A number of neurotransmitters have been detected in tumor microenvironment and proved to modulate cancer oncogenesis and progression. We previously found that biosynthesis and secretion of neurotransmitter 5-hydroxytryptamine (5-HT) was elevated in colorectal cancer (CRC) cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in CRC tumor tissues, which was further identified as a strong risk factor for CRC prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of CRC cell, as well as the epithelial-mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via Akt/mTOR pathway, which triggered cAMP responsive element binding protein 1 (CREB1) phosphorylation (Ser 133) and translocation into the nucleus, then the phosphorylated CREB1 acts as an activator for ZEB1 transcription after binding to CREB1 half-site (GTCA) at ZEB1 promoter. As a key regulator of EMT, ZEB1 therefore enhances migration and EMT process in CRC cells. We also found that HTR2B specific antagonist (RS127445) treatment significantly ameliorated metastasis and reversed EMT process in both HCT116 cell tail-vein-injected pulmonary metastasis and CT26 cell intrasplenic-injected hepatic metastasis mouse models. Implications: These findings uncover a novel regulatory role of HTR2B signaling on CRC metastasis, which provide experimental evidences for potential HTR2B-targeted anti-CRC metastasis therapy.

中文翻译：

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5-羟色胺受体 HTR2B 通过 CREB1-ZEB1 轴介导的上皮间质转化促进结直肠癌转移

在肿瘤微环境中检测到了许多神经递质，并证明它们可以调节癌症的发生和进展。我们之前发现结直肠癌 (CRC) 细胞中神经递质 5-羟色胺 (5-HT) 的生物合成和分泌升高。在这项研究中，我们发现5-HT的HTR2B受体在CRC肿瘤组织中高表达，这被进一步确定为CRC预后结果的强危险因素。药物阻断和基因敲除 HTR2B 都会损害 CRC 细胞的迁移以及上皮间质转化 (EMT) 过程。从机制上讲，HTR2B信号通过Akt/mTOR途径诱导核糖体蛋白S6激酶B1（S6K1）激活，从而触发cAMP反应元件结合蛋白1（CREB1）磷酸化（Ser 133）并易位到细胞核中，然后磷酸化的CREB1充当激活剂与ZEB1启动子处的CREB1半位点（GTCA）结合后进行ZEB1转录。作为 EMT 的关键调节因子，ZEB1 增强了 CRC 细胞的迁移和 EMT 过程。我们还发现，HTR2B 特异性拮抗剂 (RS127445) 治疗可显着改善 HCT116 细胞尾静脉注射的肺转移小鼠模型和 CT26 细胞脾内注射的肝转移小鼠模型的转移并逆转 EMT 过程。意义：这些发现揭示了 HTR2B 信号对 CRC 转移的新调节作用，为潜在的 HTR2B 靶向抗 CRC 转移治疗提供了实验证据。