Isoleucyl-tRNA synthetase 2 promotespancreatic ductal adenocarcinomaproliferation and metastasis by stabilizingb-catenin  

作　　者：Yixun Jin Xinyang Huang Zhuoxin Wang Berik Kouken Qi Wang Lifu Wang 

机构地区：[1]Department of Gastroenterology,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200001,China

出　　处：《Genes & Diseases》2025年第3期478-491,共14页基因与疾病(英文)

基　　金：supported by the National Natural Science Foundation of China(No.81870385,81702740).

摘　　要：Isoleucyl-tRNA synthetase 2(IARS2),originally regarded as an enzyme ligatingisoleucine to the corresponding tRNA,has been identified as an oncogene recently.However,its function in pancreatic ductal adenocarcinoma(PDAC)remains to be discovered.Here weexplored the biological role of IARS2 in PDAC.Up-regulated IARS2 was found in PDAC tissuesand cell lines.KaplaneMeier survival analysis indicated a worse prognosis in patients with highIARS2 expression.CCK-8,EdU,and colony formation assays showed IARS2 overexpressionenhanced PDAC proliferation,which was reduced by IARS2 knockdown.Meanwhile,IARS2down-regulation inhibited PDAC metastasis by impeding epithelialemesenchymal transition.These results were also supported by subcutaneous xenograft and metastasis assays in vivo.To figure out underlying mechanisms,differential and enrichment analyses were conductedand the WNT signaling pathway was discovered.Our results demonstrated that there was nosignificant relationship between the WNT signaling pathway key factor CTNNB1 and IARS2 atthe transcription level.However,cycloheximide assays showed that IARS2 reduced theβ-catenin degradation rate.IARS2 inhibited the phosphorylation ofβ-catenin at the Ser33/37 site andregulated downstream targets of WNT signaling including c-MYC,c-JUN,and MMP7.Theenhancement of proliferation and metastasis caused by IARS2 could be reversed by MSAB,an agent that promotesβ-catenin degradation.In summary,IARS2 facilitates PDAC proliferation and metastasis by stabilizingβ-catenin,which leads to WNT/β-catenin activation.IARS2 serves as an underlying prognosis marker and a potential therapeutic target for PDAC.

关 键 词：Aminoacyl-tRNA synthetases Isoleucyl-tRNA synthetase 2 Pancreatic ductal adenocarcinoma WNT signaling pathway b-Catenin 

分 类 号：R735.9[医药卫生—肿瘤]