Association between matrix metalloproteinases and the prognosis of esophageal squamous cell cancer
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摘要:
目的：识别新的与食管鳞癌预后紧密相关的分子标志物，构建预测效力更高的食管鳞癌预后模型。方法：系统分析基质金属蛋白酶家族（matrix metalloproteinases，MMPs）中核心成员MMP1、MMP2、MMP3、MMP7、MMP8、MMP9及MMP10在食管鳞癌中的表达情况。采用免疫组织化学方法检测MMP3在315例（训练集197例；验证集118例）食管鳞癌患者癌组织及癌旁组织中的表达情况，Cox回归分析评价MMP3蛋白表达与食管鳞癌预后的关联。整合临床病理因素，构建食管鳞癌预后预测模型。结果：MMP1、MMP3及MMP10在食管鳞癌组织中呈异常表达，免疫组织化学分析结果表明MMP3蛋白在食管鳞癌组织表达显著高于癌旁组织。训练集中，MMP3阳性表达的患者总体存活率（22.22%）显著低于MMP3阴性表达患者（49.25%，HR=2.09，95%CI：1.45~3.03，P < 0.001），这一结果在验证集及合并集中得到进一步验证。此外，整合MMP3表达与临床病理信息构建的预后预测模型，其预测能力显著优于TNM分期模型（AUC：0.733 vs. 0.689）。结论：MMP3可作为食管鳞癌预后相关分子标志物，整合临床病理因素构建的模型可更加准确地预测食管鳞癌患者的预后。
Abstract:
Objective：This study aims to identify novel ESCC prognosis related biomarkers and construct novel prognostic predictive model for ESCC. Methods：Candidate gene strategy was adopted to analyse the expressions of key members of matrix metalloproteinases：MMP1，MMP2，MMP3，MMP7，MMP8，MMP9 and MMP10 in ESCC tissues. Immunohistochemistry was applied to detect MMP3 protein expression in 315 ESCC（Training：197 cases，Validation：118 samples）tissues. Cox proportional hazard regression model was used to evaluate the association between MMP3 expression and ESCC prognosis. Finally，we constructed ESCC prognosis predictive model by integrating MMP3 and clinicopathologic factors. Results：MMP1，MMP3 and MMP10 showed aberrant increased expression in ESCC tumor tissues. Expression of MMP3 protein in tumor tissues was significantly upregulated than that in adjacent tissues. In training dataset，the overall survival（OS）of MMP3 positive patients（22.22%）was significantly lower than patients with negative expression of MMP3（49.25%，HR=2.09，95% CI：1.45-3.03，P < 0.001）. Consistent results were further observed in validation and combined datasets. In addition，the predictive ability of model that integrated MMP3 and clinicopathologic factors was higher than that contained the TNM stage alone（AUC：0.733 vs. 0.689）. Conclusion：MMP3 acted as an ESCC prognosis related biomarker，predictive model that integrated MMP3 and clinicopathologic factors could predict the prognosis of ESCC patients accurately.
