Publication
DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway
| dc.contributor.author | García-Moreno, Juan F. | |
| dc.contributor.author | Lacerda, Rafaela | |
| dc.contributor.author | da Costa, Paulo J. | |
| dc.contributor.author | Pereira, Marcelo | |
| dc.contributor.author | Gama-Carvalho, Margarida | |
| dc.contributor.author | Matos, Paulo | |
| dc.contributor.author | Romão, Luísa | |
| dc.date.accessioned | 2024-01-16T11:33:09Z | |
| dc.date.available | 2024-01-16T11:33:09Z | |
| dc.date.issued | 2023-06-20 | |
| dc.description.abstract | DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3’end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development. In the present study, we characterize the role of DIS3L2 in human colorectal cancer (CRC). Using the public RNA datasets from The Cancer Genome Atlas (TCGA), we found higher DIS3L2 mRNA levels in CRC tissues versus normal colonic samples as well as worse prognosis in patients with high DIS3L2 expression. In addition, our RNA deep-sequencing data revealed that knockdown (KD) of DIS3L2 induces a strong transcriptomic disturbance in SW480 CRC cells. Moreover, gene ontology (GO) analysis of significant upregulated transcripts displays enrichment in mRNAs encoding proteins involved in cell cycle regulation and cancer-related pathways, which guided us to evaluate which specific hallmarks of cancer are differentially regulated by DIS3L2. To do so, we employed four CRC cell lines (HCT116, SW480, Caco-2 and HT-29) differing in their mutational background and oncogenicity. We demonstrate that lack depletion of DIS3L2 results in reduced cell viability of highly oncogenic SW480 and HCT116 CRC cells, but had little or no impact in the more differentiated Caco-2 and HT-29 cells. Remarkably, the mTOR signaling pathway, crucial for cell survival and growth, is downregulated after DIS3L2 KD, whereas AZGP1, an mTOR pathway inhibitor, is upregulated. Furthermore, our results indicate that depletion of DIS3L2 disturbs metastasis-associated properties, such as cell migration and invasion, only in highly oncogenic CRC cells. Our work reveals for the first time a role for DIS3L2 in sustaining CRC cell proliferation and provides evidence that this ribonuclease is required to support the viability and invasive behavior of dedifferentiated CRC cells. | pt_PT |
| dc.description.sponsorship | This work was supported by Instituto Nacional de Saúde Doutor Ricardo Jorge and Fundação para a Ciência e a Tecnologia (FCT) [UID/MULTI/04046/2019 Research Unit Grant (to BioISI)]. Juan F. García-Moreno and Paulo J. da Costa were recipients of a fellowship from BioSys PhD programme (SFRH/BD/52495/2014, and PD/BD/142898/2018, respectively). | pt_PT |
| dc.description.version | info:eu-repo/semantics/publishedVersion | pt_PT |
| dc.identifier.citation | Cell Mol Life Sci. 2023 Jun 20;80(7):185. doi: 10.1007/s00018-023-04833-5 | pt_PT |
| dc.identifier.doi | 10.1007/s00018-023-04833-5 | pt_PT |
| dc.identifier.issn | 1420-682X | |
| dc.identifier.uri | http://hdl.handle.net/10400.18/8904 | |
| dc.language.iso | eng | pt_PT |
| dc.peerreviewed | yes | pt_PT |
| dc.publisher | Springer | pt_PT |
| dc.relation | Biosystems & Integrative Sciences Institute | |
| dc.relation | TRANSCRIPTOMIC SCREEN FOR DIS3 AND DIS3L1 EXOSOME SUBUNITS-ASSOCIATED FUNCTIONAL NETWORKS IN COLORECTAL CANCER | |
| dc.relation | The involvement od DIS3L2 in nonsense-mediated mRNA decay and its functional networks in colorectal cancer | |
| dc.relation.publisherversion | https://link.springer.com/article/10.1007/s00018-023-04833-5 | pt_PT |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | pt_PT |
| dc.subject | AZGP1 | pt_PT |
| dc.subject | Cell Migration | pt_PT |
| dc.subject | Cell Viability | pt_PT |
| dc.subject | Colorectal Cancer | pt_PT |
| dc.subject | DIS3L2 | pt_PT |
| dc.subject | mTOR | pt_PT |
| dc.subject | Cancro Colorretal | pt_PT |
| dc.subject | Expressão Génica | pt_PT |
| dc.subject | Genómica Funcional | pt_PT |
| dc.subject | Genómica Funcional e Estrutural | pt_PT |
| dc.title | DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway | pt_PT |
| dc.type | journal article | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Biosystems & Integrative Sciences Institute | |
| oaire.awardTitle | TRANSCRIPTOMIC SCREEN FOR DIS3 AND DIS3L1 EXOSOME SUBUNITS-ASSOCIATED FUNCTIONAL NETWORKS IN COLORECTAL CANCER | |
| oaire.awardTitle | The involvement od DIS3L2 in nonsense-mediated mRNA decay and its functional networks in colorectal cancer | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F52495%2F2014/PT | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT//PD%2FBD%2F142898%2F2018/PT | |
| oaire.citation.issue | 7 | pt_PT |
| oaire.citation.startPage | 185 | pt_PT |
| oaire.citation.title | Cellular and Molecular Life Sciences | pt_PT |
| oaire.citation.volume | 80 | pt_PT |
| oaire.fundingStream | 6817 - DCRRNI ID | |
| oaire.fundingStream | OE | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| 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 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.embargofct | Acesso de acordo com a política editorial da revista. | pt_PT |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | article | pt_PT |
| relation.isProjectOfPublication | 35168786-8dfc-4a00-9759-dab3669fe1ae | |
| relation.isProjectOfPublication | 40126362-9121-452c-a800-580ec6005d27 | |
| relation.isProjectOfPublication | c93cb40d-1352-4e28-985e-32ceb76f0895 | |
| relation.isProjectOfPublication.latestForDiscovery | 35168786-8dfc-4a00-9759-dab3669fe1ae |