Malic Enzyme I Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species
Malic Enzyme I Indicates Worse Prognosis in Breast Cancer and Promotes Metastasis by Manipulating Reactive Oxygen Species
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DOI：
10.2147/ott.s256970
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Hu, Xichun
中科院分区：
文献类型：
--
作者：
Liu, Chang;Cao, Jun;Hu, Xichun
目的：苹果酸酶1（ME 1）催化苹果酸生成丙酮酸，从而促进糖酵解。其在乳腺癌中的作用仍有待充分阐明。本研究旨在探讨ME 1在乳腺癌中的预后价值及其可能机制。方法：采用组织芯片免疫组化技术检测220例早期乳腺癌患者ME 1的表达，并探讨其与临床病理特征的关系。进一步进行生存分析以确定其预后价值。公共数据库用于确认组织微阵列结果。结果：乳腺癌组织中ME 1高表达与肿瘤体积、淋巴结转移率和淋巴管浸润率显著相关，ME 1高表达与肿瘤体积、淋巴结转移率和淋巴管浸润率显著相关。ME 1高表达与较差的无复发生存期（RFS）显著相关，并且是RFS的独立预后因素，这一点已由公共数据库中的mRNA结果证实。在体外，通过用病毒载体转染MCF-7细胞来上调ME 1显著增强了细胞的活力、运动性和上皮间质转化（EMT），并降低了ROS水平，而在MDA-MB-468细胞中敲低ME 1产生了与预期完全相反的效果。结论：ME 1可能是乳腺癌转移的一个新的生物标志物和潜在的治疗靶点，其生物学效应主要受ROS的调控。
Purpose: Malic enzyme 1 (ME1) catalyzes malate to pyruvate and thus promotes glycolysis. Its function in breast cancer remains to be fully clarified. The aim of this work was to investigate the prognostic value of ME1 and its possible mechanism in breast cancer.Methods: We evaluated ME1 expression in 220 early breast cancer patients with tissue microarray-based immunohistochemistry and explored the relationships between ME1 expression and clinicopathological features. Survival analyses were further performed to determine its prognostic value. The public database was used to confirm tissue microarray results. Further, cell proliferation, migration, invasion ability and reactive oxygen species (ROS) were examined in breast cancer cells.Results: In breast cancer tissues, high ME1 expression was significantly associated with larger tumor size, higher incidence of lymph node metastasis and higher incidence of lymphvascular invasion. High ME1 expression significantly correlated with worse recurrence-free survival (RFS), and was an independent prognostic factor for RFS, which was confirmed by mRNA results in the public database. In vitro, upregulation of ME1 by transfecting MCF-7 cells with virus vector remarkably enhanced viability, motility and epithelial mesenchymal transition (EMT) and decreased ROS levels, whereas knockdown in MDA-MB-468 cells produced totally opposite effects as expected. When pretreated with oxidizing agent, MCF-7 cells overexpressing ATE1 lost its motility, whereas MDA-MB-468 cells with knockdown of ME] restored its motility when pretreated with antioxidant.Conclusion: To our knowledge, these clinical and experiment works first suggested that ME1 may be a novel biomarker and potential therapeutic target for breast cancer metastasis, and its biological effect is mainly controlled by manipulating ROS.