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.
FMRP transcripts and proteins expression were analyzed in human colon samples derived from patients with sporadic CRC and healthy subjects. We used a well-established mouse model of sporadic CRC induced by Azoxymethane (AOM) 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 organoid in presence or absence of a specific FMRP antisense oligonucleotide or siRNA.
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 KO mice. The abrogation of FMRP induced spontaneous cell death in human CRC cells lines activating the necroptotic pathway. Indeed, specific immunoprecipitation experiments on human cell lines and CRC samples indicate that FMRP binds receptor-interacting protein kinase 1 (RIPK1) mRNA suggesting that FMRP acts as a master regulator of necroptosis pathway through the surveillance of RIPK1 mRNA metabolism. Treatment of human CRC cells lines and patient-derived colon cancer organoids with the FMR1 antisense results in an upregulation of RIPK1, which drives the CRC human cell towards the necroptosis.
Altogether, these data support a role for FMRP in sustaining colon tumorigenesis controlling the RIPK1 expression and ultimately abrogating the activation of the necroptotic pathway.
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The authors are extremely thankful to Vittoria Mariano for her help in making the graphical abstract using Adobe Illustrator. This work was supported by the following funds: Associazione Italiana Sindrome X Fragile, Telethon GGP15257 and Etat de Vaud to CB and by Nogra Pharma Ltd (Dublin, Ireland) to IMo. The funders had no role in study design, data analysis, decision to publish or preparation of the manuscript. We are very thankful to Laura Pacini and Maria Giulia Farace for advice and guidance.
AUTHOR CONTRIBUTIONS: ADG: performed the experiments, data analysis and interpretation, manuscript writing; IMa, GP, DDF, FL, VD, CS, EF and ER performed some of the experiments and interpreted the data; PS and GS provided the human samples; GM contributed to manuscript writing. CB conceived some of the experiments, interpreted the data and contributed to the writing of the manuscript; IMo conceived and designed the experiments, performed experiments, analysis and data interpretation, wrote the manuscript.
DISCLOSURES: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
SYNOPSIS: The identification of a specific target as FMRP that could control directly the necroptosis pathway represents a novel attractive strategy to overcoming programmed cell death resistance in CRC.
© 2020 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute.
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