The Research Of Molecular Mechanism Of RRAD In Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is a common malignancy with poor prognosis and limited therapeutic options.So many efforts have been made to reveal the mechanism of liver cancer,and the use of Sorafenib has raised the hopes of patients.However,because of the difficulties of early diagnosis of liver cancer and the high recurrence rate,HCC is still a frequently occurring malignancy with poor prognosis.Most patients have missed the best chance to take tumor resection when they seek medical advice.With average survival rates between 6 and 20 months,a better knowledge of the pathogenic mechanisms of HCC is urgently required to develop novel strategies for treating the disease.Ras-related associated with diabetes(RRAD)belongs to the subfamily ofRas-related GTPases,and is associated with several types of cancer,while its functionin HCC remains unclear.RRAD has a unique sequence and is overexpressed in the skeletal muscle of humans with type ? diabetes.In contrast to normal cells that depend on mitochondrial oxidative phosphorylation to obtain energy,most cancer cells prefer aerobic glycolysis(the Warburg effect),even though it is an inefficient way to generate adenosine triphosphate(ATP).In this study,we aim to provide an improved understanding of the roles of RRAD in HCC,and bring insights into its potential as a novel molecular target in HCC therapy.PART ?RRAD has an effect on cell proliferation,migration,apoptosis and aerobic glycolysis in human hepatocellular carcinomaAims:We aimed to elucidate the role of RRAD and whether it affects HCC,including cell proliferation,migration,apoptosis and aerobic glycolysis.Methods:We aimed to elucidate the role of RRAD and whether it affects glucose metabolism in HCC by immunohistochemically examining tissue samples from HCC patients and assessing the effect of RRAD overexpression and knockdown on the glucose metabolism,proliferation,cell cycle,and apoptosis of HCC cell lines SK-Hep-1 and Huh7,as well as and on tumor progression in vivo.Results:We demonstrated that RRAD suppressed aerobic glycolysis in HCC.On the other hand,RRAD inhibted HCC proliferation by regulating the cell cycle via downregulation of cyclins and cyclin-dependent kinases and promoted apoptosis through the mitochondrial apoptosis pathway in vitro.In addition,RRAD retarded tumor growth in vivo.RRAD expression was low in tumor tissues.Low RRAD levels were significantly correlated with large tumor size and advanced tumor stage.Furthermore,Kaplan-Meier survival curves showed that HCC patients with low RRAD expression may have a better prognosis.Conclusion:We have shown that RRAD exhibits a tumor-suppressing role in HCC,both in vitro and in vivo,thus lowering cell proliferation,arresting the cell cycle,and increasing apoptosisPART ?RRAD suppresses the Warburg effect by downregulating ACTG1 in hepatocellular carcinomaAimsTo explore the mechanisms involving RRAD in HCC.MethodsWe aimed to elucidate the role of RRAD and whether it affects glucose metabolism in HCC by immunohistochemically examining tissue samples from HCC patients and assessing the effect of RRAD overexpression and knockdown on the glucose metabolism,proliferation,cell cycle,and apoptosis of HCC cell lines SK-Hep-1 and Huh7,as well as on tumor progression in vivo.ResultsWe demonstrated that RRAD binds to actin gamma 1(ACTG1).RRAD suppressed aerobic glycolysis in HCC by downregulating ACTG1.On the other hand,ACTG1 promoted HCC proliferation by regulating the cell cycle via downregulation of cyclins and cyclin-dependent kinases and inhibited apoptosis through the mitochondrial apoptosis pathway in vitro.In addition,RRAD retarded tumor growth by downregulating ACTG1 in vivo.ACTG1 was overexpressed in HCC tissues compared with peri-tumor tissues,whereas the expression of RRAD was low in tumor tissues.Low RRAD levels were significantly correlated with large tumor size and advanced tumor stage;high ACTG1 levels were significantly correlated with advanced tumor stage.Furthermore,Kaplan-Meier survival curves showed that HCC patients with high RRAD and low ACTG1 expression may have a better prognosis.ConclusionWe have shown that RRAD exhibits a tumor-suppressing role in HCC by downregulating glucose metabolism and ACTG1 expression,thus lowering cell proliferation,arresting the cell cycle,and increasing apoptosis.These findings indicate that ACTG1 may act as a downstream effector of RRAD and open a new avenue for potential HCC treatment.