Serum nardilysin, a surrogate marker for epithelial-mesenchymal transition, predicts prognosis of intrahepatic cholangiocarcinoma after surgical resection
Serum nardilysin, a surrogate marker for epithelial-mesenchymal transition, predicts prognosis of intrahepatic cholangiocarcinoma after surgical resection
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血清甘松素是上皮间质转化的替代标志物，可预测肝内胆管癌手术切除后的预后
DOI：
10.1158/1078-0432.ccr-18-0124
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
and Nishi E.
中科院分区：
文献类型：
--
作者：
Yoh T;Hatano E;Kasai Y;Fujii H;Nishi K;Toriguchi K;Sueoka H;Ohno M;Seo S;Iwaisako K;Taura K;Yamaguchi R;Kurokawa M;Fujimoto J;Kimura T;Uemoto S;and Nishi E.
目的：很少有研究探讨肝内胆管细胞癌（ICC）患者的预后生物标志物。Nardilysin（NRDC）是M16家族的一种金属内肽酶，已被认为在炎症和几种癌症类型中发挥重要作用。我们在此研究的临床意义和NRDC在ICC.Experimental Design的生物学功能：我们测量了98例ICC谁在两个独立的队列接受手术切除，以评估其预后影响的患者血清NRDC水平。我们还分析了43例ICC患者癌组织中NRDCmRNA的水平。我们研究了NRDC在细胞增殖，迁移，吉西他滨的敏感性，并在ICC细胞株基因表达使用gene silencing.ResultsHigh血清NRDC水平的作用与较短的总生存期和无病生存的主要（n= 79）和验证（n= 19）队列。血清蛋白水平与癌组织NRDC mRNA水平呈显著正相关（斯皮尔曼ρ= 0.413;P= 0.006）。在ICC细胞系中NRDC的基因敲低减弱了异种移植物中的细胞增殖、迁移和肿瘤生长，并增加了对吉西他滨的敏感性。NRDC基因敲除还伴随着几个上皮间质转化（EMT）相关基因表达的显著变化。在ICC患者的手术标本中，观察到NRDC和EMT诱导转录因子ZEB 1和SNAI 1的mRNA水平之间存在强相关性。结论血清NRDC是反映原发性肿瘤EMT状态的可能替代标志物，可预测ICC的结果手术切除后。
PurposeFew studies have investigated prognostic biomarkers in patients with intrahepatic cholangiocarcinoma (ICC). Nardilysin (NRDC), a metalloendopeptidase of the M16 family, has been suggested to play important roles in inflammation and several cancer types. We herein examined the clinical significance and biological function of NRDC in ICC.Experimental Design:We measured serum NRDC levels in 98 patients with ICC who underwent surgical resection in two independent cohorts to assess its prognostic impact. We also analyzedNRDCmRNA levels in cancerous tissue specimens from 43 patients with ICC. We investigated the roles of NRDC in cell proliferation, migration, gemcitabine sensitivity, and gene expression in ICC cell lines using gene silencing.ResultsHigh serum NRDC levels were associated with shorter overall survival and disease-free survival in the primary (n= 79) and validation (n= 19) cohorts. A correlation was observed between serum protein levels and cancerous tissue mRNA levels ofNRDC(Spearmanρ= 0.413;P= 0.006). The gene knockdown ofNRDCin ICC cell lines attenuated cell proliferation, migration, and tumor growth in xenografts, and increased sensitivity to gemcitabine. The gene knockdown ofNRDCwas also accompanied by significant changes in the expression of several epithelial–mesenchymal transition (EMT)-related genes. Strong correlations were observed between the mRNA levels ofNRDCand EMT-inducing transcription factors,ZEB1andSNAI1, in surgical specimens from patients with ICC.ConclusionsSerum NRDC, a possible surrogate marker reflecting the EMT state in primary tumors, predicts the outcome of ICC after surgical resection.