Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway.
Endoplasmic reticulum resident oxidase ERO1-Lalpha promotes hepatocellular carcinoma metastasis and angiogenesis through the S1PR1/STAT3/VEGF-A pathway.
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DOI：
10.1038/s41419-018-1134-4
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发表时间：
2018-10-30
影响因子：
9
通讯作者：
Rao J
中科院分区：
文献类型：
--
作者：
Yang S;Yang C;Yu F;Ding W;Hu Y;Cheng F;Zhang F;Guan B;Wang X;Lu L;Rao J
越来越多的证据表明，ERO1α（一种内质网 (ER) 驻留氧化酶）的表达是多种人类癌症的不良预后因素。然而，ERO1α 的临床相关性及其与肝细胞癌 (HCC) 肿瘤进展的分子机制尚未确定。通过实时定量PCR和蛋白质印迹法检测肝癌组织和细胞中ERO1α的表达水平。将 ERO1α shRNA 和过表达载体转染至 HCC 细胞中，以下调或上调 ERO1α 表达。通过体外和体内实验研究 ERO1α 在 HCC 侵袭、转移和血管生成中的功能。我们发现 HCC 组织和细胞中 ERO1α 高表达，与转移和血管侵犯、晚期 Edmondson 分级和 TNM 分期的不良临床病理特征显着相关。功能丧失和功能获得研究表明，ERO1α 在体外和体内均可促进 HCC 细胞的迁移、侵袭、上皮间质转化 (EMT) 和血管生成。进一步的研究证实ERO1α和S1PR1之间存在正相关性，与未转移的HCC组织相比，ERO1α和S1PR1在转移性HCC组织中表达上调。 S1PR1敲低显着减弱了ERO1α对HCC细胞迁移、侵袭和血管内皮生长因子（VEGF）表达的影响。最重要的是，ERO1α敲低通过减少肿瘤远处转移显着抑制HCC异种移植小鼠模型的死亡，并通过抑制HCC细胞中S1PR1、p-STAT3和VEGF-A的表达来显着抑制宿主血管生成。我们的研究结果表明，ERO1α 与生存率降低和预后不良显着相关，并通过触发 S1PR1/STAT3/VEGF-A 信号通路促进 HCC 转移和血管生成。 ERO1α 可能是 HCC 预后和治疗的新候选者。
Mounting evidence demonstrates that expression of ERO1α, an endoplasmic reticulum (ER)-resident oxidase, is a poor prognosis factor in a variety of human cancers. However, the clinical relevance of ERO1α and its molecular mechanisms underlying tumor progression have not been determined for hepatocellular carcinoma (HCC). ERO1α expression levels in HCC tissues and cells were detected by quantitative real-time PCR and western blotting. ERO1α shRNAs and overexpression vector were transfected into HCC cells to downregulate or upregulate ERO1α expression. In vitro and in vivo assays were performed to investigate the function of ERO1α in invasion, metastasis, and angiogenesis of HCC. We found high ERO1α expression in HCC tissues and cells that was significantly associated with metastasis and poor clinicopathologic features of vascular invasion, advanced Edmondson Grade, and TNM stage. Loss-of-function and gain-of-function studies showed that ERO1α prompted migration, invasion, epithelial–mesenchymal transition (EMT), and angiogenesis of HCC cells both in vitro and in vivo. Further studies verified a positive correlation between ERO1α and S1PR1, upregulated in metastatic HCC tissues compared with HCC tissues without metastasis. S1PR1 knockdown markedly diminished the effects of ERO1α on HCC cell migration, invasion and vascular endothelial growth factor (VEGF) expression. Most importantly, ERO1α knockdown significantly repressed the death of HCC xenograft mouse models by reducing tumor distant metastasis, and host angiogenesis by suppressing the expression of S1PR1, p-STAT3, and VEGF-A in HCC cells. Our findings suggest that ERO1α is significantly correlated with reduced survival and poor prognosis, and promotes HCC metastasis and angiogenesis by triggering the S1PR1/STAT3/VEGF-A signaling pathway. ERO1α might be a novel candidate in HCC prognosis and therapy.
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影响因子：
--
作者：
Tanaka T;Kutomi G;Kajiwara T;Kukita K;Kochin V;Kanaseki T;Tsukahara T;Hirohashi Y;Torigoe T;Okamoto Y;Hirata K;Sato N;Tamura Y
通讯作者：
Tamura Y
影响因子：
254.7
作者：
Siegel, Rebecca;Ma, Jiemin;Jemal, Ahmedin
通讯作者：
Jemal, Ahmedin
影响因子：
8
作者：
May, D;Itin, A;Keshet, E
通讯作者：
Keshet, E
S1PR1-STAT3信号传导对于未来转移性位点的髓样细胞定植至关重要。
影响因子：
50.3
作者：
Deng J;Liu Y;Lee H;Herrmann A;Zhang W;Zhang C;Shen S;Priceman SJ;Kujawski M;Pal SK;Raubitschek A;Hoon DSB;Forman S;Figlin RA;Liu J;Jove R;Yu H
通讯作者：
Yu H
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Bettigole SE;Glimcher LH
通讯作者：
Glimcher LH