Adenylate Kinase-4 Is a Marker of Poor Clinical Outcomes That Promotes Metastasis of Lung Cancer by Downregulating the Transcription Factor ATF3
Adenylate Kinase-4 Is a Marker of Poor Clinical Outcomes That Promotes Metastasis of Lung Cancer by Downregulating the Transcription Factor ATF3
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DOI：
10.1158/0008-5472.can-12-1842
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发表时间：
2012-10-01
期刊：
影响因子：
11.2
通讯作者：
Hsiao, Michael
中科院分区：
文献类型：
--
作者：
Jan, Yi-Hua;Tsai, Hong-Yuan;Hsiao, Michael
预测转移能力的生物标志物可能有助于开发更好的治疗肺癌等侵袭性癌症的策略。在这项研究中，我们发现腺苷酸激酶-4 （AK4）在人类肺癌中是一个促进转移的进展相关基因。已发表的微阵列数据分析显示，与正常细胞相比，AK4在肺腺癌中表达上调。AK4高表达与晚期、疾病复发及预后不良相关。AK4表达缺失抑制了肺癌细胞系的侵袭潜力，而AK4过表达促进了体外和体内的侵袭。在机制上，转录因子ATF3被确定为AK4的关键调控靶点。同时降低AK4和ATF3的表达可消除ATF3对侵袭的抑制作用。ATF3在ak4过表达细胞中的过表达限制了侵袭活性。此外，AK4高表达和ATF3低表达的患者与AK4低表达和ATF3高表达的患者相比，结果更不利。综上所述，我们的研究结果表明AK4通过atf3依赖的方式促进转移，从而促进恶性进展和复发。癌症Res;72 (19);5119 - 29。AACR (C) 2012。
Biomarkers predicting metastatic capacity might assist the development of better therapeutic strategies for aggressive cancers such as lung cancer. In this study, we show that adenylate kinase-4 (AK4) is a progression-associated gene in human lung cancer that promotes metastasis. Analysis of published microarray data showed that AK4 was upregulated in lung adenocarcinoma compared with normal cells. High AK4 expression was associated with advanced stage, disease recurrence and poor prognosis. Loss of AK4 expression suppressed the invasive potential of lung cancer cell lines, whereas AK4 overexpression promoted invasion in vitro and in vivo. Mechanistically, the transcription factor ATF3 was identified as a pivotal regulatory target of AK4. Simultaneous reduction in AK4 and ATF3 expression abolished the inhibitory effects of ATF3 on invasion. ATF3 overexpression in AK4-overexpressing cells limits invasion activity. Furthermore, patients with high AK4 and low ATF3 expression showed unfavorable outcomes compared with patients with low AK4 and high ATF3 expression. Taken together, our findings indicated that AK4 promotes malignant progression and recurrence by promoting metastasis in an ATF3-dependent manner. Cancer Res; 72(19); 5119-29. (C)2012 AACR.