Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, 541001, Guilin, Guangxi, China.
Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
Cell Death Dis. 2022 Sep 6;13(9):768. doi: 10.1038/s41419-022-05210-z.
Angiogenesis is a fundamental process underlying the occurrence, growth and metastasis of hepatocellular carcinoma (HCC), a prevalent tumour type with an extremely poor prognosis due to abundant vasculature. However, the underlying mechanism of angiogenesis in HCC remains largely unknown. Herein, we found that sphingosine-1-phosphate receptor 1 (S1PR1) plays an important role in HCC angiogenesis. S1PR1 was found to be selectively and highly expressed in the blood vessels of HCC tissues compared with those of paratumour tissues. Functionally, high expression of S1PR1 in endothelial cells (ECs) promoted angiogenesis and progression of HCC in vitro and in vivo. Mechanistically, proangiogenic factors (S1P, IL-6, VEGFA) in conditioned medium from HCC cells induced the upregulation of S1PR1 in ECs via the phosphorylation of STAT3 at Y705. Further study also revealed that S1PR1 promotes angiogenesis by decreasing ceramide levels via CerS3 downregulation. Interestingly, we demonstrated that S1PR1 downregulates CerS3 by inducing CerS6 translocation into the nucleus to inhibit CerS3 at the transcriptional level in ECs. In addition, we found that a high concentration of Lenvatinib significantly downregulated the expression of S1PR1 and obviously enhanced S1PR1 knockdown-mediated angiogenesis inhibition, indicating that S1PR1 may be a target by which Lenvatinib combats angiogenesis in HCC. Thus, S1PR1 may be an important target for suppressing angiogenesis in HCC, and inhibiting S1PR1 is a promising approach to antitumor therapy in HCC.
血管生成是肝细胞癌（HCC）发生、生长和转移的基础过程，由于丰富的血管系统，HCC 是一种预后极差的常见肿瘤类型。然而，HCC 血管生成的潜在机制在很大程度上仍然未知。在此，我们发现 1-磷酸鞘氨醇受体 1（S1PR1）在 HCC 血管生成中起重要作用。与肿瘤周围组织相比，S1PR1 选择性地高度表达于 HCC 组织的血管中。功能上，内皮细胞（ECs）中 S1PR1 的高表达促进了 HCC 的体外和体内血管生成和进展。在机制上，HCC 细胞条件培养基中的促血管生成因子（S1P、IL-6、VEGFA）通过 Y705 处 STAT3 的磷酸化诱导 ECs 中 S1PR1 的上调。进一步的研究还揭示了 S1PR1 通过下调 CerS3 来降低神经酰胺水平从而促进血管生成。有趣的是，我们证明 S1PR1 通过诱导 CerS6 转位到细胞核来抑制 ECs 中 CerS3 的转录水平，从而促进血管生成。此外，我们发现高浓度仑伐替尼显著下调 S1PR1 的表达，并明显增强 S1PR1 敲低介导的血管生成抑制作用，表明 S1PR1 可能是仑伐替尼抑制 HCC 血管生成的靶点。因此，S1PR1 可能是抑制 HCC 血管生成的重要靶点，抑制 S1PR1 是 HCC 抗肿瘤治疗的一种有前途的方法。
