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.

Myosin Vb as a tumor suppressor gene in intestinal cancer

Abstract

Colorectal cancer causes >900,000 deaths every year and a deeper understanding of the molecular mechanisms underlying this disease will contribute to improve its clinical management and survival. Myosin Vb (MYO5B) regulates intracellular vesicle trafficking, and inactivation of this myosin disrupts the polarization and differentiation of intestinal epithelial cells causing microvillous inclusion disease (MVID), a rare congenital disorder characterized by intractable life-threatening diarrhea. Here, we show that the loss Myosin Vb interfered with the differentiation/polarization of colorectal cancer cells. Although modulation of Myosin Vb expression did not affect the proliferation of colon cancer cells, MYO5B inactivation increased their migration, invasion, and metastatic potential. Moreover, Myo5b inactivation in an intestine-specific knockout mouse model caused a >15-fold increase in the number of azoxymethane-initiated small intestinal tumors. Consistently, reduced expression of Myosin Vb in a cohort of 155 primary colorectal tumors was associated with shorter patient survival. In conclusion, we show here that loss of Myosin Vb reduces polarization/differentiation of colon cancer cells while enhancing their metastatic potential, demonstrating a tumor suppressor function for this myosin. Moreover, reduced expression of Myosin Vb in primary tumors identifies a subset of poor prognosis colorectal cancer patients that could benefit from more aggressive therapeutic regimens.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Role of Myosin Vb on the differentiation and polarization of colon cancer cells.
Fig. 2: Myosin Vb regulates the metastatic potential of colon cancer cells.
Fig. 3: Loss of Myosin Vb enhances the proliferation of normal intestinal epithelial cells.
Fig. 4: Myosin Vb does not regulate the growth of colon cancer cells.
Fig. 5: Myo5b inactivation enhances intestinal tumorigenesis in a mouse model.
Fig. 6: Low levels of Myosin Vb are associated with poor patient prognosis.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Sellers JR. Myosins: a diverse superfamily. Biochim Biophys Acta. 2000;1496:3–22.

    Article  CAS  PubMed  Google Scholar 

  3. Roland JT, Bryant DM, Datta A, Itzen A, Mostov KE, Goldenring JR. Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc Natl Acad Sci USA. 2011;108:2789–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dhekne HS, Hsiao N-H, Roelofs P, Kumari M, Slim CL, Rings EHHM, et al. Myosin Vb and Rab11a regulate phosphorylation of ezrin in enterocytes. J Cell Sci. 2014;127:1007–17.

    CAS  PubMed  Google Scholar 

  5. Weis VG, Knowles BC, Choi E, Goldstein AE, Williams JA, Manning EH, et al. Loss of MYO5B in mice recapitulates Microvillus Inclusion Disease and reveals an apical trafficking pathway distinct to neonatal duodenum. Cell Mol Gastroenterol Hepatol. 2016 ;2:131–57.

    Article  PubMed  Google Scholar 

  6. Ruemmele FM, Müller T, Schiefermeier N, Ebner HL, Lechner S, Pfaller K, et al. Loss-of-function of MYO5B is the main cause of microvillus inclusion disease: 15 novel mutations and a CaCo-2 RNAi cell model. Hum Mutat. 2010;31:544–51.

    Article  CAS  PubMed  Google Scholar 

  7. Thoeni CE, Vogel GF, Tancevski I, Geley S, Lechner S, Pfaller K, et al. Microvillus inclusion disease: loss of Myosin vb disrupts intracellular traffic and cell polarity. Traffic. 2014;15:22–42.

    Article  CAS  PubMed  Google Scholar 

  8. Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol. 2003;16:376–88.

    Article  PubMed  Google Scholar 

  9. Wodarz A, Näthke I. Cell polarity in development and cancer. Nat Cell Biol. 2007;9:1016–24.

    Article  CAS  PubMed  Google Scholar 

  10. 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  PubMed  PubMed Central  Google Scholar 

  11. Martínez-López E, Abad A, Font A, Monzó M, Ojanguren I, Pifarré A, et al. Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer. Gastroenterology. 1998;114:1180–7.

    Article  PubMed  Google Scholar 

  12. Müller T, Hess MW, Schiefermeier N, Pfaller K, Ebner HL, Heinz-Erian P, et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008;40:1163–5.

    Article  PubMed  Google Scholar 

  13. Leng C, Overeem AW, Cartón-Garcia F, Li Q, Klappe K, Kuipers J, et al. Loss of MYO5B expression deregulates late endosome size which hinders mitotic spindle orientation. PLoS Biol. 2019;17:e3000531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell. 2004;116:457–66.

    Article  CAS  PubMed  Google Scholar 

  15. Royer C, Lu X. Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ. 2011;18:1470–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Groisman GM, Sabo E, Meir A, Polak-Charcon S. Enterocyte apoptosis and proliferation are increased in microvillous inclusion disease (familial microvillous atrophy). Hum Pathol. 2000;31:1404–10.

    Article  CAS  PubMed  Google Scholar 

  17. Cartón-García F, Overeem AW, Nieto R, Bazzocco S, Dopeso H, Macaya I, et al. Myo5b knockout mice as a model of microvillus inclusion disease. Sci Rep. 2015;5:12312.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Madison BB, Dunbar L, Qiao XT, Braunstein K, Braunstein E, Gumucio DL. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J Biol Chem. 2002;277:33275–83.

    Article  CAS  PubMed  Google Scholar 

  19. Bazzocco S, Dopeso H, Carton-Garcia F, Macaya I, Andretta E, Chionh F, et al. Highly expressed genes in rapidly proliferating tumor cells as new targets for colorectal cancer treatment. Clin Cancer Res. 2015;21:3695–704.

    Article  CAS  PubMed  Google Scholar 

  20. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 1990;247:322–4.

    Article  CAS  PubMed  Google Scholar 

  21. Letellier E, Schmitz M, Ginolhac A, Rodriguez F, Ullmann P, Qureshi-Baig K, et al. Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence. Br J Cancer. 2017;117:1689–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014;513:382–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fogh J, Fogh JM, Orfeo T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. 1977;59:221–6.

    Article  CAS  PubMed  Google Scholar 

  24. Peterson MD, Mooseker MS. Characterization of the enterocyte-like brush border cytoskeleton of the C2BBe clones of the human intestinal cell line, Caco-2. J Cell Sci. 1992;102:581–600.

    Article  CAS  PubMed  Google Scholar 

  25. Hidalgo IJ, Raub TJ, Borchardt RT. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology. 1989;96:736–49.

    Article  CAS  PubMed  Google Scholar 

  26. Mariadason JM, Arango D, Corner GA, Arañes MJ, Hotchkiss KA, Yang W, et al. A gene expression profile that defines colon cell maturation in vitro. Cancer Res. 2002;62:4791–804.

    CAS  PubMed  Google Scholar 

  27. Kravtsov D, Mashukova A, Forteza R, Rodriguez MM, Ameen NA, Salas PJ. Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment. Am J Physiol Gastrointest Liver Physiol. 2014;307:G992–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Martin-Belmonte F, Perez-Moreno M. Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 2011;12:23–38.

    Article  PubMed  Google Scholar 

  29. Goldenring JR. A central role for vesicle trafficking in epithelial neoplasia: intracellular highways to carcinogenesis. Nat Rev Cancer. 2013;13:813–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol. 2009;10:513–25.

    Article  CAS  PubMed  Google Scholar 

  31. Sato T, Mushiake S, Kato Y, Sato K, Sato M, Takeda N, et al. The Rab8 GTPase regulates apical protein localization in intestinal cells. Nature. 2007;448:366–9.

    Article  CAS  PubMed  Google Scholar 

  32. Sobajima T, Yoshimura S-I, Iwano T, Kunii M, Watanabe M, Atik N, et al. Rab11a is required for apical protein localisation in the intestine. Biol Open. 2014;4:86–94.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Schimanski CC, Schmitz G, Kashyap A, Bosserhoff AK, Bataille F, Schäfer SC, et al. Reduced expression of Hugl-1, the human homologue of Drosophila tumour suppressor gene lgl, contributes to progression of colorectal cancer. Oncogene. 2005;24:3100–9.

    Article  CAS  PubMed  Google Scholar 

  34. Nakagawa S, Yano T, Nakagawa K, Takizawa S, Suzuki Y, Yasugi T, et al. Analysis of the expression and localisation of a LAP protein, human scribble, in the normal and neoplastic epithelium of uterine cervix. Br J Cancer. 2004;90:194–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kuphal S, Wallner S, Schimanski CC, Bataille F, Hofer P, Strand S, et al. Expression of Hugl-1 is strongly reduced in malignant melanoma. Oncogene. 2006;25:103–10.

    Article  CAS  PubMed  Google Scholar 

  36. Wodarz A. Tumor suppressors: linking cell polarity and growth control. Curr Biol. 2000;10:R624–6.

    Article  CAS  PubMed  Google Scholar 

  37. Partanen JI, Nieminen AI, Klefstrom J. 3D view to tumor suppression: Lkb1, polarity and the arrest of oncogenic c-Myc. Cell Cycle. 2009;8:716–24.

    Article  CAS  PubMed  Google Scholar 

  38. Melendez J, Liu M, Sampson L, Akunuru S, Han X, Vallance J, et al. Cdc42 coordinates proliferation, polarity, migration, and differentiation of small intestinal epithelial cells in mice. Gastroenterology. 2013;145:808–19.

    Article  CAS  PubMed  Google Scholar 

  39. Kravtsov DV, Ahsan MK, Kumari V, van Ijzendoorn SCD, Reyes-Mugica M, Kumar A, et al. Identification of intestinal ion transport defects in microvillus inclusion disease. Am J Physiol Gastrointest Liver Physiol. 2016;311:G142–55.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Gandalovičová A, Vomastek T, Rosel D, Brábek J. Cell polarity signaling in the plasticity of cancer cell invasiveness. Oncotarget. 2016;7:25022–49.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Williams KC, Coppolino MG. Phosphorylation of membrane type 1-matrix metalloproteinase (MT1-MMP) and its vesicle-associated membrane protein 7 (VAMP7)-dependent trafficking facilitate cell invasion and migration. J Biol Chem. 2011;286:43405–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rainero E, Caswell PT, Muller PAJ, Grindlay J, McCaffrey MW, Zhang Q, et al. Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol. 2012;196:277–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dong W, Chen X, Chen P, Yue D, Zhu L, Fan Q. Inactivation of MYO5B promotes invasion and motility in gastric cancer cells. Dig Dis Sci. 2012;57:1247–52.

    Article  CAS  PubMed  Google Scholar 

  44. Schneeberger K, Vogel GF, Teunissen H, van Ommen DD, Begthel H, El Bouazzaoui L, et al. An inducible mouse model for microvillus inclusion disease reveals a role for myosin Vb in apical and basolateral trafficking. Proc Natl Acad Sci USA. 2015;112:12408–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Goldenring JR, Nam KT. Rab25 as a tumour suppressor in colon carcinogenesis. Br J Cancer. 2011;104:33–6.

    Article  CAS  PubMed  Google Scholar 

  46. Nam KT, Lee H-J, Smith JJ, Lapierre LA, Kamath VP, Chen X, et al. Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas. J Clin Investig. 2010;120:840–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. D’Agostino L, Nie Y, Goswami S, Tong K, Yu S, Bandyopadhyay S, et al. Recycling endosomes in mature epithelia restrain tumorigenic signaling. Cancer Res. 2019;79:4099–112.

    Article  PubMed  PubMed Central  Google Scholar 

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

  49. Rowlatt C, Franks LM, Sheriff MU, Chesterman FC. Naturally occurring tumours and other lesions of the digestive tract in untreated C57BL mice. J Pathol. 1970;100:Pxii.

    CAS  PubMed  Google Scholar 

  50. Rodrigues P, Macaya I, Bazzocco S, Mazzolini R, Andretta E, Dopeso H, et al. RHOA inactivation enhances Wnt signalling and promotes colorectal cancer. Nat Commun. 2014;5:5458.

    Article  CAS  PubMed  Google Scholar 

  51. Kranz A, Fu J, Duerschke K, Weidlich S, Naumann R, Stewart AF, et al. An improved Flp deleter mouse in C57Bl/6 based on Flpo recombinase. Genesis 2010;48:512–20.

    Article  CAS  PubMed  Google Scholar 

  52. el Marjou F, Janssen K-P, Chang BH-J, Li M, Hindie V, Chan L, et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis. 2004;39:186–93.

    Article  CAS  PubMed  Google Scholar 

  53. Arango D, Laiho P, Kokko A, Alhopuro P, Sammalkorpi H, Salovaara R, et al. Gene-expression profiling predicts recurrence in Dukes’ C colorectal cancer. Gastroenterology. 2005;129:874–84.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was partially funded by grants of World Cancer Research (AICR13-0245), Instituto de Salud Carlos III (PI16/00540, PI19/00993, PI22/00773), the European Regional Development Fund (AC15/00066, AC19/00095, AC20/00022) and the Spanish Association Against Cancer (AECC GCA15152966ARAN) to DA. BB is supported by “Ajuts per a la Iniciació de la Recerca” fellowship from Diputació de Lleida- Biomedical Research Institute of Lleida.

Author information

Authors and Affiliations

Authors

Contributions

Study concept and design: DA, FC-G, AM-B. Acquisition of data: FC-G, BB, EA, HD, JT, RN, EG-V, IM, ZZ, MD, MS-M, SCDvI, SL, JH-L, SS, XM-G, SRC, AM-B. Analysis and interpretation of data: DA, FC-G, AM-B. Drafting of the manuscript: DA, FC-G, BB, AM-B.

Corresponding author

Correspondence to Diego Arango.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cartón-García, F., Brotons, B., Anguita, E. et al. Myosin Vb as a tumor suppressor gene in intestinal cancer. Oncogene 41, 5279–5288 (2022). https://doi.org/10.1038/s41388-022-02508-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02508-2

Search

Quick links