Correlation Between MANF Expression With Prognosis And Mechanism Of Sorafenib Sensitivity In Primary Liver Cancer

Background:Hepatocellular carcinoma(HCC)and Intrahepatic cholangiocarcinoma(ICC)are two most common malignant types of primary liver cancer.Despite recent therapeutic approaches such as surgical resection,radiofrequency ablation,and orthotropic liver transplantation,the prognosis of HCC and ICC remains poor.Metastasis and recurrence of them significantly reduce the survival rate and quality of life of primary liver cancer patientsSorafenib is a multi-kinase inhibitor,which has exhibited significant safety and efficacy in suppressing tumor proliferation and angiogenesis.However,drug resistance still exists and affects the treatment effect and long-term survival of HCC patients.The survival benefit of HCC patients treated with sorafenib is only about 3 months Although the efficacy of sorafenib against cholangiocarcinoma cell lines has been demonstrated in vivo and in vitro,limited clinical data are available on the efficacy of sorafenib in patients with cholangiocarcinoma.Hence,new treatment strategies are urgently needed to prolong patient survival.Sorafenib can enhance endoplasmic reticulum(ER)stress-mediated apoptosis,and ER stress and unfolded protein response are also the mechanisms by which cancer cells resist drug therapy.Mesencephalic astrocyte-derived neurotrophic factor(MANF),initially identified as a neurotrophic factor,can be regulated by ER stress activation.Mesencephalic astrocyte-derived neurotrophic factor(MANF)plays a key role in endoplasmic reticulum stress.ER stress plays a key role in HCC carcinogenesis However,the molecular mechanisms of MANF in the prognosis of primary liver cancer and its regulation of sorafenib sensitivity in tumor cells remain unclear.In this study,we explored the correlation between MANF and prognosis of primary liver cancer,and further explored the molecular mechanism by which MANF affects the sensitivity of liver cancer cell lines to sorafenibChapter Ⅰ.Correlation Between MANF Expression With Prognosis And Mechanism Of Sorafenib Sensitivity In Hepatocellular CarcinomaPurpose:The purpose of this study was to evaluate the clinical and prognostic value of MANF in HCC,investigating the possibility of whether MANF regulates the sensitivity of hepatocellular carcinoma cells to sorafenib.Methods:We investigated the expression level of MANF in HCC as recorded in databases,and the results were verified by tissue microarray assay.Survival analysis was probed by Kaplan—Meier method.Cox regression models were used to ascertain prognostic value of MANF in HCC tissue microarray.Hepatocellular carcinoma cell lines were also used to determine how MANF regulates the therapeutic effect of sorafenib and to identify the underlying mechanismsResults:Results showed that MANF was overexpressed in HCC.Patients with high MANF expression levels had a worse prognosis and higher risk of tumor recurrence.MANF knockdown could facilitate sorafenib-mediated apoptosis and increase the sensitivity of sorafenib treatment by activating excessive ER stressConclusion:MANF is a prognostic marker of hepatocellular carcinoma.MANF knockdown increases sorafenib-mediated ER stress and apoptosis in hepatocellular carcinoma cell line.This mechanism may lead to a new therapeutic strategy in hepatocellular carcinoma.Chapter Ⅱ.Correlation Between MANF Expression With Prognosis And Mechanism Of Sorafenib Sensitivity In Intrahepatic CholangiocarcinomaPurpose:The purpose of this study was to evaluate the role of MANF in cholangiocarcinoma,investigating the possibility of whether sorafenib could become a reliable strategy for cholangiocarcinoma therapy.Methods:In this study,the expression level of MANF in ICC patients was investigated by bioinformatic analysis and the results were verified by tissue microarray assay.Cholangiocarcinoma cell lines were also used to determine how MANF regulates the therapeutic effect of sorafenib and to identify the underlying mechanisms.Results:The results showed that MANF was correlated with poor prognosis of ICC patients.MANF knockdown could facilitate sorafenib-mediated apoptosis and increase the sensitivity of sorafenib treatment by activating excessive ER stress.Conclusion:MANF is a prognostic marker of cholangiocarcinoma.MANF knockdown increases sorafenib-mediated ER stress and apoptosis in the cholangiocarcinoma cell lines.This mechanism may lead to a new therapeutic strategy in cholangiocarcinoma.