SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.
SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells.
复制标题
SPHK1（鞘氨醇激酶 1）通过促进肝癌细胞中 CDH1/E-钙粘蛋白的自噬相关溶酶体降解来诱导上皮间质转化
DOI：
10.1080/15548627.2017.1291479
复制
发表时间：
2017-05-04
期刊：
影响因子：
13.3
通讯作者：
Shao RG
中科院分区：
文献类型：
--
作者：
Liu H;Ma Y;He HW;Zhao WL;Shao RG
摘要SPHK 1（鞘氨醇激酶1）是鞘脂代谢产物的调节因子，通过促进肝细胞癌（HCC）的侵袭和转移，在HCC的发生发展中起着重要作用。然而，SPHK 1信号通路促进HCC侵袭和转移的机制仍有待阐明。SPHK 1通过促进CDH 1/E-cadherin溶酶体降解，促进HepG 2细胞的侵袭和转移，诱导上皮-间质转化（EMT）。最初，我们发现SPHK 1促进细胞迁移和侵袭，并通过降低上皮标志物CDH 1的表达诱导EMT过程。此外，SPHK 1加速CDH 1的溶酶体降解以诱导EMT，这依赖于TRAF 2（TNF受体相关因子2）介导的巨自噬/自噬激活。此外，自噬的抑制恢复了CDH 1的表达，并通过延迟SPHK 1过表达细胞中CDH 1的降解来减少细胞迁移和侵袭。此外，SPHK 1的过表达产生细胞内鞘氨醇-1-磷酸（S1 P）。在S1 P刺激下，TRAF 2与BECN 1/Beclin 1结合，并催化BECN 1的赖氨酸63-连接的泛素化以触发自噬。TRAF 2的RING结构域的缺失抑制了自噬以及BECN 1和TRAF 2的相互作用。我们的研究结果定义了一种新的机制，负责通过SPHK 1-TRAF 2-BECN 1-CDH 1信号级联调节HCC细胞中的EMT。我们的工作表明，阻断SPHK 1活性以减弱自噬可能是预防和治疗HCC的有希望的策略。
ABSTRACT SPHK1 (sphingosine kinase 1), a regulator of sphingolipid metabolites, plays a causal role in the development of hepatocellular carcinoma (HCC) through augmenting HCC invasion and metastasis. However, the mechanism by which SPHK1 signaling promotes invasion and metastasis in HCC remains to be clarified. Here, we reported that SPHK1 induced the epithelial-mesenchymal transition (EMT) by accelerating CDH1/E-cadherin lysosomal degradation and facilitating the invasion and metastasis of HepG2 cells. Initially, we found that SPHK1 promoted cell migration and invasion and induced the EMT process through decreasing the expression of CDH1, which is an epithelial marker. Furthermore, SPHK1 accelerated the lysosomal degradation of CDH1 to induce EMT, which depended on TRAF2 (TNF receptor associated factor 2)-mediated macroautophagy/autophagy activation. In addition, the inhibition of autophagy recovered CDH1 expression and reduced cell migration and invasion through delaying the degradation of CDH1 in SPHK1-overexpressing cells. Moreover, the overexpression of SPHK1 produced intracellular sphingosine-1-phosphate (S1P). In response to S1P stimulation, TRAF2 bound to BECN1/Beclin 1 and catalyzed the lysine 63-linked ubiquitination of BECN1 for triggering autophagy. The deletion of the RING domain of TRAF2 inhibited autophagy and the interaction of BECN1 and TRAF2. Our findings define a novel mechanism responsible for the regulation of the EMT via SPHK1-TRAF2-BECN1-CDH1 signal cascades in HCC cells. Our work indicates that the blockage of SPHK1 activity to attenuate autophagy may be a promising strategy for the prevention and treatment of HCC.