RT Journal Article
T1 Germline gain‐of‐function MMP11 variant results in an aggressive form of colorectal cancer
A1 Martín Morales, Lorena
A1 Manzano, Sara
A1 Rodrigo Faus, María
A1 Vicente Barrueco, Adrian
A1 Lorca, Víctor
A1 Núñez Moreno, Gonzalo
A1 Bragado Domingo, Paloma
A1 Porras Gallo, Almudena
A1 Caldes, Trinidad
A1 Garre, Pilar
A1 Gutierrez‐Uzquiza, Álvaro
AB Abstract 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.
PB Wiley
SN 0020-7136
YR 2022
FD 2022-09-12
LK https://hdl.handle.net/20.500.14352/72600
UL https://hdl.handle.net/20.500.14352/72600
LA eng
NO CRUE-CSIC (Acuerdos Transformativos 2022)
NO Ministerio de Ciencia e Innovación (MICINN)
NO Comunidad de Madrid
DS Docta Complutense
RD 7 may 2024