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Myosin Vb as a tumor suppressor gene in intestinal cancer

Oncogene volume 41, pages 5279–5288 (2022)Cite this article

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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.

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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.

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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.

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Author notes

  1. These authors contributed equally: Águeda Martínez-Barriocanal, Diego Arango.

Authors and Affiliations

  1. Group of Biomedical Research in Digestive Tract Tumors, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

    Fernando Cartón-García, Bruno Brotons, Estefanía Anguita, Higinio Dopeso, Rocio Nieto, Elia García-Vidal, Irati Macaya, Zsuzsanna Zagyva, Mariona Dalmau, Águeda Martínez-Barriocanal & Diego Arango

  2. Group of Molecular Oncology, Biomedical Research Institute of Lleida (IRBLleida), Lleida, Spain

    Bruno Brotons, Estefanía Anguita, Mariona Dalmau, Águeda Martínez-Barriocanal & Diego Arango

  3. Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, Lleida, Spain

    Jordi Tarragona & Xavier Matias-Guiu

  4. Group of Oncological Pathology, Institut de Recerca Biomedica de Lleida (IRBLleida), Lleida, Spain

    Jordi Tarragona & Xavier Matias-Guiu

  5. Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain

    Manuel Sánchez-Martín

  6. Servicio de Transgénesis, Nucleus, Universidad de Salamanca, Salamanca, Spain

    Manuel Sánchez-Martín

  7. Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain

    Manuel Sánchez-Martín

  8. Department of Biomedical Sciences of Cells and Systems, Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Sven C. D. van Ijzendoorn

  9. Translational Molecular Pathology, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Stefania Landolfi, Javier Hernandez-Losa & Santiago Ramón y Cajal

  10. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain

    Stefania Landolfi, Javier Hernandez-Losa, Xavier Matias-Guiu & Santiago Ramón y Cajal

  11. Group of Drug Delivery and Targeting, Vall d’Hebron University Hospital Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

    Simo Schwartz Jr

  12. Clinical Biochemistry Department, Vall d’Hebron Hospital, Barcelona, Spain

    Simo Schwartz Jr

Authors
  1. Fernando Cartón-García
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  18. Águeda Martínez-Barriocanal
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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.

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Correspondence to Diego Arango.

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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

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