American Association for Cancer Research
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Supplementary Figure S16 from Serotonin Receptor HTR2B Facilitates Colorectal Cancer Metastasis via CREB1–ZEB1 Axis–Mediated Epithelial–Mesenchymal Transition

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journal contribution
posted on 2024-06-04, 07:41 authored by Tao Li, Lei Wei, Xin Zhang, Bin Fu, Yunjiang Zhou, Mengdi Yang, Mengran Cao, Yaxin Chen, Yingying Tan, Yongwei Shi, Leyin Wu, Chenyuan Xuan, Qianming Du, Rong Hu

This file contains Supplementary Figure S16 and its legend.


National Natural Science Foundation of China (NSFC)

Jiangsu Funding Program for Excellent Postdoctoral Talent

Natural Science Foundation of Jiangsu Province (Jiangsu Natural Science Foundation)

Distinguished Young Scholars of Nanjing



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 cells. In this study, we discovered that the HTR2B receptor of 5-HT was highly expressed in colorectal cancer tumor tissues, which was further identified as a strong risk factor for colorectal cancer prognostic outcomes. Both pharmacological blocking and genetic knocking down HTR2B impaired migration of colorectal cancer cell, as well as the epithelial–mesenchymal transition (EMT) process. Mechanistically, HTR2B signaling induced ribosomal protein S6 kinase B1 (S6K1) activation via the 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 colorectal cancer 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. These findings uncover a novel regulatory role of HTR2B signaling on colorectal cancer metastasis, which provide experimental evidences for potential HTR2B-targeted anti-colorectal cancer metastasis therapy.