The Fragile X Mental Retardation Protein Regulates RIP1K and Colorectal Cancer Resistance to Necroptosis.
- Di Grazia A Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Marafini I Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Pedini G Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
- Di Fusco D Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Laudisi F Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Dinallo V Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Rosina E Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy.
- Stolfi C Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Franzè E Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Sileri P Department of Surgery, University of 'Tor Vergata', Rome, Italy.
- Sica G Department of Surgery, University of 'Tor Vergata', Rome, Italy.
- Monteleone G Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
- Bagni C Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy; Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland. Electronic address: claudia.bagni@uniroma2.it.
- Monteleone I Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Rome, Italy. Electronic address: ivan.monteleone@uniroma2.it.
- 2020-10-22
Published in:
- Cellular and molecular gastroenterology and hepatology. - 2020
English
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
FMRP transcripts and proteins 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 organoid in presence or absence of a specific FMRP 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 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 cell lines and patient-derived colon cancer organoids with the FMR1 antisense results in up-regulation of RIPK1, which drives the CRC human cell toward the necroptosis.
CONCLUSIONS
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.
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
FMRP transcripts and proteins 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 organoid in presence or absence of a specific FMRP 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 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 cell lines and patient-derived colon cancer organoids with the FMR1 antisense results in up-regulation of RIPK1, which drives the CRC human cell toward the necroptosis.
CONCLUSIONS
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1016/j.jcmgh.2020.10.009
- PMID 33091622
- Persistent URL
- https://sonar.ch/global/documents/972
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