Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma  

作　　者：Qi-yi Zhang Wen Ding Jian-shan Mo Shu-min Ou-yang Zi-you Lin Ke-ren Peng Guo-pin Liu Jin-jian Lu Pei-bin Yue Jin-ping Lei Yan-dong Wang Xiao-lei Zhang 

机构地区：[1]National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation,Guangdong Key Laboratory of Chiral Molecule and Drug Discovery,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou,510006,China [2]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangzhou,510060,China [3]State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macao,Macao,China [4]Department of Medicine,Division of Hematology-Oncology,and Samuel Oschin Comprehensive Cancer Institute,Cedars-Sinai Medical Center,Los Angeles,CA,90048,USA

出　　处：《Acta Pharmacologica Sinica》2024年第8期1701-1714,共14页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(22077144,81973359);Guangdong Basic and Applied Basic Research Foundation(2022A1515012204);Joint Foundation of Guangdong and Macao for Science and Technology Innovation(2022A0505020024);the Science and Technology Development Fund,Macao SAR(File No.0053-2021-AGJ);The Key Research and Development Plan of Guangzhou City(202206080007);Guangdong Provincial Key Laboratory of Construction Foundation(2023B1212060022)are also appreciated.

摘　　要：Signal transducer and activator of transcription 3(STAT3)plays an important role in the occurrence and progression of tumors,leading to resistance and poor prognosis.Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma(HCC),but potent and less toxic STAT3 inhibitors have not been discovered.Here,based on antisense technology,we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA(STAT3 ASOs).Treatment with STAT3 ASOs decreased the STAT3 mRNA and protein levels in HCC cells.STAT3 ASOs significantly inhibited the proliferation,survival,migration,and invasion of cancer cells by specifically perturbing STAT3 signaling.Treatment with STAT3 ASOs decreased the tumor burden in an HCC xenograft model.Moreover,aberrant STAT3 signaling activation is one of multiple signaling pathways involved in sorafenib resistance in HCC.STAT3 ASOs effectively sensitized resistant HCC cell lines to sorafenib in vitro and improved the inhibitory potency of sorafenib in a resistant HCC xenograft model.The developed STAT3 ASOs enrich the tools capable of targeting STAT3 and modulating STAT3 activity,serve as a promising strategy for treating HCC and other STAT3-addicted tumors,and alleviate the acquired resistance to sorafenib in HCC patients.

关 键 词：STAT3 antisense oligonucleotide hepatocellular carcinoma acquired sorafenib-resistance 

分 类 号：R735.7[医药卫生—肿瘤]