Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppre
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RESEARCH
(2020) 39:253
Open Access
Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer Luciana Petti1, Giulia Rizzo2, Federica Rubbino2, Sudharshan Elangovan2, Piergiuseppe Colombo3, Silvia Restelli1, Andrea Piontini2, Vincenzo Arena4, Michele Carvello5, Barbara Romano6, Tommaso Cavalleri7, Achille Anselmo8, Federica Ungaro2, Silvia D’Alessio2, Antonino Spinelli2,5, Sanja Stifter9, Fabio Grizzi10, Alessandro Sgambato4,11, Silvio Danese1,2, Luigi Laghi7,12, Alberto Malesci2,7 and Stefania Vetrano1,2*
Abstract Background: Sphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap. Methods: We screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N = 76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2+/+) and S1PR2 deficient (S1PR2−/−) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2+/+ organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2−/−Lgr5-EGFP- mice. Results: S1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc+/min mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2−/− mice compared to S1PR2+/+ controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN. (Continued on next page)
* Correspondence: [email protected]; [email protected] 1 IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy 2 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, Pieve Emanuele, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the
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