Huntingtin-Interacting Protein-1 Is an Early-Stage Prognostic Biomarker of Lung Adenocarcinoma and Suppresses Metastasis via Akt-mediated Epithelial-Mesenchymal Transition
Huntingtin-Interacting Protein-1 Is an Early-Stage Prognostic Biomarker of Lung Adenocarcinoma and Suppresses Metastasis via Akt-mediated Epithelial-Mesenchymal Transition
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DOI：
10.1164/rccm.201412-2226oc
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发表时间：
2016-04-15
影响因子：
24.7
通讯作者：
Lu, Pei-Jung
中科院分区：
文献类型：
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作者：
Hsu, Che-Yu;Lin, Cheng-Han;Lu, Pei-Jung
理由：非小细胞肺癌（NSCLC）生存率低主要是由于转移。然而，控制NSCLC转移的分子机制尚未被描述。由于已知亨廷顿蛋白相互作用蛋白-1 （HIP1）在肿瘤发生中起作用，我们测试了HIP1在NSCLC进展和转移中的参与。目的：测定人类NSCLC肿瘤中HIP1的表达，并评估其与生存结局的相关性。此外，我们研究了HIP1抑制转移的能力。研究了HIP1抑制肿瘤转移的分子机制。方法：采用121例非小细胞肺癌患者的组织阵列，免疫组化分析HIP1的表达。为了研究HIP1表达在转移中的作用，我们使用HIP1表达水平改变的肺腺癌（AdCA）细胞评估了细胞的迁移、迁移和侵袭。采用相同细胞的人疾病小鼠模型，在体内评价HIP1抑制转移及其机制。测量结果和主要结果：发现HIP1在AdCA进展中的表达是早期预后的生物标志物，低表达与预后不良相关。我们还发现HIP1是AdCA的转移抑制因子。HIP1通过抑制AKT/糖原合成酶激酶3 β / β -catenin信号通路，在体外和体内显著抑制肺癌细胞的迁移，调控上皮-间质转化。结论：HIP1可作为早期预后生物标志物和转移抑制因子。在AdCA进展过程中，HIP1表达的降低可减轻akt介导的上皮-间质转化的抑制，从而导致晚期转移和预后不良。
Rationale: Non-small cell lung cancer (NSCLC) carries a poor survival rate mainly because of metastasis. However, the molecular mechanisms that govern NSCLC metastasis have not been described. Because huntingtin-interacting protein-1 (HIP1) is known to play a role in tumorigenesis, we tested the involvement of HIP1 in NSCLC progression and metastasis.Objectives: HIP1 expression was measured in human NSCLC tumors, and correlation with survival outcome was evaluated. Furthermore, we investigated the ability of HIP1 to suppress metastasis. The molecular mechanism by which HIP1 contributes to suppress metastasis was investigated.Methods: We used tissue arrays containing samples from 121 patients with NSCLC to analyze HIP1 expression by immunohistochemistry. To investigate the role of HIP1 expression on metastasis, we evaluated cellular mobility, migration, and invasion using lung adenocarcinoma (AdCA) cells with modified HIP1 expression levels. The human disease mouse models with the same cells were applied to evaluate the HIP1 suppressing metastasis and its mechanism in vivo.Measurements and Main Results: HIP1 expression in AdCA progression was found to be an early-stage prognostic biomarker, with low expression correlated to poor prognosis. We also found HIP1 to be a metastatic suppressor in AdCA. HIP1 significantly repressed the mobility of lung cancer cells in vitro and in vivo and regulated the epithelial-mesenchymal transition by repressing AKT/glycogen synthase kinase-3 beta/beta-catenin signaling.Conclusions: HIP1 serves as an early-stage prognostic biomarker and a metastatic suppressor. Reduced expression during AdCA progression can relieve HIP1 suppression of Akt-mediated epithelial-mesenchymal transition and thereby lead to development of late metastases and poor prognosis.