Malic enzyme 1 induces epithelial-mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma
Malic enzyme 1 induces epithelial-mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma
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苹果酸酶 1 诱导上皮间质转化并提示肝细胞癌预后不良。
DOI：
10.1007/s13277-015-3306-5
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发表时间：
2015-08-01
期刊：
影响因子：
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通讯作者：
Wu, Weizhong
中科院分区：
文献类型：
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作者：
Wen, Duo;Liu, Dongli;Wu, Weizhong
苹果酸酶1（ME 1）连接糖酵解和柠檬酸循环，对NADPH生成、谷氨酰胺代谢和脂肪生成很重要。最近，它的失调与各种癌症的进展有关。然而，ME 1在肝细胞癌（HCC）进展中的作用仍不清楚。在这项研究中，我们利用短发夹RNA介导的基因沉默来研究ME 1缺失在HCC中的生物学效应，并确定其在HCC中的预后意义。ME 1的表达检测实时（RT）-PCR和Western印迹使用5个肝癌细胞系和一个正常的肝细胞系。我们使用聚乙烯亚胺纳米颗粒来递送短发夹RNA以诱导HCC细胞中ME 1表达的停止。研究了NADPH产生和活性氧（ROS）产生的变化。在体外评估HCC细胞的转移潜能。此外，我们评估了65例HCC患者的癌旁和癌组织中ME 1的蛋白水平，并提供了详细的临床、病理和临床随访数据。患者的生存率也得到了进一步评估。在HCC细胞系中观察到ME 1表达上调。ME 1的下调减弱了NADPH的产生并刺激了ROS的产生。沉默ME 1可通过诱导E-cadherin表达和降低ROS依赖性途径中的N-cadherin和vimentin表达来抑制HCC细胞的迁移和侵袭特性。ME 1的过度表达在HCC样本的主要部分中观察到。肿瘤中较高水平的ME 1与总生存期降低（Kaplan-Meier分析，P = 0.024）和无进展生存期降低（Kaplan-Meier分析，P = 0.011）显著相关。ME 1表达的抑制通过抑制ROS诱导的途径中的上皮-间质转化（EMT）过程来减少HCC转移。ME 1过表达与HCC患者的不良预后相关，提示ME 1是肝细胞癌预后不良的预测因子。
Malic enzyme 1 (ME1) links the glycolytic and citric acid cycles and is important for NADPH production, glutamine metabolism, and lipogenesis. Recently, its deregulation has been implicated in the progression of various cancers. However, the role of ME1 in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we utilized short hairpin RNA-mediated gene silencing to investigate the biological effects of ME1 depletion in HCC and determined its prognostic significance in HCC. ME1 expression was examined by real-time (RT)-PCR and Western blot using five HCC cell lines and one normal liver cell line. We used polyethylenimine nanoparticles to deliver a short hairpin RNA to induce cessation of ME1 expression in HCC cells. Changes in NADPH production and reactive oxygen species (ROS) production were studied. Metastatic potentials of HCC cells were evaluated in vitro. Furthermore, we evaluated the protein level of ME1 in para-tumor and cancerous tissues of 65 HCC patients with detailed clinical, pathological, and clinical follow-up data. Patients' survivals were further assessed as well. Upregulated ME1 expression was observed in HCC cell lines. Downregulation of ME1 attenuated NADPH production and stimulated ROS production. Silencing ME1 was noted to inhibit migratory and invasive properties of HCC cells by inducing the E-cadherin expression and decreasing of N-cadherin and vimentin expression in a ROS-dependent pathway. Overexpression of ME1 was observed in a major fraction of HCC samples. Higher level of ME1 in tumors was significantly associated with reduced overall survival (Kaplan-Meier analysis, P = 0.024) and reduced progression-free survival (Kaplan-Meier analysis, P = 0.011). Inhibition of ME1 expression decreases HCC metastasis via suppression of epithelial-mesenchymal transition (EMT) processes in ROS-induced pathways. ME1 overexpression associates with unfavorable prognoses in patients with HCC, suggesting that ME1 is a poor prognostic predictor of hepatocellular carcinoma.