Inhibition And Molecular Mechanism Of PGC-1? On Hepatocellular Carcinoma

Background and aims:Liver cancer is the third leading cause of death.Liver cancer is divided into primary and secondary types.Hepatocellular carcinoma?HCC?is the most common type of primary liver cancer.The ability of proliferation and metastasis of hepatocellular carcinoma is very strong.At present,the traditional methods are not effective,and there is still a lack of effective targeted drugs.Therefore,drug development for potential therapeutic targets is of great significance.The peroxisome proliferator-activated receptor gamma coactivator 1-alpha?PGC-1??is a transcription coactivators that regulate energy metabolism.Energy metabolism is closely related to the growth,proliferation and metastasis of cancer cells.The expression level of PGC-1?in various cancers is closely related to the prognosis of tumors.Through bioinformatics analysis,it was found that the expression level of PGC-1?in tumors was generally lower than that in normal tissues.This phenomenon is particularly significant in liver cancer.Survival time and survival rate of patients with high expression were higher than those with low expression.This study will focus on the role of PGC-1?in the expression of hepatoma cells and the molecular mechanism of anti-hepatocarcinoma.Provide new strategies and the oretical basis for the clinical treatment of liver cancer.Methods:Expression data of various tumors were collected from the TCGA database.The expression and prognosis of PGC-1?in various tumors were analyzed.Liver cancer data were collected from the GEO database.The expression of PGC-1?in liver cancer was analyzed.All HCC PGC-1?mRNA expression data were collected from the TCGA database,and patient phenotype and survival data were obtained.To analyze the relationship between PGC-1?expression and patient survival and clinicopathological factors.The molecular mechanism of overexpression of PGC-1?in inhibiting liver cancer was predicted.Establish a cell experimental model.An overexpression plasmid was constructed.To study the effect of overexpression of PGC-1?on liver cancer cells.To investigate the effects of PGC-1?activator Forskolin on liver cancer cells.The experiment verified the molecular mechanism of overexpression of PGC-1?in inhibiting liver cancer.Results:Meta-analysis showed that the low expression of PGC-1?was positively correlated with poor prognosis of tumors?HR=0.96,95%CI=0.86-1.06?.The expression level of PGC-1?in liver cancer showed a significant positive correlation(HR=0.48,95%CI=0.33-0.69,P=1×10^-3).Survival analysis showed that high expression of PGC-1?was beneficial to patient survival(P=2.2×10^-3).Disease-free survival also indicated that high expression of PGC-1?was beneficial to patient survival(P=4.8×10^-2).COX regression analysis of clinicopathological features showed that the low expression of PGC-1?was positively correlated with the histological grading of liver cancer.The TCGA and GEO databases showed that the expression of PGC-1?in liver cancer tissues was lower than that in non-liver cancer tissues.Cell experiments showed that overexpression of PGC-1?and Forskolin could significantly inhibit the proliferation of HepG2 in hepatocellular carcinoma cells.The cell cycle was significantly blocked at G0/G1 phase.It can obviously promote apoptosis.According to the double-luciferase experiment,it was found that overexpression of PGC-1?could down-regulate the expression of CCND3 mRNA.PGC-1?blocks HepG2 hepatocellular carcinoma at G0/G1 phase by regulating the periodic gene CCND3.Conclusion:There was a significant positive correlation between the low expression of PGC-1?and poor prognosis of liver cancer.There was a significant relationship between the low expression of PGC-1?and histologic grade of hepatocellular carcinoma.The expression of PGC-1?in liver cancer was significantly lower than that in normal liver cancer.High expression of PGC-1?can improve the survival time of patients.Overexpression of PGC-1?can significantly inhibit the proliferation of HepG2in liver cancer cells,so that liver cancer cells are blocked in the G0/G1 phase and promote apoptosis.PGC-1?inhibited HCC cells at G0/G1 phase by directly down-regulating the expression of the periodic gene CCND3.Forskolin may be a potential drug for treating liver cancer.