S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression.
S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression.
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DOI：
10.1038/s41419-022-05210-z
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发表时间：
2022-09-06
影响因子：
9
通讯作者：
Jin, Junfei
中科院分区：
文献类型：
--
作者：
Wang, Xuehong;Qiu, Zhidong;Dong, Wei;Yang, Zebin;Wang, Junnan;Xu, Hailiang;Sun, Tian;Huang, Zhaoquan;Jin, Junfei
血管生成是肝细胞癌（HCC）发生、生长和转移的基本过程，肝细胞癌是一种常见的肿瘤类型，由于血管系统丰富，预后极差。然而，HCC 血管生成的潜在机制仍然很大程度上未知。在此，我们发现1-磷酸鞘氨醇受体1（S1PR1）在HCC血管生成中发挥重要作用。与癌旁组织相比，S1PR1 在 HCC 组织的血管中选择性高表达。从功能上讲，内皮细胞 (EC) 中 S1PR1 的高表达可促进体外和体内 HCC 的血管生成和进展。从机制上讲，HCC 细胞条件培养基中的促血管生成因子（S1P、IL-6、VEGFA）通过 STAT3 在 Y705 的磷酸化诱导 EC 中 S1PR1 的上调。进一步的研究还表明，S1PR1 通过下调 CerS3 降低神经酰胺水平来促进血管生成。有趣的是，我们证明 S1PR1 通过诱导 CerS6 易位到细胞核中，从而在 EC 转录水平上抑制 CerS3，从而下调 CerS3。此外，我们发现高浓度的乐伐替尼显着下调S1PR1的表达，并明显增强S1PR1敲低介导的血管生成抑制，表明S1PR1可能是乐伐替尼对抗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。
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.
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影响因子：
8.8
作者：
Ragunathrao, Vijay Avin Balaji;Anwar, Mumtaz;Mehta, Dolly
通讯作者：
Mehta, Dolly
影响因子：
5.2
作者：
Paço A;Aparecida de Bessa Garcia S;Leitão Castro J;Costa-Pinto AR;Freitas R
通讯作者：
Freitas R
长非编码RNA UBE2CP3通过激活肝细胞癌中的ERK1/2/HIF-1 α/VEGFA信号增强HCC细胞分泌VEGFA并促进血管生成
DOI：
10.1186/s13046-018-0727-1
发表时间：
2018-06-04
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Lin J;Cao S;Wang Y;Hu Y;Liu H;Li J;Chen J;Li P;Liu J;Wang Q;Zheng L
通讯作者：
Zheng L
影响因子：
9.7
作者：
Okamoto, Kiyoshi;Kodama, Kotaro;Tsuruoka, Akihiko
通讯作者：
Tsuruoka, Akihiko
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi