He Jingyi, Li Guangbing, Liu Xihan, Ma Liye, Zhang Jiayao, Zheng Shunzhen, Wang Jianping, Liu Jun
Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.
Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
Onco Targets Ther. 2020 Sep 16;13:9169-9184. doi: 10.2147/OTT.S245575. eCollection 2020.
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.
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.
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.
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.
肝内胆管癌（ICC）是一种侵袭性恶性肿瘤，具有高恶性和预后差的特点。尽管索拉非尼对胆管癌细胞系的疗效已在体内和体外得到证实，但关于索拉非尼在胆管癌患者中的疗效的临床数据有限。索拉非尼可增强内质网（ER）应激介导的细胞凋亡，而ER应激和未折叠蛋白反应也是癌细胞抵抗药物治疗的机制。中脑星形胶质细胞衍生的神经营养因子（MANF）最初被鉴定为一种神经营养因子，可受ER应激激活的调节。目前尚无关于MANF在ICC中的诊断价值和治疗意义的研究。因此，本研究的目的是评估MANF在胆管癌中的作用，探讨索拉非尼是否有可能成为胆管癌治疗的可靠策略。
在本研究中，通过生物信息学分析研究了ICC患者中MANF的表达水平，并通过组织微阵列分析验证了结果。还使用胆管癌细胞系来确定MANF如何调节索拉非尼的治疗效果并确定潜在机制。
结果表明，MANF与预后不良相关，敲低MANF可促进索拉非尼介导的细胞凋亡，并通过激活过度的ER应激增加索拉非尼治疗的敏感性。
MANF是胆管癌的预后标志物。敲低MANF可增加索拉非尼介导的胆管癌细胞系中的ER应激和细胞凋亡。这一机制可能导致胆管癌的一种新的治疗策略。
