Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation
Overproduction of Gastrointestinal 5-HT Promotes Colitis-Associated Colorectal Cancer Progression via Enhancing NLRP3 Inflammasome Activation
复制标题
胃肠道 5-HT 的过量产生通过增强 NLRP3 炎性体激活促进结肠炎相关的结直肠癌进展。
DOI：
10.1158/2326-6066.cir-20-1043
复制
发表时间：
2021-09-01
影响因子：
10.1
通讯作者：
Hu, Rong
中科院分区：
文献类型：
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作者：
Li, Tao;Fu, Bin;Hu, Rong
慢性炎症是结肠炎相关性结直肠癌的关键驱动因素。5-羟色胺(5-HT)是一种神经递质，据报道可促进胃肠道的炎症。然而，这背后的机制仍不清楚。在本研究中，我们发现在结直肠癌患者、结直肠癌小鼠模型和结直肠癌细胞系中，5-羟色胺水平以及5-羟色胺生物合成限制酶色氨酸羟化酶1(TPH1)的表达显著高于正常结直肠组织或上皮细胞系。结直肠癌细胞来源的5-羟色胺通过其离子通道受体HTR3A增强THP-1细胞中NLRP3炎症体的激活，并使骨髓来源的巨噬细胞永生化。机制上，HTR3A激活导致钙内流，随后CaMKIIα磷酸化(ThY286)和激活，进而导致Ser198(小鼠：Ser194)NLRP3磷酸化和炎性小体组装。NLRP3炎症体介导IL-1β的成熟，并通过诱导TPHI转录上调结直肠癌细胞5-羟色胺的生物合成，揭示了5-羟色胺与NLRP3信号之间的正反馈循环。在已建立的CT26和iBMDM共植入同种异体皮下结直肠癌小鼠模型中，通过短发夹状RNA沉默TPH1或HTR3A可以减缓肿瘤的生长，而TPHI抑制剂4-氯-DL-苯丙氨酸或HTR3A拮抗剂托烷司琼治疗则减缓了偶氮甲烷/葡聚糖硫酸钠诱导的结直肠癌小鼠模型的肿瘤进展。解决5-羟色胺和NLRP3信号之间的正反馈回路可能为结直肠癌提供潜在的治疗靶点。
Chronic inflammation is a key driver for colitis-associated colorectal cancer. 5-hydroxytryptarnine (5-HT), a neurotransmitter, has been reported to promote inflammation in the gastrointestinal tract. However, the mechanism behind this remains unclear. n this study, we found that 5-HT levels, as well as the expression of tryptophan hydroxylase 1 (TPH1), the 5-HT biosynthesis ratelimiting enzyme, were significantly upregulated in colorectal tumor tissues from patients with colorectal cancer, colorectal cancer mouse models, and colorectal cancer cell lines when compared with normal colorectal tissues or epithelial cell lines. Colorectal cancer celloriginated 5-HT enhanced NLRP3 inflammasome activation in THP- 1 cells and immortalized bone marrow-derived macrophages (iBMDM) via its ion channel receptor, HTR3A. Mechanistically, HTR3A activation led to Ca2+ influx, followed by CaMKII alpha phosphorylation (ThY286) and activation, which then induced NLRP3 phosphorylation at Ser198 (mouse: Ser194) and inflammasome assembling. The NLRP3 inflammasome mediated IL 1 beta maturation, and release upregulated 5-HT biosynthesis in colorectal cancer cells by inducing TPHI transcription, revealing a positive feedback loop between 5-HT and NLRP3 signaling. Silencing TPH1 or HTR3A by short hairpin RNA slowed down tumor growth in an established CT26 and iBMDM coimplanted subcutaneous allograft colorectal cancer mouse model, whereas treatment with TPHI inhibitor 4-chloro-DL-phenylalanine or HTR3A antagonist tropisetron alleviated tumor progression in an azoxymethane/dextran sodium sulfate-induced colorectal cancer mouse model. Addressing the positive feedback loop between 5-HT and NLRP3 signaling could provide potential therapeutic targets for colorectal cancer.