The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, China.
The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia, China.
Biochim Biophys Acta Mol Basis Dis. 2022 Jul 1;1868(7):166401. doi: 10.1016/j.bbadis.2022.166401. Epub 2022 Mar 26.
The bioactive lipid sphingosine 1-phosphate (S1P) is implicated in many pivotal processes for the physiological and pathological actions via activating five types of G-protein-coupled S1P receptors (S1PR1-5). The role of S1P in renal cell carcinoma (RCC) and its receptor subtype specific mediating mechanism are poorly studied. So we focus on the regulatory role of S1P in RCC progression and the receptor subtypes involved in S1P-induced actions, intending to further clarify a novel therapeutic target for RCC. Analysis of The Cancer Genome Atlas (TCGA) databases showed that the patients with high expression of S1PR3 had significantly worse overall than with low expression. We further demonstrated that S1P could promote proliferation, migration, and epithelial-mesenchymal transition (EMT) of renal cancer cells in vitro, and the actions were enhanced with the increase of S1PR3 expression. Meanwhile, the results in animal experiments also showed that S1PR3 could accelerate tumorigenesis and metastasis of RCC. Our study also clarified the mechanism for S1P induced cell proliferation is mediated by S1PR3/Gi/p38/Akt/p65/cyclin D1-CDK4 pathway and the main pathway for migration is S1PR3/Gi/q/ERK/p38/p65. In addition, S1PR3 was involved in epidermal growth factor (EGF)-induced actions by enhancing protein expression, not by transactivation of epidermal growth factor receptor (EGFR). These results also further supported our conclusion that the carcinogenic role of S1P/S1PR3 axis. Thus, our findings provide that S1PR3 may be a promising small molecular therapeutic target for S1PR3 expressed cancers.
生物活性脂质鞘氨醇 1-磷酸（S1P）通过激活五种类型的 G 蛋白偶联 S1P 受体（S1PR1-5），参与许多生理和病理作用的关键过程。S1P 在肾细胞癌（RCC）中的作用及其受体亚型特异性介导机制研究甚少。因此，我们专注于 S1P 在 RCC 进展中的调节作用及其涉及的受体亚型，旨在进一步阐明 RCC 的新治疗靶点。对癌症基因组图谱（TCGA）数据库的分析表明，S1PR3 高表达的患者总生存期明显比低表达的患者差。我们进一步证明 S1P 可以促进肾癌细胞在体外的增殖、迁移和上皮间质转化（EMT），并且随着 S1PR3 表达的增加，作用增强。同时，动物实验结果也表明 S1PR3 可以加速 RCC 的肿瘤发生和转移。我们的研究还阐明了 S1P 诱导细胞增殖的机制是通过 S1PR3/Gi/p38/Akt/p65/cyclin D1-CDK4 途径介导的，而迁移的主要途径是 S1PR3/Gi/q/ERK/p38/p65。此外，S1PR3 通过增强蛋白表达而不是表皮生长因子受体（EGFR）的转激活参与表皮生长因子（EGF）诱导的作用。这些结果也进一步支持了我们的结论，即 S1P/S1PR3 轴具有致癌作用。因此，我们的研究结果表明，S1PR3 可能是表达 S1PR3 的癌症有前途的小分子治疗靶点。
