Transfer of suppressor of cytokine signaling 3 by an oncolytic adenovirus induces potential antitumor activities in hepatocellular carcinoma.
The constitutive activation of signal transducer and activator of transcription 3 (STAT3) participates in carcinogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators, such as Bcl-xL, cyclins D1 and D2, and c-myc. Suppressor of cytokine signaling 3 (SOCS3) is one of the negative regulators of cytokine signaling and is frequently silenced in diverse cancers. In this study, we explored whether restoration of SOCS3 by oncolytic adenoviral vectors could inhibit the constitutive activation of the Janus kinase/STAT pathway and suppress tumor growth. Our data showed that SOCS3 was down-expressed in all liver tumor cell lines. The incorporation of SOCS3 or SOCS3 fused with cell-penetrating peptides (cpp-SOCS3) did not alter adenoviral replication selectively in liver tumor cells. The infection of cells with adenovirus CN305 (AdCN305)-SOCS3 and AdCN305-cpp-SOCS3 resulted in dramatic cytotoxicity in liver tumor cells. However, no cytotoxic effect was observed in normal cells infected with these vectors. Infection of liver tumor cells with AdCN305-SOCS3 and AdCN305-cpp-SOCS3 resulted in nearly complete inhibition of STAT3 phosphorylation and down-regulation of cyclin D1 and Bcl-xL. Treatment of the established tumor by AdCN305-SOCS3 and AdCN305-cpp-SOCS3 caused significant suppression of tumor growth. The suppression of tumor growth was due to the inhibition of STAT3 phosphorylation and induction of tumor cell death.


CONCLUSIONS
This study suggests that transfer of SOCS3 by an oncolytic adenovirus represents a potent approach for cancer therapy.
Cui
Qiang
Q
Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
Jiang
Wei
W
Wang
Yingxin
Y
Lv
Chen
C
Luo
Jingjing
J
Zhang
Wei
W
Lin
Fang
F
Yin
Yuexiang
Y
Cai
Rong
R
Wei
Ping
P
Qian
Cheng
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D002352:Carrier Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D014779:Virus Replication
D002352:Carrier Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins