Plasminogen Activator Inhibitor-2 Plays a Leading Prognostic Role among Protease Families in Non-Small Cell Lung Cancer

Background
In lung cancer, uPA, its receptor (uPAR), and the inhibitors PAI-1 and PAI-2 of the plasminogen activator family interact with MMP-2 and MMP-9 of the MMP family to promote cancer progression. However, it remains undetermined which of these markers plays the most important role and may be the most useful indicator to stratify the patients by risk.
Methods
We determined the individual prognostic value of these 6 markers by analyzing a derivation cohort with 98 non-small cell lung cancer patients by immunohistochemical staining. The correlation between the IHC expression levels of these markers and disease prognosis was investigated, and an immunohistochemical panel for prognostic prediction was subsequently generated through prognostic model analysis. The value of the immunohistochemical panel was then verified by a validation cohort with 91 lung cancer patients.
Results
In derivation cohort, PAI-2 is the most powerful prognostic factor (HR = 2.30; P = 0.001), followed by MMP-9 (HR = 2.09; P = 0.019) according to multivariate analysis. When combining PAI-2 and MMP-9, the most unfavorable prognostic group (low PAI-2 and high MMP-9 IHC expression levels) showed a 6.40-fold increased risk of a poor prognosis compared to the most favorable prognostic group (high PAI-2 and low MMP-9 IHC expression levels). PAI-2 and MMP-9 IHC panel could more precisely identify high risk patients in both derivation and validation cohort.
Conclusions
We revealed PAI-2 as the most powerful prognostic marker among PA and MMP protease family even after considering their close relationships with each other. By utilizing a combination of PAI-2 and MMP-9, more precise prognostic information than merely using pathological stage alone can be obtained for lung cancer patients.

背景
在肺癌中，尿激酶型纤溶酶原激活物（uPA）、其受体（uPAR）以及纤溶酶原激活物家族的抑制剂PAI-1与PAI-2，可与基质金属蛋白酶（MMP）家族的MMP-2、MMP-9相互作用，进而促进癌症进展。但目前仍未明确上述标志物中哪一种发挥最为关键的作用，也尚未确定可用于患者风险分层的最具应用价值的指示指标。
方法
本研究通过免疫组化（Immunohistochemistry, IHC）染色分析包含98例非小细胞肺癌患者的推导队列，明确了这6种标志物各自的预后价值。研究探究了这些标志物的免疫组化表达水平与疾病预后之间的相关性，并通过预后模型分析构建了用于预后预测的免疫组化标志物组合。随后，利用包含91例肺癌患者的验证队列对该免疫组化组合的应用价值进行了验证。
结果
在推导队列中，多因素分析结果显示，PAI-2是最为强效的预后因子（风险比HR=2.30；P=0.001），其次为MMP-9（HR=2.09；P=0.019）。将PAI-2与MMP-9联合分析时，预后最差的亚组（PAI-2低表达且MMP-9免疫组化高表达）相较于预后最优的亚组（PAI-2高表达且MMP-9免疫组化低表达），其不良预后风险升高了6.40倍。PAI-2与MMP-9的免疫组化组合可在推导队列与验证队列中更精准地识别高危患者。
结论
本研究证实，即便考虑到纤溶酶原激活物（PA）与基质金属蛋白酶（MMP）家族成员间的紧密关联，PAI-2仍是该两类蛋白酶家族中最为强效的预后标志物。联合应用PAI-2与MMP-9，可为肺癌患者提供比单纯依据病理分期更为精准的预后信息。