Targeting nonsense-mediated mRNA decay in colorectal cancers with microsatellite instability

被引：64

作者：

Bokhari, Adem ^{[1
]}

Jonchere, Vincent ^{[1
]}

Lagrange, Anais ^{[1
]}

Bertrand, Romane ^{[1
]}

Syrcek, Magali ^{[1
,2
]}

Marisa, Laetitia ^{[1
,3
]}

Buhard, Olivier ^{[1
]}

Greene, Malorie ^{[1
]}

Demidova, Anastasia ^{[1
]}

Jia, Jieshuang ^{[4
]}

Adriaenssens, Eric ^{[5
]}

Chassat, Thierry ^{[6
]}

Biard, Denis S. ^{[7
]}

Flejou, Jean-Francois ^{[1
,2
]}

Lejeune, Fabrice ^{[4
]}

Duval, Alex ^{[1
]}

Collura, Ada ^{[1
]}

机构：

[1] UPMC Univ Paris 06, Sorbonne Univ, INSERM,Equipe Labellisee Ligue Canc,Ctr Rech St A, UMRS 938,SIRIC CURAMUS,Equipe Instabilite Microsa, F-75012 Paris, France

[2] Hop St Antoine, AP HP, Serv Anat & Cytol Pathol, Paris, France

[3] Ligue Natl Canc, Programme Cartes Identite Tumeurs, Paris, France

[4] Univ Lille, CNRS, Inst Pasteur Lille, UMR 8161,M3T, F-59000 Lille, France

[5] Univ Lille, Cell Plast & Canc, INSERM U908, F-59655 Villeneuve Dascq, France

[6] Pasteur Lille, PLEHTA Plateforme Experimentat & Haute Technol An, F-59019 Lille, France

[7] Ctr Etud Atom, Direct Sci Vivant, Inst Malad Emergentes & Therapies Innovantes, Serv Etud Prions & Infect Atyp, Fontenay Aux Roses, France

来源：

ONCOGENESIS | 2018年 / 7卷

关键词：

MISMATCH REPAIR; SURVEILLANCE COMPLEX; NMD FACTORS; INHIBITION; GENE; DISEASE; MUTATIONS; SMG-1; CHEMOTHERAPY; COMPONENTS;

D O I：

10.1038/s41389-018-0079-x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：9

共 45 条

[1] ORAL MEDICINE Amlexanox [J].