NF-κB and EGFR participate in S1PR3-mediated human renal cell carcinomas progression
NF-κB and EGFR participate in S1PR3-mediated human renal cell carcinomas progression
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NF-κB 和 EGFR 参与 S1PR3 介导的人肾细胞癌进展
DOI：
10.1016/j.bbadis.2022.166401
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发表时间：
2022-04-05
影响因子：
6.2
通讯作者：
Damirin, Alatangaole
中科院分区：
文献类型：
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作者：
Yan, Yali;Bao, Gegentuya;Damirin, Alatangaole
生物活性脂质鞘氨醇1-磷酸（S1P）通过激活五种g蛋白偶联S1P受体（S1PR1-5）参与许多生理和病理活动的关键过程。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较少。因此，我们将重点研究S1P在RCC进展中的调节作用以及参与S1P诱导作用的受体亚型，以期进一步阐明RCC的新治疗靶点。Cancer Genome Atlas （TCGA）数据库分析显示，S1PR3高表达患者的总体预后明显差于低表达患者。我们进一步在体外证明了S1P可以促进肾癌细胞的增殖、迁移和上皮间质转化（EMT），并且这种作用随着S1PR3表达的增加而增强。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通路介导的，主要的迁移途径是S1PR3/Gi/ q/ERK/p38/p65。此外，S1PR3通过增强蛋白表达参与表皮生长因子（EGF）诱导的作用，而不是通过表皮生长因子受体（EGFR）的反激活。这些结果也进一步支持了我们关于S1P/S1PR3轴的致癌作用的结论。因此，我们的研究结果表明，S1PR3可能是S1PR3表达的癌症的一个有希望的小分子治疗靶点。
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 epithelialmesenchymal 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.