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 (Htr2b^ΔIEC and Htr2b^ΔIEC-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 Htr2b^ΔIEC 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 Htr2b^ΔIEC-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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