Studies On Cancer Therapy By Oncolytic Adenovirus Expressing Cpp-Fused SOCS3

Nowadays, cancer is becoming one of the most threatening diseases for the human health.Methods for cancer therapy were developed by many scientists. Many traditionally therapeutictechniques were limited for malignant tumors such as surgery,actinotheraphy,chemotherapy etal. Considered these obstacles, it is very important to optimize cancer therapy.Gene therapy was a kind of new scientific fields for disease therapy recently. Since 1980s,gene therapy had been raised, and some of these method,s were put into clinical phases of which63% was applied for cancer. But cancer gene therapy remained to be optimized, specially in thechoice of the gene and vectors. The vectors used widely were included lentivirus, bacilliformvirus, adeno-associated virus and replication-defective adenovirus, but most of these were shortof tumor selectivity. Recently, tumor-selective replication adenovirus (oncolytic virus) became tobe focused. Because that they could selectively replicated in tumor cells and kill them, at thesame time, they had little toxicity with normal cells. So adenoviral vectors were promising to bedeveloped for banker gene therapy.SOCS3 could negatively regulate JAK/STAT pathway to keep physiological function. It hasbeen revealed that SOCS3 is frequently silenced in some tumor cells due to hypermethylation atCpG island of its functional promoter. Thus, its silence in tissues may result in unregulatedSTAT3 phosphorylation. STATs are activated in response to cytokines and growth factors and arerecruited to specific receptor phosphotyrosines at which they are phosphorylated by JAK kinases.After activation, STATs dimerize and translocate to the nucleus where it can active target genetranslation including apoptosis-associated and cell cycle regulatory genes, such as Cyclin D1,Bcl-2, Bcl-xL et al to promote oncogenesis. These findings suggest that restoration of SOCS3 intumor cells may inhibit STAT3 activity and control tumor cell growth via gene transfer approach.In this study, we have explored whether restoration of SOCS3 by oncolytic adenoviral vectorPCN305 could inhibit the constitutive activation of JAK/STAT pathway and suppress tumorgrowth.Our data showed that SOCS3 was down-expressed in all tumor cell lines. Incorporation ofSOCS3 or SOCS3 fused with cell-penetrating peptides (cpp-SOCS3) did not selectively alteradenoviral replication in tumor cells. Infection of cells with AdCN305-SOCS3 andAdCN305-cpp-SOCS3 resulted in dramatic cytotoxicity in tumor cells. However, no cytotoxic effect could be observed in normal cells infected with these vectors. Infection of tumor cells withAdCN305-SOCS3 and AdCN305-cpp-SOCS3 resulted in nearly complete inhibition of STAT3phosphrylation and down-regulation of Cyclin D1 and Bcl-xL. Treatment of the establishedtumor by AdCN305-SOCS3 and AdCN305-cpp-SOCS3 caused significant suppression of tumorgrowth. The suppression of tumor growth was due to the inhibition of STAT3 phosphorylationand induction of tumor cell death.This study suggests that transfer of SOCS3 by oncolytic adenovirus represents a potentapproach for cancer therapy.