Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

Abstract

Aims Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. Methods We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data were then compared in benign and malignant tissues from the same organ/tissue using the student t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. Results We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (either in nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft tissues and uterus) show differences for only one S1PR (cytoplasmic or nuclear), and twenty three organs/tissues show no significant difference in IHC score of any S1PR (cytoplasmic or nuclear) between benign and malignant changes. Conclusion This is the first study to evaluate the expression level of all S1PRs in benign and malignant tissues from multiple human organs. This study provides data regarding the systemic distribution, subcellular localization and differences in expression of all five S1PRs in benign and malignant changes for each organ/tissue.

TGFβ-induced metabolic reprogramming during epithelial-to-mesenchymal transition in cancer

“…S1P mediated EMT by regulating the autocrine production of TGFβ1, which contributed to a fibrotic response in A549 lung cancer cells [148]. High levels of serum S1P in hepatocellular carcinoma were found to be associated with poor clinical prognosis [149]. In a recent study, S1P was found to activate PI3K/AKT signaling pathway, resulting in increased MMP-7 expression.…”

Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR2, ERK and SF‐1

“…adrenal cortex remains enigmatic but appears likely under cholestatic situations, since the bile acid receptors FXR, TGR5 and S1PR2 are expressed in adrenal cortex cells. [18][19][20] In this study, we consequently aimed to unravel the direct regulatory effects of bile acids on adrenal steroidogenesis and the underlying signalling pathways with the combined aid of mouse models and in vitro experiments using human adrenocortical H295R cells. Based on our experimental results, we herein provide novel direct evidence that bile acids increase steroidogenesis in mouse adrenals.…”

“…In addition, bile acids can enter the brain by apical sodium‐dependent bile acid transporter (ASBT) and suppress the transcript and protein level of CRH, which may account for the suppression of the HPA axis. However, the specific role of bile acids in directly regulating steroidogenesis in the adrenal cortex remains enigmatic but appears likely under cholestatic situations, since the bile acid receptors FXR, TGR5 and S1PR2 are expressed in adrenal cortex cells …”

Time to Revisit Non-Pharmacological Research Approaches to Ameliorate Multiple Sclerosis Symptoms

“…As pointed out earlier, natalizumab (Tysabri) was designed to prevent movement of immune cells from the blood to the tissues, thereby crippling the immune response to infection as well as developing cancers, with often disastrous consequences for some MS patients. Fingolimod (Gilenya) downregulates sphingosine-1-phosphate receptors, thereby trapping a subset of lymphocytes within lymph nodes and, thus, unable to enter the CNS [83,84]. Ignored in all this is that sphingosine-1-phosphate receptors are widely distributed throughout the body and not just in lymph nodes [85].…”