The Efficiency Of Oncolytic Adenorirus Expressing SOCS3 Treating Colorectal Cancer

Colorectal carcinoma (CRC) is one of common malignant tumors and ranks as the third type of gastrointestinal tumors. CRC usually is localized in rectum or the juncture of rectum and sigmoid colon. Sixty-five percent of colorectal carcinoma patients appear after the age of 40 and the morbility ratio of men to women is two or three to one. With great development of our economy and society, the ratio of morbility in china is increasing. Presently, the popular treatment of CRC is surgical approach and about fifty percent of patients die of the disease thin five years once be diagnosed. So, an ideal approach is needed badly for eliminating thoroughly the malignant cells or extending life of patients.Oncolytic adenovirus is recombinant virus that is tumor specific replicating viral vector driving from manually reconstructed wild type virus and thus dissolves carcinoma cells. The progeny virus from the dissolved cells could infect surrounding tumor cells and dissolve them. At the same time, the oncolytic adenovirus has no capacity of replicating in normal cells or harmful effect to normal cell. In addition to dissolving carcinoma cells, the virus could be a vector which delivery therapeutic genes to target cells.JAK (Janus kinase)/STAT (Signal transducers and activators of transcription) pathway was reported playing a crucial role during the carcinogenesis and tumor cell malignant proliferation. SOCS3 (Suppressor of cytokine signaling 3) is one of negative regulators in the JAK/STAT signal pathway. Many studies shows that SOCS3 is frequently silenced in some tumor cells because of hypermethylation at its functional promoter, which may result in the constitutive activation of STAT3. Thus a few apoptosis-promoted and cell cycle-checked genes in tumor cells were upregulated. As a result, research for the relationship between JAK/STAT signal pathway and tumor proliferation become more popular.Our group performed an oncolytic adenoviral vector CN305 (pCN305) which carried SOCS3 gene fused with cpp( cell-penetrated peptide gene) in application to colon carcinoma treatment. AdCN305 could specifically replicate and propagate in tumor cells to eliminate carcinoma. Meanwhile , SOCS3 is overexpressed by an endogenous adenoviral major late promoter (MLP) through internal ribosome entry site(IRES) so that it can repress overactivated JAK/STAT pathway to inhibit tumor growth. This system has several advantages:â‘ pCN305 vector system can effectively transfer SOCS3 into tumor tissues.â‘¡CPP, which is 14 amino acids long and is inserted into the N terminal of SOCS3 protein, can intrigue side effect in uninfected tumor cells. Thus it can enhance the inhibition effect of SOCS3.â‘¢It is the first time to study the relationship between JAK/STAT pathway and SOCS3 in colorectal carcinoma. Our data in vitro shows that AdCN305-cppSOCS3 can effectively and specifically replicate in colon tumor cells and kill them. This study provides a novel strategy for the anti-colorectal carcinoma drugs development.