The Effect Of Survivin Targeting On Cell Proliferation And Apoptosis In Hepatocellular Carcinoma

Background and objectiveTumorigenesis is close association with the uncontrol of cell proliferation and diminished apoptosis. The recent studies indicate that survivin which is the smallest of IAPs( inhibitor of apoptosis protein) family plays an important role in the interface between cell proliferation and apoptosis. Survivin deserves attention as a selective target for cancer therapy because it lacks expression in differentiated adult tissues but is expressed in a variety of human tumors. It showed that 'molecular antagonists' of survivin while directed into tumor cells could be an attractive strategy for tumor therapy. Although survivin has been widely recognized as an attractive target for cancer therapy, the use of antisense survivin expression to induce tumor cell apoptosis and inhibit tumor cell proliferation has only recently been described. Whereas there are still many questions remained to be resolved in the application study of survivin. First, the effective target to inhibit the expression of survivin must be seeked. The antisense oligonucleotide targeting with different coding region of survivin mRNA 1619bp is different with survivin expression inhibition. Experimentin vivo or in vitro must be carried out to study secure and effective antisense oligonucleotide sequence and make out a curve between its dose and reaction. Secondly, the role and mechanism of survivin should be interpreted in cellular activities such as apoptosis, cell cycle and division while survivin's structure has been clearly testified and its anti-apoptosis function has been widely accepted. Furthermore, survivin is differently expressed in different tumors, whether survivin targeting might affect the development of common tumor is relied on much experiments in vitro as well as ones in vivo.Induction of tumor cell apoptosis is the fundamental mechanism of chemotherapeutic drugs killing tumor cell. Survivin's overexpression results in inhibition of apoptosis and chemoresistance. Antisense technique by enclosing the overexpression of apoptotic gene can induce apoptosis and enhance the sensibility of chemotherapeutic drugs. This is a novel and promising tactics to reverse the resistance of drugs. The recent studies have testified that antisense inhibition of survivin expression can enhance therapeutic sensibility in tumor cells including hepatocarcinoma. However such studies are based on sensible tumor cell. Whether antisense inhibition of survivin expression sensibilizes the drug-resistant tumor cell and even enhance the sensibility of the drug-resistant tumor cell resistanceing to the same drug remain to be determined. It has the potentially great value in the prevention of tumor development and postoperative recurrence. Liver cancer is leading causes of cancer death, and their incidence continues to rise. The main reasons for the unfavorable prognosis of these tumors are their propensity to metastasize early and develop resistance to a wide range of functionally anticancer agents. Recent studies show that expression of survivin was detected in HepG2. Huh7, Sk-Hepl cell lines and hepatocellular carcinoma tissues remarkably which have close correlation with its apoptosis and proliferation that renders resistance to chemotherapy and resistance to radioactive treatment.ObjectiveTo design, screen and decide the effective antisense compound to inhibit the hepatocellular carcinoma cells, and to further investigate its effect on hepatocellular carcinoma proliferation and apoptosis; by using antisense interfering with survivin's anti-apoptosis, to investigate the effect of antisense survivin compound on cell cycle, division and subcellular localization of survivin proteins in hepatocellular carcinoma cells; to investigate the significant correlation between the expression levels of survivin and drug-resistance of hepatocellular carcinoma cells and to reverse the resistance in HepG2/ADM, and to reveal that the combination of antisense compounds with ADM is possibly a reasonable approach in future the clinical treatment of drug-resistant/ADM-res...