Effects And Mechanisms Of Stat1Delivered By Attenuated Salmonella On Treating Glioma

Glioma are originally in neuroepithelial cells, are the most common malignanttumor of the central nervous system, accounted for intracranial tumors by more thanhalf, is one of neurosurgical disease treatment difficulties. Because of the highdegree of malignant, pathogenesis is unclear, early diagnosis difficult,5-yearsurvival rate is low and thus become a worldwide problem in the field ofneurosurgery, as well as neurosurgeons rush research focus and hot spot. At presentis the main means of treatment of malignant gliomas surgery combined withradiotherapy and chemotherapy after surgery. Although there has been a lot ofimprovement on the specific methods, but the overall effect has not beensignificantly improved, mortality rates remain high, so for Glioma of etiology,pathogenesis, biological characteristics, as well as new research on effectivetreatments are still hot topics in neurosurgery.STAT is a signal transducer and activator of transcription proteins,cytokine/growth factor is important in signaling cytoplasmic transcription factors isavailable from more than one regulating cell growth and survival, differentiationand apoptosis. As important members of the family of Stat1, its role is particularlyprominent. Recent studies have shown that STAT1protein may be involved in theoccurrence and development of a variety of tumors, mainly in4areas:①Stat1protein of tyrosine kinase signaling pathway is selectively activated;②Persistentactivation of Stat1mutations can be induced by certain cell transformation;③Stat1mutations can block the dependence of tyrosine kinase-induced Stat1transcriptionand activation;④Stat1abnormal activation of the process of tumor formation leadsto inhibition of cell proliferation and apoptosis in gene expression. Reports showthat Stat1abnormal expression is associated with a variety of tumor progression andprognosis, as a potential tumor suppressor.We collected70cases of patients with primary glioma tumor tissue and15cases derived from tumor and brain hematoma clearance and internaldecompression craniotomy craniocerebral injury patients with normal brain tissue,by means of Stat1in normal brain tissues and glial tumor of immunohistochemical staining, Stat1expression in normal brain tissue is abundant, located primarily inglial cells in the cytoplasm. And expressed in glioma tissues is reduced, and itsexpression level and tumor malignant degree of negative correlation (P<0.01). Inthe process of study of recurrent glioma, we found that the average expression levelof Stat1in recurrence than in primary glioma has decreased, and the downward inthe primary tumor is low grade glioma relapse after Stat1expression leveldifference is more apparent. To this end, we have established a nude mouse gliomasubcutaneous xenograft model, through the tail vein injection of attenuatedSalmonella carrying the Stat1plasmid into tumor tissue. Observe the average tumorweight and volume; found that the attenuated salmonella carrying of Stat1intreatment group compared with control group, the tumor significantly reduce weightand volume reduced obviously. TUNEL experiments showed that attenuatedsalmonella carrying Stat1in the treatment group compared with the control group,tumor cell apoptosis significantly. By Western blot analysis of apoptosis relatedgene protein Cleaved-Caspase3, Cleaved-Caspase9Caspase8and cyto-c, the Bcl-2, Bax and p21gene detection, Stat1in the treatment group compared to thecontrol group may raise Caspase8, Cleaved-Caspase3, Cleaved-Caspase9, cyto-c,Expression of p21and Bax protein, reduced expression of Bcl-2proteins. It showsthat apoptosis of Stat1in the beginning phase can be a variety of channels, such asthe intrinsic pathway and the extrinsic pathway to promote apoptosis of tumortissue.And we through HE staining, it was found that attenuated Salmonellatyphimurium bacteria in this new carrier for Stat1in the treatment group and thecontrol group in nude mice, the heart, liver, spleen, lung and kidney did not changein morphology, and for the role of apoptosis in tumor tissue. This may be related totumor hypoxia environment suitable for attenuated Salmonella typhimurium growth.Stat1in U87MG human glioma cell lines with the over-expression, in thecultivation of distance between cells grows, connection loose, Flow Cytometryfound that21.4%of the cells were induced apoptosis, and the negative controlgroup and blank control group growth vigorous, cell closely bonded, stackedtogether, apoptosis rates were12.5%and11.6%（P<0.01）. On over-expression ofStat1the U87cell migration capacity analysis, we find that in the control groupafter the3h and negative control cells began to migrate, and after the24h, controlgroup negative control groups of cells and cell migration is very quickly, trauma almost completely healed, the healing index reached94.6%and94.9%. Stat1over-expression group healing capacity fell sharply, is only7.1%, indicating thatincreased expression of Stat1extremely inhibit the migration ability of the gliomacells.In summary, Stat1as a tumor suppressor, in the apoptosis the beginningthrough different ways, such as the intrinsic pathway and the extrinsic pathway,activated apoptotic pathway, to promote tumor tissue and apoptosis, increased theexpression also inhibit glioma cell migration, for further research on Stat1andprovide theoretical basis for the mechanism of action of glioma. Therefore, we thinkStat1could be a new potential target treatment of glioma.