CN110618271B - 非小细胞肺癌的预后预测方法 - Google Patents

非小细胞肺癌的预后预测方法 Download PDF

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CN110618271B
CN110618271B CN201910956013.9A CN201910956013A CN110618271B CN 110618271 B CN110618271 B CN 110618271B CN 201910956013 A CN201910956013 A CN 201910956013A CN 110618271 B CN110618271 B CN 110618271B
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赫捷
吕志民
高亦博
杨雪莹
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Abstract

提供一种非小细胞肺癌的预后预测方法，包括：检测癌细胞的果糖激酶A和乙酰辅酶A合成激酶2的S659位点磷酸化水平。本发明基于果糖激酶A和/或乙酰辅酶A合成激酶2的S659位点磷酸化，通过免疫组化技术，检测果糖激酶A和/或乙酰辅酶A合成激酶2的S659位点磷酸化表达水平，独立预测非小细胞肺癌生存期。

Description

非小细胞肺癌的预后预测方法
技术领域
本发明涉及肿瘤学领域，具体地涉及基于果糖激酶A与乙酰辅酶A合成激酶2的S659位点磷酸化在非小细胞肺癌中的预后预测方法。
背景技术
肿瘤代谢重编程是肿瘤的一个非常重要的特点，在肿瘤代谢重编程的过程中，肿瘤代谢向合成代谢转化，为肿瘤细胞的生长提供更有利的产物和环境。近些年来研究表明果糖激酶A(KHK-A)与乙酰辅酶A合成激酶2的S659位点磷酸化(ACSS2 pS659)在肿瘤代谢重编程中不仅发挥代谢酶的作用，而且发挥非代谢酶的作用，从而促进肿瘤的发生发展。
在肝细胞肝癌中，KHK-C(果糖激酶C)向KHK-A转化，KHK-A磷酸化下游基因从而促进核酸合成进而促进肿瘤的发生发展，而且在缺氧的环境下，KHK-A还可以帮助肿瘤细胞克服这种缺氧环境来促进肿瘤生长，此外高表达KHK-A的肝癌患者预后差。目前KHK-A仅在肝细胞肝癌中做过预后研究，具有应用局限性。
由于肿瘤细胞生长速度快，经常发生营养缺乏，近来研究表明在营养缺乏的脑胶质瘤细胞中，乙酰辅酶A合成激酶2的S659位点会发生磷酸化，从而介导其入核使其结合在溶酶体相关基因与自噬相关基因的启动子上，促进下游基因的表达及肿瘤发展。现只有ACSS2在肾细胞癌，膀胱癌，胃癌，肝癌的研究，而且预后作用不一致，但没有ACSS2 pS659在肿瘤中预后作用的相关研究。
发明内容
为克服上述缺陷，本发明提供一种基于果糖激酶A与乙酰辅酶A合成激酶2的S659位点磷酸化在非小细胞肺癌中的预后预测方法。
本发明提供一种非小细胞肺癌的预后预测方法，包括：检测癌细胞的果糖激酶A和/或乙酰辅酶A合成激酶2的S659位点磷酸化水平。
根据本发明的一实施方式，当果糖激酶A(KHK-A)和/或乙酰辅酶A合成激酶2的S659位点磷酸化(ACSS2 pS659)与参考水平相比升高时，代表患者预后差。
根据本发明的另一实施方式，所述非小细胞肺癌包括TNM分期I期、II期、III期、IV期。
根据本发明的另一实施方式，所述参考水平是来自非癌细胞的水平。
根据本发明的另一实施方式，所述参考水平是来自早期或低度癌细胞的水平。
本发明基于KHK-A与ACSS2 pS659，通过免疫组化技术，检测KHK-A和ACSS2 pS659表达水平，独立预测非小细胞肺癌(MSCLC)生存期。
附图说明
通过参照附图详细描述其示例实施方式，本发明的上述和其它特征及优点将变得更加明显。
图1是非小细胞肺癌和与其匹配的正常组织中KHK-A和ACSS2-pS659的免疫组化评分。
图2A是利用Kaplan-Meier生存分析评价非小细胞肺癌的KHK-A表达的相关性结果图。
图2B是利用Kaplan-Meier生存分析评价非小细胞肺癌的ACSS2-pS659表达的相关性结果图。
图2C是利用Kaplan-Meier生存分析评价非小细胞肺癌的KHK-A和ACSS2-pS659表达的相关性结果图。
具体实施方式
下面结合具体实施方式对本发明作详细说明。
本发明的目的在于提供一种基于免疫组化技术检测标志物果糖激酶A(KHK-A)与乙酰辅酶A合成激酶2的S659位点磷酸化(ACSS2 pS659)的表达水平，使用这两种标志物预测非小细胞肺癌患者的预后。
本发明涉及的术语“预后”表示提供对癌症可能的进程和结果的预测。它既包括判断疾病的特定后果(如康复，某种症状、体征和并发症等其它异常的出现或消失及死亡)，也包括提供时间线索，如预测某段时间内发生某种结局的可能性。预后可包括癌症并发症、转移、扩散的可能性，癌症的可能的结果，恢复的可能性，总生存率和/或总死亡率。优选地，预后是患者恢复或具有癌症的复发/再发的概率。例如“预后较好”是指癌症不易发生复发转移，“预后较差”是指癌症更易发生复发转移。实施例1果糖激酶A(KHK-A)和乙酰辅酶A合成激酶2的S659位点磷酸化(ACSS2 pS659)单指标或联合应用与预后的相关性。
1、肿瘤样本
303例非小细胞肺癌样本，其中76例鳞癌、227例腺癌、297对配对样本。
2、IHC检测KHK-A和ACSS2 pS659表达
从图1可以看出，KHK-A和ACSS2 pS659在大部分肿瘤样本中高于配对的正常样本。
3、通过Kaplan-Meier分析KHK-A和ACSS2 pS659的预后
K-Means聚类分析用于将癌症患者分成KHK-A和ACSS2 pS659表达水平高和低两组。
图2A和图2B分别示出，KHK-A和ACSS2 pS659表达越高预示NSCLC患者的生存期越短(所有P＜0.001)。
图2C示出KHK-A和ACSS2 pS659联合使用，从图中可以看出，KHK-A低表达和ACSS2pS659低表达预后最好，KHK-A高表达和ACSS2 pS659高表达预后最差(P＜0.001)。
4、KHK-A和ACSS2 pS659在肿瘤中生存期的独立预测
4.1单因素Cox回归分析和多因素Cox回归分析显示在NSCLC中KHK-A及ACSS2pS659均为独立预后因子，即KHK-A：HR＝1.533，95％CI＝1.120-2.099，P＝0.008；ACSS2pS659：HR＝2.313，95％CI＝1.687-3.172，P＜0.001(表1)。
表1.非小细胞肺癌单因素及多因素分析
Figure BSA0000191799510000031
Figure BSA0000191799510000041
4.2单因素Cox回归分析和多因素Cox回归分析显示在NSCLC中KHK-A与ACSS2pS659联合指标为独立预后因子，KHK-A高表达与ACSS2 pS65高表达风险度最高，KHK-A低表达与ACSS2 pS65低表达风险度最低(II vs I：HR＝2.803，95％CI＝1.920-4.094，P＜0.001；III vs I：HR＝2.319，95％CI＝1.366-3.936P＝0.002；IV vs I：HR＝3.587，95％CI＝2.413-5.331，P＜0.001(表2)。
表2.非小细胞肺癌单因素及多因素分析
Figure BSA0000191799510000042
I，KHK-A低/ACSS2pS659低；II，KHK-A低/ACSS2pS659高；
III，KHK-A高/ACSS2pS659低；IV，KHK-A高/ACSS2pS659高
缩写：CI：置信区间，HR：风险比；
通过单因素COX回归分析及多因素COX回归分析，可以看出KHK-A、ACSS2 pS659、KHK-A和ACSS2 pS659联合使用均为独立预后因子。所有这些结果强烈支持KHK-A和ACSS2pS659对非小细胞肺癌中的预后评估具有重要作用。
当然，本发明还可有其它多种实施例，在不背离本发明精神及其实质的情况下，熟悉本领域的技术人员当可根据本发明作出各种相应的改变和变形，但这些相应的改变和变形都应属于本发明所附的权利要求的保护范围。

Claims (5)

1.一种检测癌细胞的果糖激酶A和/或乙酰辅酶A合成激酶2的S659位点磷酸化水平在制备非小细胞肺癌预后预测产品中的应用。
2.根据权利要求1所述的应用，其中当果糖激酶A和/或乙酰辅酶A合成激酶2的S659位点磷酸化与参考水平相比升高时，代表患者预后差。
3.根据权利要求1所述的应用，其中所述非小细胞肺癌包括TNM分期I期、II期、III期和IV期。
4.根据权利要求2所述的应用，其中所述参考水平是来自非癌细胞的水平。
5.根据权利要求2所述的应用，其中所述参考水平是来自早期或低度癌细胞的水平。
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