Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma.
Sphingosine-1-phosphate transporter spinster homolog 2 is essential for iron-regulated metastasis of hepatocellular carcinoma.
复制标题
DOI：
10.1016/j.ymthe.2021.09.012
复制
发表时间：
2022-02-02
期刊：
影响因子：
--
通讯作者：
Ling C
中科院分区：
文献类型：
--
作者：
Li M;Tang Y;Wang D;Zhai X;Shen H;Zhong C;Yao M;Jin A;Zhou Z;Zhou S;Fan J;Ling CQ;Ling C
铁代谢紊乱与肝细胞癌的发生有关。然而，铁在肝细胞癌转移中的作用尚不清楚。本研究旨在阐明铁促进肝细胞癌转移的潜在机制。除体外培养的肝癌细胞株和临床标本外，还采用无铁饮食和转铁蛋白受体基因敲除的方法建立缺铁(ID)小鼠模型，然后通过原位或异位途径给药。临床转移性肝细胞癌标本有明显的ID状态，并伴有SPNS2的过度表达。从机制上讲，ID增加了SPNS2的表达，导致了细胞培养和小鼠模型中的肝癌转移。ID不仅改变了荷瘤小鼠肝、肺淋巴亚群表型所示的抗肿瘤免疫功能，而且通过SPNS2以一种肿瘤细胞自主的方式促进了肝癌的转移。由于种系敲除SPNS2基因显著降低了肝细胞癌的转移，我们进一步发展了肝靶向重组腺相关病毒载体来敲除SPNS2的表达，并抑制铁调控的肝细胞癌转移。我们的观察表明铁在肝细胞癌肺转移中的作用，并提示SPNS2可能成为预防肝细胞癌肺转移的潜在治疗靶点。铁络合剂是在10例晚期肝细胞癌患者的临床研究中提出的。然而，通讯作者和同事观察到缺铁导致肝细胞癌肺转移。癌细胞SPNS2是预防肝细胞癌肺转移的潜在机制和潜在的治疗靶点。
Iron dyshomeostasis is associated with hepatocellular carcinoma (HCC) development. However, the role of iron in HCC metastasis is unknown. This study aimed to elucidate the underlying mechanisms of iron’s enhancement activity on HCC metastasis. In addition to the HCC cell lines and clinical samples in vitro, iron-deficient (ID) mouse models were generated using iron-free diet and transferrin receptor protein knockout, followed by administration of HCC tumors through either orthotopic or ectopic route. Clinical metastatic HCC samples showed significant ID status, accompanied by overexpression of sphingosine-1-phosphate transporter spinster homolog 2 (SPNS2). Mechanistically, ID increased SPNS2 expression, leading to HCC metastasis in both cell cultures and mouse models. ID not only altered the anti-tumor immunity, which was indicated by phenotypes of lymphatic subsets in the liver and lung of tumor-bearing mice, but also promoted HCC metastasis in a cancer cell autonomous manner through the SPNS2. Since germline knockout of globe SPNS2 showed significantly reduced HCC metastasis, we further developed hepatic-targeting recombinant adeno-associated virus vectors to knockdown SPNS2 expression and to inhibit iron-regulated HCC metastasis. Our observation indicates the role of iron in HCC pulmonary metastasis and suggests SPNS2 as a potential therapeutic target for the prevention of HCC pulmonary metastasis. Iron chelator was proposed in a clinical study of ten patients with advanced HCC. However, corresponding authors and colleagues observed that iron deficiency led to HCC pulmonary metastasis. Cancer cell SPNS2 is the underlying mechanism and a potential therapeutic target for the prevention of HCC pulmonary metastasis.
登录
查看更多内容
影响因子：
4.8
作者：
Ling, Chen;Wang, Yuan;Ling, Chang-Quan
通讯作者：
Ling, Chang-Quan
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
细胞外α-突触核蛋白和铁暴露导致星形胶质细胞中铁调素与铁蛋白的比率降低
影响因子：
5.3
作者：
Cui, Juntao;Guo, Xinli;Xie, Junxia
通讯作者：
Xie, Junxia
影响因子：
3.7
作者：
Charlebois E;Pantopoulos K
通讯作者：
Pantopoulos K
DOI：
10.1073/pnas.1811717115
发表时间：
2018-10-23
影响因子：
11.1
作者：
Liang W;Li Q;Ferrara N
通讯作者：
Ferrara N