Department of Pathology and Institute of Oncology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350004, PR China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, 350108, PR China.
Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
Mol Cell Endocrinol. 2022 Mar 1;543:111543. doi: 10.1016/j.mce.2021.111543. Epub 2022 Jan 4.
Nuclear receptor farnesoid X receptor (FXR) is generally considered a cell protector of enterohepatic tissues and a suppressor of liver cancer and colorectal carcinoma (CRC). Loss or reduction of FXR expression occurs during carcinogenesis, and the FXR level is inversely associated with the aggressive behaviors of the malignancy. Global deletion of FXR and tissue-specific deletion of FXR display distinct effects on tumorigenesis. Epigenetic silencing and inflammatory context are two main contributors to impaired FXR expression and activity. FXR exerts its antitumorigenic function via the following mechanisms: 1) FXR regulates multiple metabolic processes, notably bile acid homeostasis; 2) FXR antagonizes hepatic and enteric inflammation; 3) FXR impedes aberrant activation of some cancer-related pathways; and 4) FXR downregulates a number of oncogenes while upregulating some tumor suppressor genes. Restoring FXR functions via its agonists provides a therapeutic approach for patients with liver cancer and CRC. However, an in-depth understanding of the species-specific pharmacological effects is a prerequisite for assessing the clinical safety and efficacy of FXR agonists in human cancer treatment.
核受体法尼醇 X 受体 (FXR) 通常被认为是肠肝组织的细胞保护因子，可抑制肝癌和结直肠癌 (CRC)。在癌变过程中会发生 FXR 的表达缺失或减少，并且 FXR 水平与恶性肿瘤的侵袭性行为呈负相关。FXR 的全局缺失和组织特异性缺失对肿瘤发生有不同的影响。表观遗传沉默和炎症环境是导致 FXR 表达和活性受损的两个主要因素。FXR 通过以下机制发挥其抗肿瘤作用：1）FXR 调节多种代谢过程，特别是胆汁酸稳态；2）FXR 拮抗肝和肠炎症；3）FXR 阻止某些与癌症相关的途径异常激活；4）FXR 下调许多癌基因，同时上调一些肿瘤抑制基因。通过其激动剂恢复 FXR 的功能为肝癌和 CRC 患者提供了一种治疗方法。然而，深入了解种属特异性的药理作用是评估 FXR 激动剂在人类癌症治疗中的临床安全性和疗效的前提。
