5-HT2B-mediated serotonin activation in enterocytes suppresses colitis-associated cancer initiation and promotes cancer progression.
5-HT2B-mediated serotonin activation in enterocytes suppresses colitis-associated cancer initiation and promotes cancer progression.
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肠上皮细胞中 5-HT2B 介导的血清素激活抑制结肠炎相关癌症的发生并促进癌症进展
DOI：
10.7150/thno.70762
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Liu, Xicheng
中科院分区：
文献类型：
--
作者：
Mao, Liyuan;Xin, Fang;Ren, Jie;Xu, Shuai;Huang, Haixia;Zha, Xu;Wen, Xinxin;Gu, Guoqing;Yang, Guang;Cheng, Yuan;Zhang, Chen;Wang, Wei;Liu, Xicheng
基本原理：血清素（5-羟色胺，5-HT）通常被认为与结肠炎相关癌症（CAC）有关，但以前的研究得出了不一致的结果，关于5-HT对CAC的影响。5-HT 2B是5-HT的受体之一，该受体在肠上皮细胞（IEC）中表达。然而，5-HT 2B在CAC中的功能尚不清楚。我们的工作证明了5-HT/5-HT 2B信号在小鼠CAC的发生和发展中的可变功能。研究方法：我们构建了两种IEC中编码5-HT 2B基因的突变小鼠（Htr 2b ΔIEC和Htr 2b ΔIEC-ER），以研究5-HT 2B在AOM/DSS诱导的CAC模型中的作用。使用体重、结肠长度和结肠炎严重程度评分以及结肠组织的组织学分析来测量炎症。通过肿瘤数量、负荷和结肠肿瘤组织的组织学分析评估肿瘤严重程度。结果：AOM/DSS可诱导Htr 2b ΔIEC小鼠结肠炎和肿瘤严重程度增加。这一过程是由于TGF-β/SMAD信号通路的抑制和IL-6/STAT 3信号通路的激活所致。IL-6抗体处理逆转了Htr 2b缺失对肿瘤发生的刺激作用。然而，在AOM/DSS治疗的第48天，在注射他莫昔芬的Htr 2b Δ IEC-ER小鼠中肿瘤严重程度降低。敲除Akt 1可消除5-HT促进肿瘤细胞生长的功能。结论：我们的工作阐明了5-HT/5-HT 2B/TGF-β信号传导在CAC起始期间作为关键的肿瘤抑制轴，但在CAC晚期作为癌症进展的促进剂。我们的研究结果提供了一个新的理解5-HT在CAC的启动和发展的作用，提供了一个新的视角，长期的争论5-HT信号是否促进或抑制肿瘤。
Rationale: Serotonin (5-hydroxytryptamine, 5-HT) is generally considered to be involved in colitis-associated cancer (CAC), but previous research has yielded inconsistent results regarding the effect of 5-HT on CAC. 5-HT2B is one of the receptors of 5-HT, and the receptor is expressed in intestinal epithelial cells (IECs). However, the functions of 5-HT2B in CAC remain unclear. Our work demonstrates the variable functions of 5-HT/5-HT2B signaling in the initiation and progression of CAC in mice. Methods: We constructed two types of mutant mice homozygous knockout of Htr2b, the gene encoding 5-HT2B, in IECs (Htr2bΔIEC and Htr2bΔIEC-ER) to study the role of 5-HT2B in AOM/DSS-induced CAC model. Inflammation was measured using the body weight, colon length, and colitis severity score, and by histologic analysis of colon tissues. Tumor severity was assessed by tumor quantity, load, and histologic analysis of colon tumor tissues. Results: In Htr2bΔIEC mice, AOM/DSS induced an enhancement of colitis and tumor severity. This process was due to the inhibition of TGF-β/SMAD signaling pathway and activation of IL-6/STAT3 signaling pathway. IL-6 antibody treatment reversed the stimulating effect of Htr2b deletion on tumorigenesis. However, tumor severity decreased in Htr2bΔIEC-ER mice injected with tamoxifen on day 48 of AOM/DSS treatment. Knockout Akt1 eliminated the function of 5-HT in promoting tumor cells. Conclusion: Our work elucidates 5-HT/5-HT2B/TGF-β signaling as a critical tumor suppressing axis during CAC initiation but as a promoter of cancer progression in the late-stage of CAC. Our findings provide a new understanding of the role of 5-HT in the initiation and progression of CAC, offering a new perspective on the long-standing debate on whether the 5-HT signal promotes or inhibits tumors.
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