cell surface mucin gene family in adenocarcinomas. Int J Oncol. 2004 Oct;25(4):1119-26 Shimamura T, Ito H, Shibahara J, Watanabe A, Hippo Y, Taniguchi H, Chen Y, Kashima T, Ohtomo T, Tanioka F, Iwanari H, Kodama T, Kazui T, Sugimura H, Fukayama M, Aburatani H. Overexpression of MUC13 is associated with intestinal-type gastric cancer. Cancer Sci. 2005 May;96(5):26573 Lang T, Hansson GC, Samuelsson T. An inventory of mucin genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part of a locus of related gel-forming mucins. BMC Genomics. 2006 Aug 3;7:197 Gastric cancer Disease Gastric cancer is the second most common cause of cancer related deaths worldwide, accounting for approximately 803000 deaths each year (WHO, 2009). In the United States, 21130 people were diagnosed with gastric cancer and 10620 died due to gastric cancer (Jemal et al., 2009). When diagnosed with localized gastric cancer, the survival rate is approximately 60%; however, if gastric cancer has metastasized to distant sites, the survival rate is very low (4%) (Jemal et al., 2009). Oncogenesis Shimamura et al detected an increased expression of MUC13 at both mRNA and protein levels (Shimamura et al., 2005). In normal tissue, MUC13 protein was detected at the luminal surface of crypts in both the small and large intestines, but not in normal gastric Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) Walsh MD, Young JP, Leggett BA, Williams SH, Jass JR, McGuckin MA. The MUC13 cell surface mucin is highly expressed by human colorectal carcinomas. Hum Pathol. 2007 Jun;38(6):883-92 Chauhan SC, Vannatta K, Ebeling MC, Vinayek N, Watanabe A, Pandey KK, Bell MC, Koch MD, Aburatani H, Lio Y, Jaggi M. Expression and functions of transmembrane mucin MUC13 in ovarian cancer. Cancer Res. 2009 Feb 1;69(3):765-74 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49 This article should be referenced as such: Maher D, Gupta B, Ebeling M, Nagata S, Jaggi M, Chauhan SC. MUC13 (mucin 13, cell surface associated). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1020-1023. 1023