Germline gain‐of‐function MMP11 variant results in an aggressive form of colorectal cancer

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dc.contributor.authorMartín Morales, Lorena
dc.contributor.authorManzano, Sara
dc.contributor.authorRodrigo Faus, María
dc.contributor.authorVicente Barrueco, Adrian
dc.contributor.authorLorca, Víctor
dc.contributor.authorNúñez Moreno, Gonzalo
dc.contributor.authorBragado Domingo, Paloma
dc.contributor.authorPorras Gallo, Almudena
dc.contributor.authorCaldes, Trinidad
dc.contributor.authorGarre, Pilar
dc.contributor.authorGutierrez‐Uzquiza, Álvaro
dc.date.accessioned2023-06-22T12:28:20Z
dc.date.available2023-06-22T12:28:20Z
dc.date.issued2022-09-12
dc.descriptionCRUE-CSIC (Acuerdos Transformativos 2022)
dc.description.abstractAbstract Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.
dc.description.departmentSección Deptal. de Bioquímica y Biología Molecular (Farmacia)
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación (MICINN)
dc.description.sponsorshipComunidad de Madrid
dc.description.statuspub
dc.eprint.idhttps://eprints.ucm.es/id/eprint/75410
dc.identifier.doi10.1002/ijc.34289
dc.identifier.issn0020-7136
dc.identifier.officialurlhttps://doi.org/10.1002/ijc.34289
dc.identifier.urihttps://hdl.handle.net/20.500.14352/72600
dc.journal.titleInternational Journal of Cancer
dc.language.isoeng
dc.publisherWiley
dc.relation.projectID(PI16/01292, SAF2016-76588-C2-1-R and PID2019-104143RB-C22 and PID2019- 104991RB-I00)
dc.relation.projectID(2017-T1/ BMD-5468); PEJ-2020-AI/BMD-18610)
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España
dc.rights.accessRightsopen access
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.subject.keywordcolorectal cancer
dc.subject.keywordfamilial colorectal cancer type X
dc.subject.keywordmatrix metalloproteinase 11
dc.subject.keywordproline for serine exchange in the 78 amino acid position of a protein
dc.subject.keywordwhole exome sequencing
dc.subject.ucmBioquímica (Medicina)
dc.subject.ucmOncología
dc.subject.unesco3201.01 Oncología
dc.titleGermline gain‐of‐function MMP11 variant results in an aggressive form of colorectal cancer
dc.typejournal article
dspace.entity.typePublication
relation.isAuthorOfPublicationaf6d6daf-5919-4e1c-b9e5-bb496fa46397
relation.isAuthorOfPublication.latestForDiscoveryaf6d6daf-5919-4e1c-b9e5-bb496fa46397
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