Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma.
Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma.
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缺氧诱导的 VASP 上调促进肝细胞癌的侵袭和转移。
作者：
Liu Z;Wang Y;Dou C;Xu M;Sun L;Wang L;Yao B;Li Q;Yang W;Tu K;Liu Q
理由：肝细胞癌（HCC）患者预后不良，主要是由于肝内和远端转移。血管舒张刺激磷蛋白（VASP）是一种肌动蛋白细胞骨架和细胞迁移的调节因子，在HCC中过表达，与其恶性特征和不良预后相关。关于它在HCC中的作用知之甚少。方法：采用qRT-PCR、Western blot和免疫组化方法检测VASP在组织和细胞中的表达。用Transwell和伤口愈合试验检测HCC细胞的迁移和侵袭能力。免疫印迹和免疫荧光法用于检测HCC细胞中上皮向间质转化（EMT）的进展。使用肺转移小鼠模型来评估HCC在体内的转移。通过公共数据库和双荧光素酶报告基因测定公开了miR-204的推定靶点。IP用于显示VASP和CRKL之间的相互作用。ChIP法分析HIF-1α与VASP启动子区的结合。结果如下：我们的数据涉及获得和丧失功能的研究表明，VASP激活AKT和ERK信号，并促进肝癌的迁移和侵袭在体外和体内通过改变EMT表型和MMPs的表达。我们研究了VASP和衔接蛋白CRKL之间的正相关性。VASP动态共定位于CRKL的SH 3 N结构域并介导其功能。HIF-1α通过直接结合VASP启动子区的两个缺氧反应元件（HRE）介导VASP在转录水平的过表达。此外，我们确定了低氧诱导的miR-204的下调，其在转录后水平上作为VASP过表达的调节剂发挥作用。此外，低氧激活的p-Smad 3依赖性TGF-β信号间接促进VASP表达。结论：低氧诱导的VASP表达上调可能与多种分子机制有关。这些机制涉及CRKL、HIF-1α、miR-204和TGF-β激活AKT和ERK信号，从而促进EMT和MMPs的表达。综上所述，我们的研究结果将VASP定义为HCC发病机制和转移的癌基因，具有作为预后生物标志物的潜力。
Rational: Patients with hepatocellular carcinoma (HCC) have a poor prognosis mostly due to intrahepatic as well as distal metastasis. Vasodilator-stimulated phosphoprotein (VASP), a regulator of actin cytoskeleton and cell migration, is overexpressed in HCC and correlated with its malignant features and poor prognosis. Very little is known about its function in HCC. Methods: qRT-PCR, Western blot and IHC were used to detect the VASP expression in tissues and cells. Transwell and wound healing assays were used to measure the migration and invasion of HCC cells. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. A lung metastasis mouse model was used to evaluate metastasis of HCC in vivo. The putative targets of miR-204 were disclosed by public databases and a dual-luciferase reporter assay. IP was used to show the interaction between VASP and CRKL. ChIP was used to analyze the binding of HIF-1α to VASP promoter region. Results: Our data involving both gain- and loss-of-function studies revealed that VASP activated AKT and ERK signaling and promoted HCC migration and invasion in vitro and in vivo by altering the EMT phenotype and expression of MMPs. We investigated the positive correlation between VASP and an adapter protein, CRKL. VASP dynamically co-localized at the SH3N domain of CRKL and mediated its function. Mechanistically, VASP overexpression at the transcriptional level was mediated by HIF-1α through direct binding to two hypoxia response elements (HRE) in the VASP promoter region. Furthermore, we identified hypoxia-induced down-regulation of miR-204, which functioned as the regulator of VASP overexpression at the post-transcriptional level. Also, hypoxia-activated p-Smad3 dependent TGF-β signaling indirectly promoted VASP expression. Conclusion: A variety of hypoxia-induced molecular mechanisms contributed to the upregulation of VASP at transcriptional and post-transcriptional levels. These mechanisms involved CRKL, HIF-1α, miR-204, and TGF-β activating the AKT and ERK signaling to promote EMT and expression of MMPs. Taken together, our results defined VASP as an oncogene of HCC pathogenesis and metastasis with the potential to serve as a prognostic biomarker.
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