Antisense oligonucleotides targeting midkine inhibit tumor growth in an in situ human hepatocellular carcinoma model

作     者：Li-cheng DAI~(2,5) Xiang WANG~2 Xing YAO~3 Li-shan MIN~3 Jin-liang PING~4 Jian-fang HE~2 ~2Huzhou Key Laboratory of Molecular Medicine,~3Department of General Surgery and ~4Department of Pathology Huzhou Central Hospital,Huzhou 313000,China 

作者机构：HuzhouKeyLaboratoryofMolecularMedicineHuzhouCentralHospitalHuzhou313000China DepartmentofGeneralSurgeryHuzhouCentralHospitalHuzhou313000China DepartmentofPathologyHuzhouCentralHospitalHuzhou313000China 

出 版 物：《Acta Pharmacologica Sinica》 (中国药理学报(英文版))

年 卷 期：2007年第28卷第3期

页      面：453-458页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Project supported by a grant from the Zhejiang Province Medicine and Sanitation Research Foundation(No 2003A077) Huzhou Natural Science Foundation(No 2004SZX07-11). 

主　　题：oligonucleotides antisense midkine carcinoma hepatocellular 

摘      要：Aim:To evaluate the in vivo antitumor effects of antisense oligonucleotides tar-geting midkine(MK-AS).Methods:An in situ human hepatocellular carcinoma(HCC)model was established in mice livers orthotopically.The MK-AS and 5-fluorouracil(5-Fu)were administered intravenously.The tumor sizes and plasmaalpha-fetoprotein(AFP)were measured by calipers and radiation immunoassayrespectively.The morphology of tumors was evaluated by hematoxylin-eosinstaining of histological sections.Human MK,p53,Bax,Bcl-2,and caspase-3protein content were detected by Western blotting.Results:MK-AS signifi-cantly inhibited in situ human HCC growth in mice compared with the saline groupin a dose-dependent manner.After the treatment with MK-AS or with 5-Fu,theplasma AFP concentration decreased in a dose-dependent manner.Interestingly,MK-AS also clearly downregulated the protein level of Bcl-2,and upregulatedp53,Bax,and caspase-3 in the hepatocellular carcinoma tissue.Conclusion:Theseresults demonstrated that MK-AS was an effective antitumor antisense oligo-nucleotide in vivo in mice;its antitumor effect is associated with the increase ofpro-apoptotic proteins,such as p53,Bax,and caspase-3,and the decrease of theanti-apoptotic protein,Bcl-2.