Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3.
OBJECTIVE
Hepatocellular carcinoma (HCC) is an aggressive malignancy and is a devastating clinical complication of chronic liver disease. Therapeutic options are limited mainly because the genetic and biochemical understanding of this disease remains fragmented. We intended to study the role of signal transducer and activator of transcription 3 (STAT3) aberrant signaling in HCC malignancy, and the therapeutic potential of inhibition of STAT3 expression for HCC.


METHODS
A 2'-O-methoxyethylribose-modified phosphorothioate antisense oligonucleotide (ASO) was used to knock down STAT3 expression in different human HCC cell lines, including the highly metastatic HCCLM3 derived from orthotopic implantation and subsequent lung metastasis in athymic mice. The effects of STAT3 ASO treatment on HCC cells, metastasis, and animal survival following HCCLM3 orthotopic implantation were evaluated.


RESULTS
Specific suppression of phosphorylated STAT3 reduced its DNA-binding activity, inhibited the expression of vascular endothelial growth factor, survivin, matrix metalloproteinases 2 and 9, reduced cell proliferation and migratory potential, induced apoptosis in vitro, and inhibited intradermal angiogenesis and s.c. tumorigenesis upon injection in mice. In mice bearing orthotopically implanted HCCLM3, STAT3 inhibition following therapeutic treatment with STAT3 ASO reduced circulating vascular endothelial growth factor and basic fibroblast growth factor, decreased intratumor CD34-positive microvessel density, intrahepatic and intraperitoneal transmission, and lung metastasis. HCC tumor volume and weight were reduced and the survival time of mice bearing orthotopically xenografted HCC was approximately doubled in STAT3 ASO-treated mice (P < 0.05).


CONCLUSIONS
Constitutively activated STAT3 is essential for the growth, survival, and metastasis of HCC, suggesting that STAT3-targeted therapy may have utility for HCC.
Li
Wen-Chang
WC
Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
Ye
Sheng-Long
SL
Sun
Rui-Xia
RX
Liu
Yin-Kun
YK
Tang
Zhao-You
ZY
Kim
Youngsoo
Y
Karras
James G
JG
Zhang
Hong
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011237:Predictive Value of Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A