Li Yuanqiang, Hong Yangjian, Shen Huize, Zhou Jingnan, Cesar Daniel, Eleutério José, Matsuura Motoki, Liu Yanyang, Luo Cong, Li Qinglin
Key Laboratory of Integrated Chinese and Western Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
Wenzhou Medical University, Wenzhou, China.
Transl Cancer Res. 2025 Apr 30;14(4):2440-2456. doi: 10.21037/tcr-2025-522. Epub 2025 Apr 27.
The Farnesoid X receptor (FXR) is a nuclear receptor known for its role in inflammation regulation and tumor suppression in various cancers. However, its functional significance and underlying mechanisms in cervical cancer (CC) remain unclear. The persistent activation of the nuclear factor kappa B (NF-κB) signaling pathway due to inflammation is a key driver of cancer progression. This study investigates the effects of FXR activation in CC and its interaction with the NF-κB pathway.
CC cells were treated with GW4064, an FXR agonist (3 µM), and xenograft tumor models were assigned to receive 30 mg/kg GW4064. NF-κB-mediated transcriptional activity was assessed using a dual-luciferase reporter assay. Gene expression in CC cells and mouse tissues was analyzed via quantitative real-time polymerase chain reaction (qRT-PCR), while key proteins in the NF-κB and STAT3 signaling pathways were examined using Western blotting. Cell proliferation, migration, and invasion were evaluated through methylthiazolyldiphenyl-tetrazolium bromide (MTT), wound healing, and real-time cellular analysis (RTCA), respectively. Apoptosis was measured using a fluorescein isothiocyanate (FITC) Annexin V Apoptosis Detection Kit I.
FXR deletion in 6- to 8-week-old C57B/6 female mice led to abnormal upregulation of inflammatory genes in the cervix and aberrant NF-κB activation. Treatment with GW4064 suppressed NF-κB-regulated gene expression in Hela and Siha CC cells and inhibited NF-κB activity at the transcriptional level. Mechanistically, FXR activation suppressed tumor necrosis factor alpha (TNFα)-induced phosphorylation of NF-κB inhibitor alpha (IκBα) by directly binding to the promoter of inhibitor of nuclear factor kappa B kinase regulatory subunit gamma (IKBKG), thereby inhibiting its transcription. Additionally, FXR activation reduced CC cell proliferation and migration. In vivo, xenograft experiments in Hela cell-bearing Bagg's albino (BALB/c) nude female mice confirmed that FXR activation significantly suppressed tumor growth.
These findings highlight FXR activation as a potential therapeutic strategy for CC by targeting the NF-κB pathway as shown in both and .
法尼醇X受体（FXR）是一种核受体，以其在多种癌症的炎症调节和肿瘤抑制中的作用而闻名。然而，其在宫颈癌（CC）中的功能意义和潜在机制仍不清楚。由于炎症导致的核因子κB（NF-κB）信号通路的持续激活是癌症进展的关键驱动因素。本研究调查了FXR激活在CC中的作用及其与NF-κB通路的相互作用。
用FXR激动剂GW4064（3 μM）处理CC细胞，并将异种移植肿瘤模型设定为接受30 mg/kg的GW4064。使用双荧光素酶报告基因检测评估NF-κB介导的转录活性。通过定量实时聚合酶链反应（qRT-PCR）分析CC细胞和小鼠组织中的基因表达，同时使用蛋白质免疫印迹法检测NF-κB和STAT3信号通路中的关键蛋白。分别通过甲基噻唑基二苯基四氮唑溴盐（MTT）、伤口愈合和实时细胞分析（RTCA）评估细胞增殖、迁移和侵袭。使用异硫氰酸荧光素（FITC）膜联蛋白V凋亡检测试剂盒I测量细胞凋亡。
6至8周龄C57B/6雌性小鼠中的FXR缺失导致子宫颈中炎症基因异常上调和NF-κB异常激活。用GW4064处理可抑制Hela和Siha CC细胞中NF-κB调节的基因表达，并在转录水平抑制NF-κB活性。机制上，FXR激活通过直接结合核因子κB激酶调节亚基γ（IKBKG）抑制剂的启动子，抑制肿瘤坏死因子α（TNFα）诱导的NF-κB抑制剂α（IκBα）磷酸化，从而抑制其转录。此外，FXR激活降低了CC细胞的增殖和迁移。在体内，对携带Hela细胞的Bagg白化（BALB/c）雌性裸鼠进行的异种移植实验证实，FXR激活显著抑制肿瘤生长。
这些发现突出了FXR激活作为CC的一种潜在治疗策略，如体内和体外实验所示，通过靶向NF-κB通路发挥作用。
