Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability
Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal canc...
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| Veröffentlicht in: | Oncogenesis (New York, NY) NY), 2018-09, Vol.7 (9), p.70-9, Article 70 |
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| creator | Bokhari, A’dem Jonchere, Vincent Lagrange, Anaïs Bertrand, Romane Svrcek, Magali Marisa, Laetitia Buhard, Olivier Greene, Malorie Demidova, Anastasia Jia, Jieshuang Adriaenssens, Eric Chassat, Thierry Biard, Denis S. Flejou, Jean-François Lejeune, Fabrice Duval, Alex Collura, Ada |
| description | Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7. Suppression of NMD activity led to the re-expression of dozens of PTC mRNAs. Amongst these, several encoded mutant proteins with putative deleterious activity against MSI tumorigenesis (e.g., HSP110DE9 chaperone mutant). Inhibition of NMD in vivo using amlexanox reduced MSI tumor growth, but not that of MSS tumors. These results suggest that inhibition of the oncogenic activity of NMD may be an effective strategy for the personalized treatment of MSI CRC. |
| doi_str_mv | 10.1038/s41389-018-0079-x |
| format | Article |
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The role of this system in cancer is still quite poorly understood. In the present study, we evaluated the functional consequences of NMD activity in a subgroup of colorectal cancers (CRC) characterized by high levels of mRNAs with a PTC due to widespread instability in microsatellite sequences (MSI). In comparison to microsatellite stable (MSS) CRC, MSI CRC expressed increased levels of two critical activators of the NMD system, UPF1/2 and SMG1/6/7. Suppression of NMD activity led to the re-expression of dozens of PTC mRNAs. Amongst these, several encoded mutant proteins with putative deleterious activity against MSI tumorigenesis (e.g., HSP110DE9 chaperone mutant). Inhibition of NMD in vivo using amlexanox reduced MSI tumor growth, but not that of MSS tumors. These results suggest that inhibition of the oncogenic activity of NMD may be an effective strategy for the personalized treatment of MSI CRC.</description><identifier>ISSN: 2157-9024</identifier><identifier>EISSN: 2157-9024</identifier><identifier>DOI: 10.1038/s41389-018-0079-x</identifier><identifier>PMID: 30228267</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 13/89 ; 38/39 ; 38/79 ; 38/90 ; 45/77 ; 631/67/1504 ; 631/67/68 ; Apoptosis ; Cancer ; Cell Biology ; Colorectal cancer ; Human Genetics ; Internal Medicine ; Life Sciences ; Medicine ; Medicine & Public Health ; Microsatellite instability ; mRNA turnover ; Nonsense mutation ; Nonsense-mediated mRNA decay ; Oncology ; Tumorigenesis</subject><ispartof>Oncogenesis (New York, NY), 2018-09, Vol.7 (9), p.70-9, Article 70</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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Alex</au><au>Collura, Ada</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability</atitle><jtitle>Oncogenesis (New York, NY)</jtitle><stitle>Oncogenesis</stitle><addtitle>Oncogenesis</addtitle><date>2018-09-19</date><risdate>2018</risdate><volume>7</volume><issue>9</issue><spage>70</spage><epage>9</epage><pages>70-9</pages><artnum>70</artnum><issn>2157-9024</issn><eissn>2157-9024</eissn><abstract>Nonsense-mediated mRNA decay (NMD) is responsible for the degradation of mRNAs with a premature termination codon (PTC). 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| subjects | 13/2 13/89 38/39 38/79 38/90 45/77 631/67/1504 631/67/68 Apoptosis Cancer Cell Biology Colorectal cancer Human Genetics Internal Medicine Life Sciences Medicine Medicine & Public Health Microsatellite instability mRNA turnover Nonsense mutation Nonsense-mediated mRNA decay Oncology Tumorigenesis |
| title | Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability |
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