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.

The atypical cadherin MUCDHL antagonizes colon cancer formation and inhibits oncogenic signaling through multiple mechanisms

Oncogene volume 40, pages 522–535 (2021)Cite this article

Subjects

Abstract

Cadherins form a large and pleiotropic superfamily of membranous proteins sharing Ca2+-binding repeats. While the importance of classic cadherins such as E- or N-cadherin for tumorigenesis is acknowledged, there is much less information about other cadherins that are merely considered as tissue-specific adhesion molecules. Here, we focused on the atypical cadherin MUCDHL that stood out for its unusual features and unique function in the gut. Analyses of transcriptomic data sets (n > 250) established that MUCDHL mRNA levels are down-regulated in colorectal tumors. Importantly, the decrease of MUCDHL expression is more pronounced in the worst-prognosis subset of tumors and is associated with decreased survival. Molecular characterization of the tumors indicated a negative correlation with proliferation-related processes (e.g., nucleic acid metabolism, DNA replication). Functional genomic studies showed that the loss of MUCDHL enhanced tumor incidence and burden in intestinal tumor-prone mice. Extensive structure/function analyses revealed that the mode of action of MUCDHL goes beyond membrane sequestration of ß-catenin and targets through its extracellular domain key oncogenic signaling pathways (e.g., EGFR, AKT). Beyond MUCDHL, this study illustrates how the loss of a gene critical for the morphological and functional features of mature cells contributes to tumorigenesis by dysregulating oncogenic pathways.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1: Reduced expression of MUCDHL in human colon tumors is an adverse event.
Fig. 2: Loss of Mucdhl expression enhances intestinal tumorigenesis in mice.
Fig. 3: MUCDHL M antagonizes the transcriptional activity of ß-catenin by multiple mechanisms.
Fig. 4: The extracellular region of MUCDHL M inhibits ß-catenin by interfering with EGFR signaling.
Fig. 5: MUCDHL M can enhance the proteasome-mediated degradation of ß-catenin.
Fig. 6: Both intracellular and extracellular domains of MUCDHL M have antitumor potential.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Google Scholar 

  2. Gehart H, Clevers H. Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol. 2019;16:19–34.

    Article  Google Scholar 

  3. Hughes LAE, Simons C, van den Brandt PA, van Engeland M, Weijenberg MP. Lifestyle, diet, and colorectal cancer risk according to (Epi)genetic instability: current evidence and future directions of molecular pathological epidemiology. Curr Colorectal Cancer Rep. 2017;13:455–69.

    Article  Google Scholar 

  4. Markowitz SD, Dawson DM, Willis J, Willson JK. Focus on colon cancer. Cancer Cell. 2002;1:233–6.

    Article  CAS  Google Scholar 

  5. Novellasdemunt L, Antas P, Li VS. Targeting Wnt signaling in colorectal cancer. A review in the theme: cell signaling: proteins, pathways and mechanisms. Am J Physiol Cell Physiol. 2015;309:C511–21.

    Article  CAS  Google Scholar 

  6. Basu S, Haase G, Ben-Ze’ev A. Wnt signaling in cancer stem cells and colon cancer metastasis. F1000Res. 2016;5:F1000.

    PubMed  PubMed Central  Google Scholar 

  7. Gul IS, Hulpiau P, Saeys Y, van Roy F. Evolution and diversity of cadherins and catenins. Exp Cell Res. 2017;358:3–9.

    Article  CAS  Google Scholar 

  8. Goldberg M, Wei M, Tycko B, Falikovich I, Warburton D. Identification and expression analysis of the human mu-protocadherin gene in fetal and adult kidneys. Am J Physiol Ren Physiol. 2002;283:F454–63.

    Article  CAS  Google Scholar 

  9. Crawley SW, Shifrin DA Jr., Grega-Larson NE, McConnell RE, Benesh AE, Mao S, et al. Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion. Cell. 2014;157:433–46.

    Article  CAS  Google Scholar 

  10. Goldberg M, Peshkovsky C, Shifteh A, Al-Awqati Q. mu-Protocadherin, a novel developmentally regulated protocadherin with mucin-like domains. J Biol Chem. 2000;275:24622–9.

    Article  CAS  Google Scholar 

  11. Bujko M, Kober P, Statkiewicz M, Mikula M, Ligaj M, Zwierzchowski L, et al. Epigenetic-mediated downregulation of mu-protocadherin in colorectal tumours. Gastroenterol Res Pr. 2015;2015:317093.

    Google Scholar 

  12. Hinkel I, Duluc I, Martin E, Guenot D, Freund JN, Gross I. Cdx2 controls expression of the protocadherin Mucdhl, an inhibitor of growth and beta-catenin activity in colon cancer cells. Gastroenterology. 2012;142:875–85.e3.

    Article  CAS  Google Scholar 

  13. Losi L, Parenti S, Ferrarini F, Rivasi F, Gavioli M, Natalini G, et al. Down-regulation of mu-protocadherin expression is a common event in colorectal carcinogenesis. Hum Pathol. 2011;42:960–71.

    Article  CAS  Google Scholar 

  14. Blasius FM, Meller S, Stephan C, Jung K, Ellinger J, Glocker MO, et al. Loss of cadherin related family member 5 (CDHR5) expression in clear cell renal cell carcinoma is a prognostic marker of disease progression. Oncotarget. 2017;8:75076–86.

    Article  Google Scholar 

  15. Ding X, Tian X, Liu W, Li Z. CDHR5 inhibits proliferation of hepatocellular carcinoma and predicts clinical prognosis. Ir J Med Sci. 2019;189:439–47.

    Article  Google Scholar 

  16. Parenti S, Ferrarini F, Zini R, Montanari M, Losi L, Canovi B, et al. Mesalazine inhibits the beta-catenin signalling pathway acting through the upregulation of mu-protocadherin gene in colo-rectal cancer cells. Aliment Pharm Ther. 2010;31:108–19.

    Article  CAS  Google Scholar 

  17. Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10:e1001453.

    Article  CAS  Google Scholar 

  18. Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21:1350–6.

    Article  CAS  Google Scholar 

  19. Balbinot C, Armant O, Elarouci N, Marisa L, Martin E, De Clara E, et al. The Cdx2 homeobox gene suppresses intestinal tumorigenesis through non-cell-autonomous mechanisms. J Exp Med. 2018;215:911–26.

    Article  CAS  Google Scholar 

  20. Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  Google Scholar 

  21. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13.

    Article  CAS  Google Scholar 

  22. Colnot S, Niwa-Kawakita M, Hamard G, Godard C, Le Plenier S, Houbron C, et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab Invest. 2004;84:1619–30.

    Article  CAS  Google Scholar 

  23. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, et al. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science. 1997;275:1784–7.

    Article  CAS  Google Scholar 

  24. Gottardi CJ, Wong E, Gumbiner BM. E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol. 2001;153:1049–60.

    Article  CAS  Google Scholar 

  25. van Roy F. Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer. 2014;14:121–34.

    Article  Google Scholar 

  26. Hu T, Li C. Convergence between Wnt-beta-catenin and EGFR signaling in cancer. Mol Cancer. 2010;9:236.

    Article  Google Scholar 

  27. Lee CH, Hung HW, Hung PH, Shieh YS. Epidermal growth factor receptor regulates beta-catenin location, stability, and transcriptional activity in oral cancer. Mol Cancer. 2010;9:64.

    Article  CAS  Google Scholar 

  28. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.

    Article  CAS  Google Scholar 

  29. McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL, et al. GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget. 2014;5:2881–911.

    Article  Google Scholar 

  30. Borowicz S, Van Scoyk M, Avasarala S, Karuppusamy Rathinam MK, Tauler J, Bikkavilli RK, et al. The soft agar colony formation assay. J Vis Exp. 2014:e51998.

  31. Montorsi L, Parenti S, Losi L, Ferrarini F, Gemelli C, Rossi A, et al. Expression of mu-protocadherin is negatively regulated by the activation of the beta-catenin signaling pathway in normal and cancer colorectal enterocytes. Cell Death Dis. 2016;7:e2263.

    Article  CAS  Google Scholar 

  32. O’Connell MJ, Lavery I, Yothers G, Paik S, Clark-Langone KM, Lopatin M, et al. Relationship between tumor gene expression and recurrence in four independent studies of patients with stage II/III colon cancer treated with surgery alone or surgery plus adjuvant fluorouracil plus leucovorin. J Clin Oncol. 2010;28:3937–44.

    Article  Google Scholar 

  33. Martin-Belmonte F, Perez-Moreno M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 2012;12:23–38.

    Article  CAS  Google Scholar 

  34. Shih IM, Wang TL, Traverso G, Romans K, Hamilton SR, Ben-Sasson S, et al. Top-down morphogenesis of colorectal tumors. Proc Natl Acad Sci USA. 2001;98:2640–5.

    Article  CAS  Google Scholar 

  35. Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Goktuna SI, Ziegler PK, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell. 2013;152:25–38.

    Article  CAS  Google Scholar 

  36. Mazzolini R, Dopeso H, Mateo-Lozano S, Chang W, Rodrigues P, Bazzocco S, et al. Brush border myosin Ia has tumor suppressor activity in the intestine. Proc Natl Acad Sci USA. 2012;109:1530–5.

    Article  CAS  Google Scholar 

  37. Moulton DE, Crandall W, Lakhani R, Lowe ME. Expression of a novel cadherin in the mouse and human intestine. Pediatr Res. 2004;55:927–34.

    Article  CAS  Google Scholar 

  38. Danielsen SA, Eide PW, Nesbakken A, Guren T, Leithe E, Lothe RA. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim Biophys Acta. 2015;1855:104–21.

    CAS  PubMed  Google Scholar 

  39. Fichera A, Little N, Jagadeeswaran S, Dougherty U, Sehdev A, Mustafi R, et al. Epidermal growth factor receptor signaling is required for microadenoma formation in the mouse azoxymethane model of colonic carcinogenesis. Cancer Res. 2007;67:827–35.

    Article  CAS  Google Scholar 

  40. Chantret I, Rodolosse A, Barbat A, Dussaulx E, Brot-Laroche E, Zweibaum A, et al. Differential expression of sucrase-isomaltase in clones isolated from early and late passages of the cell line Caco-2: evidence for glucose-dependent negative regulation. J Cell Sci. 1994;107:213–25.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Drs. C. Perret, M. Rousset, H. Clevers, E. Fearon, A. Sorkin, B. Gumbiner, and A. Jung for reagents.

Funding

This work was supported by the financial support of INSERM (2013–2019), Fondation ARC (#SFI20101201854), and La Ligue Contre Le Cancer (Haute-Marne 2013, Haut-Rhin 2016); MBe, MBa, EB, AMS, and IH were fellows of the French government (Ministère de l’Enseignement Supérieur et de la Recherche). MBe and MBawere also fellows of Fondation ARC, and EB of the FRM.

Author information

Author notes

  1. These authors contributed equally: Marine Beck, Mathilde Baranger

Authors and Affiliations

  1. Université de Strasbourg, Inserm, IRFAC UMR-S1113, 67200, Strasbourg, France

    Marine Beck, Mathilde Baranger, Ahlam Moufok-Sadoun, Emilie Bersuder, Isabelle Hinkel, Georg Mellitzer, Elisabeth Martin, Isabelle Duluc, Christian Gaiddon, Jean-Noel Freund & Isabelle Gross

  2. Ligue Nationale Contre le Cancer, Paris, France

    Laetitia Marisa & Aurelien de Reynies

Authors
  1. Marine Beck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mathilde Baranger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahlam Moufok-Sadoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emilie Bersuder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabelle Hinkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Georg Mellitzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elisabeth Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laetitia Marisa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isabelle Duluc
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Aurelien de Reynies
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christian Gaiddon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean-Noel Freund
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Isabelle Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isabelle Gross.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Beck, M., Baranger, M., Moufok-Sadoun, A. et al. The atypical cadherin MUCDHL antagonizes colon cancer formation and inhibits oncogenic signaling through multiple mechanisms. Oncogene 40, 522–535 (2021). https://doi.org/10.1038/s41388-020-01546-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-020-01546-y

Search

Advanced search

Quick links