OncoTargets and Therapy (Sep 2020)
Mesencephalic Astrocyte-Derived Neurotrophic Factor, a Prognostic Factor of Cholangiocarcinoma, Affects Sorafenib Sensitivity of Cholangiocarcinoma Cells by Deteriorating ER Stress
Abstract
Jingyi He,1,2 Guangbing Li,1,2 Xihan Liu,3 Liye Ma,1,2 Jiayao Zhang,1,2 Shunzhen Zheng,1,2 Jianping Wang,1,2 Jun Liu1,2 1Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China; 2Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; 3Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, ChinaCorrespondence: Jun LiuDepartment of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 324, Jing 5 Road, Jinan 250021, Shandong, ChinaTel +86 531 87925615Email [email protected]: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant tumor characterized by high malignancy and poor prognosis. 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. 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. There are no available studies on the diagnostic value and therapeutic significance of MANF in ICC. Hence, 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 and 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.Keywords: intrahepatic cholangiocarcinoma, MANF, sorafenib, prognosis
