Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

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. Conclusions In normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5. Graphical Abstract. Schematic drawing of the role of S1PR2 in normal mucosa and colorectal cancer. In the normal mucosa, S1PR2 is highly expressed by differentiated cells at the upper region of both colon and intestinal crypts (S1PR2 ON), but not by the undifferentiated stem cell at the base of the crypts (S1PR2 OFF), in which acts as a negative proliferative regulator promoting epithelial differentiation. Its loss leads to the expansion of stem cells and reduced levels of PTEN and Axin-2, two negative regulators respectively of PI3K/AKT and Wnt signaling that control β-catenin signaling. The translocation of β-catenin into the nucleus promotes the transcription of target genes involved in the proliferation and malignant transformation. Thereby, S1PR2 works in the intestine as a tumor suppressor

Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases: Keeping Lymphocytes Out of the Intestine

“…S1PR1 activation proceeds in a STAT3-dependent manner and simultaneously triggers the RAS–ERK1/2 pathway and the PI3K-AKT and the PI3K–RAC pathways [ 22 , 25 , 26 ] ( Figure 1 ). Several specific roles of the different S1PRs have been identified: S1PR1 is mainly involved in T cells regulation, S1PR2 regulates macrophage activation, S1PR3 endorses leukocyte rolling, S1PR4 controls the differentiation and activation of the dendritic cell (DC) and, finally, S1PR5 mainly participates in monocyte egressing from the bone marrow [ 15 , 27 , 28 ] ( Figure 1 ). Once the lymphocytes are inside the lymphoid organs, the concentrations of cell-surface S1PR1 increase, so that the exit of lymphocytes from the lymphoid organs follows the S1P concentration gradient [ 17 , 21 , 22 ].…”

Roles of G Protein-Coupled Receptors (GPCRs) in Gastrointestinal Cancers: Focus on Sphingosine 1-Shosphate Receptors, Angiotensin II Receptors, and Estrogen-Related GPCRs

“…As for the roles of S1PR2 in the development of CRC, Petti et al [ 31 ] claimed that S1PR2 suppressed CRC and CAC progression by preventing epithelial stem cell proliferation and blocking their malignant transformation. Overexpression of S1PR2 increased the levels of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and axis inhibition protein 2 (Axin2), and then down-regulated the PI3K/Akt and Wnt/β-catenin signaling pathway, respectively.…”

“…Overexpression of S1PR2 increased the levels of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and axis inhibition protein 2 (Axin2), and then down-regulated the PI3K/Akt and Wnt/β-catenin signaling pathway, respectively. As a result, cell proliferation and malignant transformation are suppressed [ 31 ]. Similarly, S1PR2 also showed anti-tumor effects on B-cell lymphoma and melanoma by inhibiting tumor growth, invasion, and migration [ 54 ].…”

Microbiome-Mediated Immune Signaling in Inflammatory Bowel Disease and Colorectal Cancer: Support From Meta-omics Data

“…However, disruptions in arachidonic acid metabolism and PG production ( Chan et al, 2009 ) may indicate undetected upstream changes in sphingolipid composition. Experimental evidence has tied sphingolipid receptor expression to tumour suppression in CRC ( Petti et al, 2020 ). Due to their role in intestinal epithelial barrier maintenance and their varied capability for immune signaling, further characterization of sphingolipids in intestinal disease is warranted.…”