法尼酯X受体在肝胆胰恶性肿瘤中的研究进展

Research progress of farmesoid X receptor in hepatobiliary and pancreatic malignancies

目的通过对法尼酯X受体(FXR)与肝细胞性肝癌、胆管癌、胰癌的发生发展、预后及耐药等相关方面进行探讨,以期为肝胆胰恶性肿瘤的防治提供新方向和思路。方法以"FXR,肝细胞性肝癌,胆管癌,胰腺癌"为关键词,应用PubMed及CNKI期刊全文数据库检索系统,检索2005-2021的相关文献。纳入标准:(1)FXR的生物活性及其生理功能;(2)FXR与肝胆胰肿瘤发生发展、侵袭转移及耐药的相关机制研究。排除标准:(1)研究资料不全;(2)低质量文献。最终纳入分析46篇文献。结果文献报道中FXR在肝癌组织中的表达明显减弱,且FXR基因敲除小鼠的肝肿瘤发生率为100%。FXR缺失可使Wnt/β-catenin、RalA-GTP等致癌通路激活导致肝癌发生。在乙肝引发的肝癌中,正是通过减弱FXR-KNG1信号转录活性从而促进肝癌的发生。当使用FXR激动剂后不仅可以降低HBV-DNA复制,而且可以使肝癌细胞侵袭力减弱,从而降低其对遗传性化疗药物的耐药性。胆汁淤积及胆管炎症是胆管癌发生的重要因素,而FXR激活后恰好可以减轻胆汁酸及炎症反应对胆管细胞的刺激。奥贝胆酸作为FXR激动剂,不仅可以用于原发性胆汁性肝硬化的治疗,更能促进胆管癌细胞凋亡,抑制肿瘤侵袭,增强化疗敏感性。FXR在胰腺癌中的作用尚存在争论,但多数的研究认为胰腺癌组织中FXR高表达将促进胰腺癌细胞增殖和迁移,缩短生存时间。FXR拮抗剂可降低FXR表达,减弱肿胰腺癌侵袭性,减少肿瘤间质化,增强化疗敏感性。结论 FXR在肝胆胰恶性肿瘤的发生发展过程中起到重要的作用,可能为肝胆胰恶性肿瘤精准防治提供方向和思路。

Objective Farmesoid X rexeptor(FXR)is one of the ligand-dependent transcription factors,a member of the nuclear receptor superfamily,and has important regulatory effects on cell damage repair and material metabolism.This study explored the development,prognosis and drug resistance of FXR and hepatocellular carcinoma,cholangiocarcinoma,pancreatic cancer and other related aspects,in order to provide new directions and ideas for the prevention and treatment of hepatobiliary and pancreatic malignancies.Methods With " FXR,hepatocellular carcinoma,cholangiocarcinoma,pancreatic cancer" as keywords,PubMed and CNKI journal full-text database retrieval systems were used to retrieve relevant literature from 2005 to 2021.Inclusion criteria:(1)The biological activity and physiological functions of FXR;(2)Research on the related mechanism of FXR and hepatobiliary and pancreatic tumor development,invasion,metastasis and drug resistance.Exclusion criteria:(1)incomplete research data;(2)low-quality literature.Finally,46 articles were included in the analysis.Results According to reports,the expression of FXR in liver cancer tissue is obviously weakened,and the incidence of liver tumor in FXR knockout mice is 100%.FXR deletion can activate Wnt/β-catenin,Rala GTP and other carcinogenic pathways,leading to hepatocarcinogenesis.In the liver cancer caused by HBV,it is through weakening the FXR-KNG1 signal transcription activity that the occurrence of liver cancer is promoted.When FXR agonist is used,it can not only reduce HBV-DNA replication,but also weaken the invasiveness of liver cancer cells,thus reducing their resistance to hereditary chemotherapy drugs.Cholestasis and bile duct inflammation are important factors in the occurrence of cholangiocarcinoma,and FXR activation can just reduce the stimulation of bile acid and inflammation on bile duct cells.As an FXR agonist,Obecholate can not only be used in the treatment of primary biliary cirrhosis,but also promote the apoptosis of cholangiocarcinoma cells,inhibit tumor invasion and enhance chemotherapy sensitivity.The role of FXR in pancreatic cancer is still controversial,but most studies believe that the high expression of FXR in pancreatic cancer will promote the proliferation and migration of pancreatic cancer cells and shorten the survival time.FXR antagonist can reduce the expression of FXR,weaken the invasion of pancreatic cancer,reduce the tumor interstitial and enhance the chemotherapy sensitivity.Conclusion FXR plays an important role in the occurrence and development of hepatobiliary and pancreatic malignancies,and may provide directions and ideas for the precise prevention and treatment of hepatobiliary and pancreatic malignancies.