Author contributions: Wen-Ming Chu conceived and directed the project and performed a large body of experiments.
To date, aquaporin‑4 (AQP4) has been considered as a critical contributor to neuroinflammation, but little is known about the underlying mechanism. Previous studies have shown that a critical enzyme involved in the sphingomyelin cycle, sphingosine kinase 1 (SPHK1), is implicated in inflammatory processes and contributes to chronic neuroinflammation. The present study investigated the role of AQP4 in proinflammatory cytokine release from astrocytes, with an emphasis on the SPHK1/mitogen‑activated protein kinase (MAPK)/protein kinase B (AKT) pathway. Using primary cultures isolated from AQP4+/+ and AQP4‑/‑ embryos, the production of tumor necrosis factor‑α (TNF‑α)/interleukin‑6 (IL‑6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. The results showed increased secretion of TNF‑α/IL‑6 in the two groups following LPS treatment, but a significantly lower level was observed in the AQP4‑/‑ group compared with that in the AQP4+/+ group. Although upregulation of SPHK1 was detected in the two genotypes, only a mild increase in SPHK1 was found in the AQP4‑/‑ genotype. The phosphorylation of MAPK/AKT was also confirmed to be attenuated in the AQP4‑/‑ group, suggesting decreased MAPK/AKT signaling over time in AQP4‑/‑ astrocytes. Overall, the study findings demonstrated that AQP4 deficiency alleviates proinflammatory cytokine release from astrocytes, in association with the SPHK1/MAPK/AKT pathway. This data improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.
Sphingosine-1-phosphate (S1P) is a bioactive phospholipid that serves as a potent mediator of cell proliferation, differentiation and apoptosis by binding to S1P receptors (S1PRs). S1P signalling is involved in the pathogenesis of numerous types of disease, including cancer. To the best of our knowledge, however, little is known about the expression patterns of S1PRs and their role in human colorectal cancer (CRC) cell migration and invasion. The aim of the present study was to investigate the role of S1P signalling in the metastasis of colon cancer cells and the expression of S1PRs in patients with CRC. The protein and mRNA expression levels of S1PRs and sphingosine kinases (SPHKs) in 55 patients with CRC were detected by western blotting (WB), immunohistochemical (IHC) analysis and reverse transcription-quantitative PCR. The levels of S1P in serum from patients and healthy individuals were quantified by ELISA. S1PRs antagonists JTE013, FTY720 and S1PR2-small interfering (si)RNA were used to determine the role of S1PR2 in human CRC LOVO and SW480 cell lines. Migration and invasion assays were performed for functional analysis. The levels of S1P in serum were significantly increased in patients with CRC compared with healthy individuals. The relative mRNA expression levels of S1PR2 were significantly downregulated in tumour compared with normal tissue, whereas S1PR1 and SPHK1 were upregulated. WB showed that 58% (32/55 cases) of patients presented downregulated S1PR2 protein expression. IHC analysis indicated that expression of S1PR2 was lower in tumour than in normal tissue in 65.5% (36/55 cases) of patients. Exogenous addition of S1P promoted migration and invasion in the different cell types. S1P stimulated the migration and invasion of SW480 cells. The inhibition of S1PR2 by JTE013 or S1PR2-siRNA significantly promoted the migration and invasion of SW480 cells, while FTY720 reversed these effects. The present study indicated that expression levels of S1PRs, particularly S1PR2, were associated with migration and invasion of CRC cells. The present findings revealed a novel mechanism by which S1P inhibited tumour cell migration and invasion via a S1PR2-dependent pathway, suggesting that S1PR2 may be a therapeutic target for treatment of colon cancer.
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