The Fragile X Mental Retardation Protein Regulates RIPK1 and Colorectal Cancer Resistance to Necroptosis.
Cell Mol Gastroenterol Hepatol
; 11(2): 639-658, 2021.
Article
en En
| MEDLINE
| ID: mdl-33091622
ABSTRACT
BACKGROUND & AIMS:
The fragile X mental retardation protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated.METHODS:
FMR1 mRNA transcript and FMRP protein expression were analyzed in human colon samples derived from patients with sporadic colorectal cancer (CRC) and healthy subjects. We used a well-established mouse model of sporadic CRC induced by azoxymethane to determine the possible role of FMRP in CRC. To address whether FMRP controls cancer cell survival, we analyzed cell death pathway in CRC human epithelial cell lines and in patient-derived colon cancer organoids in presence or absence of a specific FMR1 antisense oligonucleotide or siRNA.RESULTS:
We document a significant increase of FMRP in human CRC relative to non-tumor tissues. Next, using an inducible mouse model of CRC, we observed a reduction of colonic tumor incidence and size in the Fmr1 knockout mice. The abrogation of FMRP induced spontaneous cell death in human CRC cell lines activating the necroptotic pathway. Indeed, specific immunoprecipitation experiments on human cell lines and CRC samples indicated that FMRP binds receptor-interacting protein kinase 1 (RIPK1) mRNA, suggesting that FMRP acts as a regulator of necroptosis pathway through the surveillance of RIPK1 mRNA metabolism. Treatment of human CRC cell lines and patient-derived colon cancer organoids with the FMR1 antisense resulted in up-regulation of RIPK1.CONCLUSIONS:
Altogether, these data support a role for FMRP in controlling RIPK1 expression and necroptotic activation in CRC.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil
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Proteína Serina-Treonina Quinasas de Interacción con Receptores
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Recurrencia Local de Neoplasia
Tipo de estudio:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
Cell Mol Gastroenterol Hepatol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Italia