The Study On Fuction And Molecular Mechanism Of P28^Gank、IRAK1 In Macrophage And HCC

Part ⅠThe role and mechanism of p28^Gank in macrophageThe inflammatory microenvironment,in which macrophages played important roles as immune cells driving from monocytes,was involved in the development of many diseases.Therefore,the research of inflammation related signaling pathways based on macrophages is of great significance for guiding the treatment of inflammation-associated diseases.p28^Gank（also known as p28,Gankyrin or PSMD10）is an onco-protein overexpressed in hepatocellular carcinoma,played important roles in regulating cell cycle,cell apoptosis and tumor-initiating cells.Our previous study showed that IL-1β/IRAK-1signal pathway could upregulate p28^Gankank expression via p300/CBP/NF-Y axis,indicating p28^Gankank as a linker of inflammation with tumor.Up to now,there were few reports about the roles of p28^Gank in the inflammatory microenvironment.Combined the tips from our previous study that p28^Gank had some relationships with inflammatory related signal pathways,it was meaningful to carry out the research of p28^Gank in inflammatory related signal pathways in macrophages.The p28^Gankank conditional over-expression and knockout mice which were unique in our laboratory were used in this study.Through the endotoxin shock model in vivo and peritoneal macrophage inflammatory model in vitro,the regulating function of p28^Gank in inflammation related signal pathways were studied.The results as follows:endogenous p28^Gank increased significantly in response to different agonists either in the peritoneal or bone marrow-derived macrophages of mice;moreover,deletion of p28^Gank in macrophage alleviated the endotoxic shock,diminished the production of IL-6 and TNF-α,while overexpression p28^Gank in macrophage promoted both secretions;interestingly,under LPS treatment,sustained activation of PI3K/AKT signal pathway by the deficiency of p28^Gank may result in the changes of inflammatory factors.These findings had the important guiding significance for understanding the role and mechanism of p28^Gankank in the inflammatory and inflammatory related microenvironment.Part ⅡThe role and mechanism of interleukin-1 receptor-associated kinase 1（IRAK1）in HCCPrimary hepatocellular carcinoma（hepatocellular carcinoma,HCC）,which is one of the most common malignant tumors,is the third malignant tumor in China.In the face of the grim situation,although accumulated years of liver cancer research experience,we still had to admit that: the pathogenesis mechanism of hepatocellular carcinoma has not yet been elucidated by now and the cure of liver cancer is still lack of good methods.Therefore,the study of the molecular mechanism of the occurrence and development of HCC and then finding new diagnostic markers and therapeutic targets in further are still the most important goals of scientific research.In the previous research,our team found that IL-1 beta /IRAK1 signaling pathways could up-regulation of p28 Gank and affect the prognosis of HCC patients.On this basis,further study of the function of IRAK1 molecules in hepatocellular carcinoma were carried out.As the result,the over-expression of IRAK1 in hepatocellular carcinoma tissues was found by the clinical samples detection.Besides,through the study of different HCC cell lines,IRAK1 was found to promote the proliferation,tumor formation and anti-apoptosis fuction of hepatocellular carcinoma cells.For the mechanisms: IRAK1 promoted the proliferation of HCC cell lines by regulating the level of Cyclin D1;it inhibited apoptosis of HCC cell lines by the exogenous apoptotic pathways instead of the mitochondrial pathway,thereby enhanced the chemotherapeutic drug cisplatin tolerance;it might also promote the nuclear translocation NF-κB/p65 and thereby affect the expression of its down-stream anti apoptosis genes.In this study,the proliferation promoting and anti-apoptotic function of IRAK1 in HCC tissues were discovered firstly,which had the great significance for further understanding of the biological functions of IRAK1 in hepatocellular carcinoma.