Publication
Internal ribosome entry site-mediated translation of UPF1 contributes to its oncogenic role in colorectal cancer
| dc.contributor.author | Lacerda, Rafaela | |
| dc.contributor.author | Menezes, Juliane | |
| dc.contributor.author | Elias, Adriana | |
| dc.contributor.author | Romão, Luísa | |
| dc.date.accessioned | 2024-01-22T10:36:10Z | |
| dc.date.embargo | 2028-12-31 | |
| dc.date.issued | 2023-01-26 | |
| dc.description.abstract | Colorectal cancer (CRC) is the third cause of death worldwide and projections point towards an increase for the next two decades. Many genes are misregulated in CRC, contributing to the development of the disease. Up-frameshift 1 (UPF1) is involved in many cellular mechanisms such as nonsense-mediated mRNA decay, cell cycle progression, or telomere maintenance and homeostasis. It also works as a tumour suppressor protein in most cancers but not in CRC, in which UPF1 plays an oncogenic role. We used the Xena platform to perform in silico analyses that revealed UPF1 is overexpressed in CRC contrary to several other analysed cancers. Besides, UPF1 expression levels are increased in CRC compared to the counterpart normal tissues. Experimentally, we confirmed these data and observed that endogenous UPF1 expression is maintained in different CRC cell lines under endoplasmic reticulum (ER) stress. To understand the mechanism underlying such maintenance, we used a bicistronic reporter construct to test whether UPF1 5’UTR can mediate alternative translation initiation and we concluded that such sequence contains an internal ribosome entry site (IRES) that maintains UPF1 expression in both normal and stress conditions in a 5’ cap-independent way. Deletional and mutational analysis of UPF1 5’UTR showed that nucleotides 1–100 (stem loop (SL) I) and 151–275 (SL III) — out of 275 nucleotides — are the minimal required sequences for the IRES to work properly. Using RNA antisense oligonucleotides (ASOs) targeting UPF1 IRES SL I and III, we observed a reduced UPF1 expression in HCT116 (CRC) cells. Altogether, these results suggest that UPF1 expression levels are maintained by the IRES-mediated translation mechanisms under conditions impairing canonical translation, such as those that mimic the tumour microenvironment. Thus, ASOs may be an upcoming therapy to target such alternative mechanism of translation initiation and prevent CRC development. | pt_PT |
| dc.description.sponsorship | Work supported by INSA and UIDB/04046/2020 (DOI: 10.54499/UIDB/04046/2020 ) and UIDP/04046/2020 (DOI: 10.54499/UIDP/04046/2020) Centre grants from FCT, Portugal (to BioISI). | pt_PT |
| dc.description.version | N/A | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.18/8932 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.relation | Biosystems and Integrative Sciences Institute | |
| dc.relation | Biosystems and Integrative Sciences Institute | |
| dc.subject | Colorectal Cancer | pt_PT |
| dc.subject | Up-frameshift 1 (UPF1) | pt_PT |
| dc.subject | Genómica Funcional | pt_PT |
| dc.subject | Expressão Génica | pt_PT |
| dc.subject | Genómica Funcional e Estrutural | pt_PT |
| dc.title | Internal ribosome entry site-mediated translation of UPF1 contributes to its oncogenic role in colorectal cancer | pt_PT |
| dc.type | conference object | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Biosystems and Integrative Sciences Institute | |
| oaire.awardTitle | Biosystems and Integrative Sciences Institute | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04046%2F2020/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04046%2F2020/PT | |
| oaire.citation.conferencePlace | Lisboa, Portugal | pt_PT |
| oaire.citation.title | RNA in Disease - IX ptRNA meeting, 26-27 January 2023 | pt_PT |
| oaire.fundingStream | 6817 - DCRRNI ID | |
| oaire.fundingStream | 6817 - DCRRNI ID | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | embargoedAccess | pt_PT |
| rcaap.type | conferenceObject | pt_PT |
| relation.isProjectOfPublication | dc433369-36fd-4935-bd52-c56aa49c72e1 | |
| relation.isProjectOfPublication | e8390b4d-1833-4925-a0ab-5fff0527efaa | |
| relation.isProjectOfPublication.latestForDiscovery | dc433369-36fd-4935-bd52-c56aa49c72e1 |