RT Journal Article
T1 Germline gain‐of‐function MMP11 variant results in an aggressive form of colorectal cancer
A1 Martin‐Morales, Lorena
A1 Manzano Figueroa, Sara
A1 Rodrigo‐Faus, Maria
A1 Vicente‐Barrueco, Adrián
A1 Lorca, Victor
A1 Núñez‐Moreno, Gonzalo
A1 Bragado Domingo, Paloma
A1 Porras Gallo, María Almudena
A1 Caldes, Trinidad
A1 Garre, Pilar
A1 Gutiérrez Uzquiza, Álvaro
AB 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 prematureor 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.
PB Wiley
SN 0020-7136
SN 1097-0215
YR 2022
FD 2022-10-03
LK https://hdl.handle.net/20.500.14352/113476
UL https://hdl.handle.net/20.500.14352/113476
LA eng
NO Martin‐Morales, Lorena, et al. «Germline Gain‐of‐function MMP11 Variant Results in an Aggressive Form of Colorectal Cancer». International Journal of Cancer, vol. 152, n.o 2, enero de 2023, pp. 283-97. DOI.org (Crossref), https://doi.org/10.1002/ijc.34289.
NO Comunidad de Madrid
NO Ministerio de Ciencia e innovacion (España)
NO Consejería de Educacion e Investigación de la Comunidad de Madrid
DS Docta Complutense
RD 18 abr 2025