Zeng Ye, Yao Xinghong, Chen Li, Yan Zhiping, Liu Jingxia, Zhang Yingying, Feng Tang, Wu Jiang, Liu Xiaoheng
Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, China.
State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Oncotarget. 2016 Sep 27;7(39):63324-63337. doi: 10.18632/oncotarget.11450.
Sphingosine-1-phosphate (S1P) induces epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). However, its underlying mechanism remains largely unknown. In the present study, we investigated the correlation between S1P and syndecan-1 in HCC, the molecular mechanism involved, as well as their roles in EMT of HCC. Results revealed a high serum S1P level presents in patients with HCC, which positively correlated with the serum syndecan-1 level. A significant inverse correlation existed between S1P1 and syndecan-1 in HCC tissues. S1P elicits activation of the PI3K/AKT signaling pathways via S1P1, which triggers HPSE, leading to increases in expression and activity of MMP-7 and leading to shedding and suppression of syndecan-1. The loss of syndecan-1 causes an increase in TGF-β1 production. The limited chronic increase in TGF-β1 can convert HCC cells into a mesenchymal phenotype via establishing an MMP-7/Syndecan-1/TGF-β autocrine loop. Finally, TGF-β1 and syndecan-1 are essential for S1P-induced epithelial to mesenchymal transition. Taken together, our study demonstrates that S1P induces advanced tumor phenotypes of HCC via establishing an MMP-7/syndecan-1/TGF-β1 autocrine loop, and implicates targetable S1P1-PI3K/AKT-HPSE-MMP-7 signaling axe in HCC metastasis.
鞘氨醇-1-磷酸（S1P）可诱导肝细胞癌（HCC）发生上皮-间质转化（EMT）。然而，其潜在机制仍 largely 未知。在本研究中，我们调查了 HCC 中 S1P 与 syndecan-1 之间的相关性、涉及的分子机制，以及它们在 HCC 的 EMT 中的作用。结果显示，HCC 患者血清 S1P 水平较高，且与血清 syndecan-1 水平呈正相关。HCC 组织中 S1P1 与 syndecan-1 之间存在显著的负相关。S1P 通过 S1P1 激活 PI3K/AKT 信号通路，进而触发 HPSE，导致 MMP-7 的表达和活性增加，从而导致 syndecan-1 的脱落和抑制。syndecan-1 的缺失导致 TGF-β1 产生增加。有限的慢性 TGF-β1 增加可通过建立 MMP-7/Syndecan-1/TGF-β 自分泌环将 HCC 细胞转化为间充质表型。最后，TGF-β1 和 syndecan-1 对于 S1P 诱导的上皮向间质转化至关重要。综上所述，我们的研究表明，S1P 通过建立 MMP-7/syndecan-1/TGF-β1 自分泌环诱导 HCC 的晚期肿瘤表型，并暗示可靶向的 S1P1-PI3K/AKT-HPSE-MMP-7 信号轴在 HCC 转移中的作用。
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