Inhibition of hepatocarcinoma and tumor metastasis to liver by gene therapy with recombinant CBD-HepII polypeptide of fibronectin.
Unlike the intact fibronectin (FN) molecule, some proteolytic or recombinant fragments of FN possess inhibitory activities on tumor, providing potential strategies in tumor therapeutics. Using the hydrodynamics-based gene delivery technique, we demonstrated that the treatment by in vivo expression of a recombinant CBD-HepII polypeptide of FN, designated as CH50, strongly inhibited the tumor growth, tumor invasion and angiogenesis. Such inhibitory effects of CH50 on tumor were partly ascribed to its influence on the activities of MMP-9 and alphavbeta3 integrin. The in vivo expressed CH50 decreased both the production and the activity of MMP-9 in tumor tissues. CH50 also down-regulated alphavbeta3 expression in tumor cells and endothelial cells in vitro. The decreased activity of alphavbeta3 integrin was proved by its reduced binding ability to fibrinogen and the down-regulation of cdc2 expression. The gene therapy with CH50 not only prolonged the survival of mice bearing hepatocarcinoma in the liver, but also suppressed the growth and invasive ability of tumor in spleen and its metastasis to liver. Taken together, these findings suggest a prospective utility of CH50 in the gene therapy of liver cancer.
Liu
Yi
Y
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
Huang
Bo
B
Yuan
Ye
Y
Gong
Wei
W
Xiao
Han
H
Li
Dong
D
Yu
Zhi-Rui
ZR
Wu
Feng-Hua
FH
Zhang
Gui-Mei
GM
Feng
Zuo-Hua
ZH
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
C478562:CH50 recombinant polypeptide; D005353:Fibronectins; D039302:Integrin alphaVbeta3; D010455:Peptides; D011994:Recombinant Proteins; D006493:Heparin; D020780:Matrix Metalloproteinase 9