Potential Antitumor Activity Of Oncolytic Adenovirus-mediated SOCS1 For Hepatocellular Carcinoma

Hepatocyte carcinoma (HCC), holding the characters of malignancy and high mortality, is frequently among Chinese and could rob ten thousands lives annually in China. Conventional tumor therapeutic approaches, including surgery and chemo radiation, have limited efficiency and are also harmfully to normal tissues and cells. Gene-therapy is a newly potential treatment of disease, which induces exogenous genes or other genetic materials into cells and thus correcting aberrant conducts of the host cells or tissues. Many of them are applied in the area of tumor treatment. As a result, gene-therapy is becoming a more attractive manner for defending against hepatocyte carcinoma.Gene-therapy for tumor is a biomedical method that explores a kind of efficient vector to delivery therapeutic genes or anti-tumor genes into the tumor cells and finally ruins them. Therefore,the key strategies of anti-tumor are the selected genes and a effective vector. Presently, the vector, oncolytic adenoviral vector is one of most ideal anti-tumor vectors.SOCS1 (Suppressor of cytokine signaling 1) is a crucial suppressor of JAK/Stat(Janus kinase/Signal transducers and activators of transcription factors) pathway which plays a important role in remaining homeostasis. Increasing evidences indicate that SOCS1 is transcriptional silenced or down-regulated by the methylation of its promoter, and consequently the transcriptional factor STAT3 is under hyperphosphorylation and remaining persistent activation. That is very common in HCC cells. Extensive activation of Stat3 will consequently induce certain anti-apoptosis associated genes up-expression and conducts of some cell cycle factors, Bxl-xl, c-myc, survivin and cyclinD1/D2 for instance, and promotes the occurrence and development of malignancy. Stat3 could be a candidate of the anti-tumor targets. Naturally, we infer that over-expression of suppressor SOCS1 may attenuate activated Stat3 in HCC cells and get the results of suppressing HCC. Our present work, a new dual-aimed oncolytic adenovirus vector harboring cell-penetrating peptide modified SOCS1 gene, is based on above.Lots of investigators reported that promoter methylation-induced SOCS1 silencing present in many HCC cell lines. Our AdCN305-cppSOCS1 adenoviral vector occupy the ability of efficient expression of SOCS1 and the results from our experiments revealed the vector showed out cytotoxicity for HCC cells, but not normal cells and the downstream factors of STAT3 pathway, c-myc bcl-xl, cyclin D1and survivin, have a down-regulated expression. The same phenomenon is also observed in mouse Xenograft models.Our work showed that dual-aimed oncolytic adenovirus, which could express cppSOCS1 protein, possessed suppression effects on HCC for the first time. This will pave a way for subsequent lab and clinical research work of cancer.