谷胱甘肽过氧化物酶2在肺腺癌中的表达及临床意义

doi:10.3877/cma.j.issn.1674-0785.2020.06.001

目的

探讨谷胱甘肽过氧化物酶2（GPX2）在肺腺癌中的表达及临床意义。

方法

收集皖南医学院弋矶山医院病理科和徐州市中心医院病理科2010年1月至2013年12月存档的152例原发性肺腺癌及其癌旁正常组织标本蜡块。标本行免疫组织化学检测GPX2与ATP结合盒转运蛋白（ABCB6）在肺腺癌组织中的表达。正电子发射计算机断层成像（PET/CT）结果由患者术前检查获得。利用在线工具GEPIA、cBioPortal分析GPX2 mRNA在肺腺癌组织的表达。采用采取t检验比较GPX2表达量和¹⁸F-FDG的最大化标准摄取值在肺癌组织和正常组织的差异，采用Pearson相关性分析分析GPX2与ABCB6蛋白表达的相关性，采取χ²检验比较GPX2蛋白表达在不同临床病理特征之间的差异，同时应用Kaplan-Meier法分析肺腺癌患者的生存预后。

结果

基于TCGA和GTEx数据，GPX2 mRNA在肺腺癌组织（483例）的表达较正常组织（347例）明显升高，且与ABCB6表达水平呈正相关（r=0.57，P<0.001）。在本研究的样本中，89例（58.6%）肺腺癌组织的GPX2蛋白表达较正常组织升高（P<0.001），同样，GPX2与ABCB6蛋白表达水平正相关（r=0.697，P<0.001）；其中，GPX2高表达患者（29例）的¹⁸F-FDG的最大化标准摄取值也高于GPX2低表达患者（26例），差异具有统计学意义（t=4.262，P<0.001）。虽然GPX2蛋白表达在不同临床病理特征之间的差异均无统计学意义（P>0.05），但是GPX2表达升高的患者较GPX2低表达患者无进展生存期减少［平均34.75个月（95%CI：29.746~39.747） vs 48.91个月（95%CI： 41.033~56.779），P=0.009］。

结论

GPX2在肺腺癌发挥癌基因作用，其作用机制可能与ABCB6介导的糖酵解有关。

关键词: 腺癌，肺, 谷胱甘肽过氧化物酶, ATP结合盒转运蛋白, 正电子发射计算机断层显像, 预后

Objective

To explore the significance of expression of glutathione peroxidase 2 (GPX2) in lung adenocarcinoma (LUAD).

Methods

One hundred and fifty-two cases of primary LUAD and matched paracancerous tissue samples were collected from January 2010 to December 2013 at the Department of Pathology of Yijishan Hospital of Wannan Medical College and the Department of Pathology of Xuzhou Central Hospital. Immunohistochemistry was used to detect the protein expression of GPX2 and ATP binding cassette subfamily B member 6 (ABCB6). Positron emission tomography/computed tomography (PET/CT) was performed preoperatively. The expression of GPX2 mRNA in LUAD tissues was analyzed online with GEPIA and cBioPortal tools. The t-test was used to compare the difference between GPX2 expression and maximum standardized uptake value (SUV) of 18-fluorodeoxyglucose (¹⁸F-FDG) in lung cancer tissues and normal tissues, Pearson correlation analysis was performed to analyze the correlation between GPX2 expression and ABCB6 protein expression, the χ²-test was used to compare the difference between different clinicopathological features, and Kaplan-Meier method was used to analyze the survival prognosis of lung adenocarcinoma patients.

Results

Based on the TCGA and GTEx data, GPX2 mRNA expression was upregulated in LUAD tissues (n=483) compared with that in normal tissues (n=347), and it was positively correlated with ABCB6 mRNA expression (r=0.57, P<0.001). In our cohort, there were 89 (58.6%) cases showing a higher level of GPX2 protein expression in tumor tissues than in adjacent normal tissues (P<0.001). Also, GPX2 protein expression was positively correlated with ABCB6 expression (r=0.697, P<0.001). Furthermore, the maximum SUV of ¹⁸F-FDG was higher in the GPX2 high expression group (n=29) than in the GPX2 low expression group (n=26). Although there were no correlations between GPX2 expression and patients′ clinicopathological features, LUAD patients with elevated GPX2 expression had a shorter disease-free survival (DFS) than those with low GPX2 expression [mean 34.75 (95%CI: 29.746-39.747) months vs 48.91 (95%CI: 41.033-56.779) months, P=0.009].

Conclusion

GPX2 acts as an oncogene in LUAD and promotes LUAD progression by regulating ABCB6-mediated glycolysis.

Key words: Adenocarcinoma, lung, Glutathione peroxidase, ATP binding cassette subfamily B member 6, Positron emission tomography/computed tomography, Prognosis

图1 GPX2与ABCB6表达情况　图a为GEPIA在线工具分析肺腺癌与正常组织GPX2 mRNA表达水平；图b为cBioPortal在线工具分析GPX2与ABCB6 mRNA的关系；图c为本研究样本GPX2与ABCB6蛋白表达的关系；图d为不同GPX2表达量在¹⁸F-FDG SUVmax上的差异

图2 肺腺癌患者GPX2、ABCB6蛋白表达（×200）与PET/CT结果的典型对照　病例1 GPX2与ABCB6均为高表达（连续切片），最大化标准摄取值值较高；病例2 GPX2低表达，ABCB6中表达（连续切片），最大化标准摄取值值较低

表1 GPX2蛋白表达与肺腺癌临床病理特征的关系（例）

病理因素		例数	高/中表达	低表达	χ²值	P值
性别		?	?	?	0.547	0.460
?	男	85	52	33	?	?
?	女	67	37	30	?	?
年龄（岁）		?	?	?	0.269	0.604
?	<60	71	40	31	?	?
?	≥60	81	49	32	?	?
肿瘤大小（cm）		?	?	?	0.344	0.557
?	>3	67	41	26	?	?
?	≤3	85	48	37	?	?
分化程度		?	?	?	1.703	0.192
?	好/中	102	56	46	?	?
?	差	50	33	17	?	?
淋巴结转移		?	?	?	1.280	0.258
?	无	81	44	37	?	?
?	有	71	45	26	?	?
TNM分期		?	?	?	1.596	0.206
?	Ⅰ/Ⅱ	68	36	32	?	?
?	Ⅲ/Ⅳ	84	53	31	?	?

表1 GPX2蛋白表达与肺腺癌临床病理特征的关系（例）

病理因素		例数	高/中表达	低表达	χ²值	P值
性别		?	?	?	0.547	0.460
?	男	85	52	33	?	?
?	女	67	37	30	?	?
年龄（岁）		?	?	?	0.269	0.604
?	<60	71	40	31	?	?
?	≥60	81	49	32	?	?
肿瘤大小（cm）		?	?	?	0.344	0.557
?	>3	67	41	26	?	?
?	≤3	85	48	37	?	?
分化程度		?	?	?	1.703	0.192
?	好/中	102	56	46	?	?
?	差	50	33	17	?	?
淋巴结转移		?	?	?	1.280	0.258
?	无	81	44	37	?	?
?	有	71	45	26	?	?
TNM分期		?	?	?	1.596	0.206
?	Ⅰ/Ⅱ	68	36	32	?	?
?	Ⅲ/Ⅳ	84	53	31	?	?

图3 GPX2表达与肺腺癌预后　图a为GEPIA在线工具分析GPX2 mRNA表达与总生存率的关系；图b为本研究选取的样本中，不同GPX2蛋白表达水平患者总生存率的差异，图c为不同GPX2蛋白表达水平患者无进展生存率的差异；GPX2为谷胱甘肽过氧化物酶2

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Clinical significance of expression of glutathione peroxidase 2 in lung adenocarcinoma

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Clinical significance of expression of glutathione peroxidase 2 in lung adenocarcinoma