Carregant...
Fitxers
Tipus de document
ArticleVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/208724
The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas
Títol de la revista
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS-and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
Matèries
Matèries (anglès)
Citació
Citació
SANCHEZ TILLO, E., PEDROSA, Leire, VILA, I., CHEN, Yao, GYORFFY, B., SÁNCHEZ MORAL, L., SILES MENA, Laura, LOZANO SALVATELLA, Juan josé, ESTEVE CODINA, A., DARLING, Douglas s., CUATRECASAS FREIXAS, Miriam, CASTELLS GARANGOU, Antoni, MAUREL SANTASUSANA, Joan, POSTIGO, Antonio. The EMT factor ZEB1 paradoxically inhibits EMT in BRAF-mutant carcinomas. _Jci Insight_. 2023. Vol. 8, núm. 20, pàgs. e164629. [consulta: 24 de gener de 2026]. ISSN: 2379-3708. [Disponible a: https://hdl.handle.net/2445/208724]