Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition

Oncogene volume 30, pages 1449–1459 (2011)Cite this article

Subjects

Abstract

Increased motility and invasiveness of pancreatic cancer cells are associated with epithelial to mesenchymal transition (EMT). Snai1 and Slug are zinc-finger transcription factors that trigger this process by repressing E-cadherin and enhancing vimentin and N-cadherin protein expression. However, the mechanisms that regulate this activation in pancreatic tumors remain elusive. MUC1, a transmembrane mucin glycoprotein, is associated with the most invasive forms of pancreatic ductal adenocarcinomas (PDA). In this study, we show that over expression of MUC1 in pancreatic cancer cells triggers the molecular process of EMT, which translates to increased invasiveness and metastasis. EMT was significantly reduced when MUC1 was genetically deleted in a mouse model of PDA or when all seven tyrosines in the cytoplasmic tail of MUC1 were mutated to phenylalanine (mutated MUC1 CT). Using proteomics, RT–PCR and western blotting, we revealed a significant increase in vimentin, Slug and Snail expression with repression of E-Cadherin in MUC1-expressing cells compared with cells expressing the mutated MUC1 CT. In the cells that carried the mutated MUC1 CT, MUC1 failed to co-immunoprecipitate with β-catenin and translocate to the nucleus, thereby blocking transcription of the genes associated with EMT and metastasis. Thus, functional tyrosines are critical in stimulating the interactions between MUC1 and β-catenin and their nuclear translocation to initiate the process of EMT. This study signifies the oncogenic role of MUC1 CT and is the first to identify a direct role of the MUC1 in initiating EMT during pancreatic cancer. The data may have implications in future design of MUC1-targeted therapies for pancreatic cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Al Masri A, Gendler SJ . (2005). Muc1 affects c-Src signaling in PyV MT-induced mammary tumorigenesis. Oncogene 24: 5799–5808.

    Article  CAS  PubMed  Google Scholar 

  • Bardeesy N, DePinho RA . (2002). Pancreatic cancer biology and genetics. Nat Rev Cancer 2: 897–909.

    Article  CAS  PubMed  Google Scholar 

  • Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J et al. (2000). The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2: 84–89.

    Article  CAS  PubMed  Google Scholar 

  • Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A . (2003). The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with snail and E47 repressors. J Cell Sci 116: 499–511.

    Article  CAS  PubMed  Google Scholar 

  • Burris III HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al. (1997). Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15: 2403–2413.

    Article  CAS  PubMed  Google Scholar 

  • Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG et al. (2000). The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2: 76–83.

    Article  CAS  PubMed  Google Scholar 

  • Carson DD . (2008). The cytoplasmic tail of MUC1: a very busy place. Sci Signal 1: pe35.

    Article  PubMed  Google Scholar 

  • Chang BW, Siccion E, Saif MW . (2010). Updates in locally advanced pancreatic cancer. Highlights from the ‘2010 ASCO Annual Meeting’. Chicago, IL, USA. June 4–8, 2010. JOP 11: 313–316.

    PubMed  Google Scholar 

  • Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E et al. (2001). The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7: 1267–1278.

    Article  CAS  PubMed  Google Scholar 

  • Das Roy L, Pathangey LB, Tinder TL, Schettini JL, Gruber HE, Mukherjee P . (2009). Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis. Breast Cancer Res 11: R56.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dymicka-Piekarska V, Matowicka-Karna J, Gryko M, Kemona-Chetnik I, Kemona H . (2007). Relationship between soluble P-selectin and inflammatory factors (interleukin-6 and C-reactive protein) in colorectal cancer. Thromb Res 120: 585–590.

    Article  CAS  PubMed  Google Scholar 

  • Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA . (2003). MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 113: 207–219.

    Article  CAS  PubMed  Google Scholar 

  • Glinskii AB, Smith BA, Jiang P, Li XM, Yang M, Hoffman RM et al. (2003). Viable circulating metastatic cells produced in orthotopic but not ectopic prostate cancer models. Cancer Res 63: 4239–4243.

    CAS  PubMed  Google Scholar 

  • Guaita S, Puig I, Franci C, Garrido M, Dominguez D, Batlle E et al. (2002). Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J Biol Chem 277: 39209–39216.

    Article  CAS  PubMed  Google Scholar 

  • Hattrup CL, Gendler SJ . (2008). Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol 70: 431–457.

    Article  CAS  PubMed  Google Scholar 

  • Hingorani SR, Petricoin III EF, Maitra A, Rajapaske V, King C, Jacobetz MA et al. (2003). Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4: 437–450.

    Article  CAS  PubMed  Google Scholar 

  • Hollingsworth MA, Swanson BJ . (2004). Mucins in cancer: protection and control of the cell surface. Nat Rev Cancer 4: 45–60.

    Article  CAS  PubMed  Google Scholar 

  • Hwang SI, Lundgren DH, Mayya V, Rezaul K, Cowan AE, Eng JK et al. (2006). Systematic characterization of nuclear proteome during apoptosis: a quantitative proteomic study by differential extraction and stable isotope labeling. Mol Cell Proteomics 5: 1131–1145.

    Article  CAS  PubMed  Google Scholar 

  • Justinger C, Schluter C, Oliviera-Frick V, Kopp B, Rubie C, Schilling MK . (2008). Increased growth factor expression after hepatic and pancreatic resection. Oncol Rep 20: 1527–1531.

    PubMed  Google Scholar 

  • Kaikita K, Ogawa H, Yasue H, Sakamoto T, Suefuji H, Sumida H et al. (1995). Soluble P-selectin is released into the coronary circulation after coronary spasm. Circulation 92: 1726–1730.

    Article  CAS  PubMed  Google Scholar 

  • Kufe DW . (2008). Targeting the human MUC1 oncoprotein: a tale of two proteins. Cancer Biol Ther 7: 81–84.

    Article  CAS  PubMed  Google Scholar 

  • Lan MS, Batra SK, Qi WN, Metzgar RS, Hollingsworth MA . (1990). Cloning and sequencing of a human pancreatic tumor mucin cDNA. J Biol Chem 265: 15294–15299.

    CAS  PubMed  Google Scholar 

  • Li Y, Kufe D . (2001). The Human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn). Biochem Biophys Res Commun 281: 440–443.

    Article  CAS  PubMed  Google Scholar 

  • Mroczko B, Szmitkowski M, Wereszczynska-Siemiatkowska U, Jurkowska G . (2005). Hematopoietic cytokines in the sera of patients with pancreatic cancer. Clin Chem Lab Med 43: 146–150.

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee P, Basu GD, Tinder TL, Subramani DB, Bradley JM, Arefayene M et al. (2009). Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J Immunol 182: 216–224.

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee P, Tinder TL, Basu GD, Gendler SJ . (2005). MUC1 (CD227) interacts with lck tyrosine kinase in Jurkat lymphoma cells and normal T cells. J Leukoc Biol 77: 90–99.

    Article  CAS  PubMed  Google Scholar 

  • Nieto MA . (2002). The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3: 155–166.

    Article  CAS  PubMed  Google Scholar 

  • Patton S, Gendler SJ, Spicer AP . (1995). The epithelial mucin, MUC1, of milk, mammary gland and other tissues. Biochim Biophys Acta 1241: 407–423.

    Article  CAS  PubMed  Google Scholar 

  • Peinado H, Quintanilla M, Cano A . (2003). Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem 278: 21113–21123.

    Article  CAS  PubMed  Google Scholar 

  • Quin RJ, McGuckin MA . (2000). Phosphorylation of the cytoplasmic domain of the MUC1 mucin correlates with changes in cell-cell adhesion. Int J Cancer 87: 499–506.

    Article  CAS  PubMed  Google Scholar 

  • Ren J, Bharti A, Raina D, Chen W, Ahmad R, Kufe D . (2006). MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 25: 20–31.

    Article  CAS  PubMed  Google Scholar 

  • Ren J, Li Y, Kufe D . (2002). Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem 277: 17616–17622.

    Article  CAS  PubMed  Google Scholar 

  • Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ . (2003). MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion. Oncogene 22: 1324–1332.

    Article  CAS  PubMed  Google Scholar 

  • Schroeder JA, Thompson MC, Gardner MM, Gendler SJ . (2001). Transgenic MUC1 interacts with EGFR and correlates with MAP kinase activation in the mouse mammary gland. J Biol Chem 276: 13057–13064.

    CAS  PubMed  Google Scholar 

  • Simpson-Herren L, Lloyd HH . (1970). Kinetic parameters and growth curves for experimental tumor systems. Cancer Chemother Rep 54: 143–174.

    CAS  PubMed  Google Scholar 

  • Singh PK, Hollingsworth MA . (2006). Cell surface-associated mucins in signal transduction. Trends Cell Biol 16: 467–476.

    Article  CAS  PubMed  Google Scholar 

  • Spicer AP, Rowse GJ, Lidner TK, Gendler SJ . (1995). Delayed mammary tumor progression in Muc-1 null mice. J Biol Chem 270: 30093–30101.

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP . (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442–454.

    Article  CAS  PubMed  Google Scholar 

  • Thompson EJ, Shanmugam K, Hattrup CL, Kotlarczyk KL, Gutierrez A, Bradley JM et al. (2006). Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways. Mol Cancer Res 4: 489–497.

    Article  CAS  PubMed  Google Scholar 

  • Tinder TL, Subramani DB, Basu GD, Bradley JM, Schettini J, Million A et al. (2008). MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. J Immunol 181: 3116–3125.

    Article  CAS  PubMed  Google Scholar 

  • Wen Y, Caffrey TC, Wheelock MJ, Johnson KR, Hollingsworth MA . (2003). Nuclear association of the cytoplasmic tail of MUC1 and beta-catenin. J Biol Chem 278: 38029–38039.

    Article  CAS  PubMed  Google Scholar 

  • Wolpin BM, Michaud DS, Giovannucci EL, Schernhammer ES, Stampfer MJ, Manson JE et al. (2007). Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts. Br J Cancer 97: 98–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto M, Bharti A, Li Y, Kufe D . (1997). Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion. J Biol Chem 272: 12492–12494.

    Article  CAS  PubMed  Google Scholar 

  • Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M et al. (2004). Dual regulation of snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6: 931–940.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the funding provided by NIH CA R01CA118944. We thank Dr Jennifer Curry for critically reviewing the manuscript. We thank Cathy S Madison and Carole M Viso for their technical help with the confocal microscopy. We also acknowledge all the technicians in the animal facility and in the histology core facilities at The Mayo Clinic.

Author information

Authors and Affiliations

  1. Department of Biology, University of North Carolina Charlotte, Charlotte, NC, USA,

    L D Roy, M Sahraei, D Besmer, S Nath & P Mukherjee

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic School of Medicine in Arizona, Scottsdale, AZ, USA,

    D B Subramani, T L Tinder, E Bajaj, K Shanmugam & S J Gendler

  3. Carolinas Healthcare Center, Charlotte, NC, USA

    Y Y Lee & S I L Hwang

Authors
  1. L D Roy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Sahraei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D B Subramani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Besmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Nath
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T L Tinder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Bajaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Shanmugam
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Y Y Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S I L Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S J Gendler
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. P Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Mukherjee.

Ethics declarations

Competing interests

Drs Mukherjee and Gendler work have been funded by the NIH. All other authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roy, L., Sahraei, M., Subramani, D. et al. MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30, 1449–1459 (2011). https://doi.org/10.1038/onc.2010.526

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2010.526

Keywords

This article is cited by

Search

Advanced search

Quick links