Neutrophil elastase as a diagnostic marker and therapeutic target in colorectal cancers.
Neutrophil elastase as a diagnostic marker and therapeutic target in colorectal cancers.
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DOI：
10.18632/oncotarget.1631
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发表时间：
2014-01-30
期刊：
影响因子：
--
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Ho AS;Chen CH;Cheng CC;Wang CC;Lin HC;Luo TY;Lien GS;Chang J
中性粒细胞弹性蛋白酶（NE）是一种由中性粒细胞分泌的丝氨酸蛋白酶，有助于癌症的进展，从而增强肿瘤的侵袭和转移。据报道，结直肠癌组织周围的区域通常装饰有增加的中性粒细胞积聚或聚集，伴随着较高的NE沉积/表达。因此，我们推测NE在结直肠癌（CRC）患者中的表达水平升高可能是CRC的假定生物标志物之一。本研究的目的是通过检测结直肠癌患者血清和组织中NE的表达水平来评估和证实我们的假设。此外，我们还提出了一种潜在的治疗策略，通过使用西维来司阻断NE的酶活性来抑制肿瘤发展的进展。定量测定并比较结直肠癌患者标本组织中中性粒细胞浸润数和血清中NE分泌形式。为了评价血清NE作为结直肠癌患者的生物标志物之一的价值，采用受试者工作特征（ROC）曲线确定血清NE的临界值，为结直肠癌的诊断提供依据。为了评价NE作为CRC的治疗靶点，使用NE抑制剂西维来司他并将其施用到CRC异种移植物中。测量NE表达水平和肿瘤体积，并在对照和西维来司治疗的异种移植物之间进行比较。我们发现，与正常组织相比，在癌组织中检测到更多浸润的中性粒细胞和增加的NE表达。CRC患者血清NE浓度明显高于健康对照组（0.56±0.08 μg/ml vs. 0.22± 0.03 μ g/ml）（p<0.05），表明血清NE可能是CRC的一个推定标志物。为了研究NE在肿瘤发生中的作用，使用体内成像系统（IVIS）检测HCT-15异种移植物中的NE活性。与正常小鼠相比，异种移植物中活性NE的量显著高于正常对照动物。在治疗特性研究中，我们发现sivelestat可以抑制HCT-15诱导的异种移植瘤的生长。本研究表明，NE不仅可以作为CRC的推定诊断生物标志物，而且可以作为CRC患者的潜在治疗靶点。
Neutrophil elastase (NE), a serine protease secreted by neutrophils, contributes to the progression of cancers to enhance tumor invasion and metastasis. It has been well reported that the regions surrounding the colorectal cancerous tissues usually are decorated with increased accumulation or aggregation of neutrophils coupled with a higher deposition/expression of NE. Therefore, we hypothesized that an increased expressional level of NE in patients with colorectal cancer (CRC) may represent as one of putative biomarkers for CRC. The aim of this study was to evaluate and assure our hypothesis by measurements of the expressional level of NE in the sera and tissues from CRC patients. Moreover, we also proposed a potential therapeutic strategy by blocking enzymatic activity of NE using sivelestat to inhibit the progression of tumor developments. The infiltrated numbers of neutrophils from specimen tissues of CRC patients, and the secreted forms of NE in the sera were quantitatively measured and compared. To evaluate the serum NE as one of putative biomarkers of CRC patients, the receiver operating characteristic (ROC) curve was made to determine the cut-off value of NE in sera for assurance of CRC diagnosis. To evaluate NE as therapeutic target for CRC, sivelestat, a NE inhibitor, was used and administrated into the CRC xenografts. NE expression level coupled with tumor volume were measured and compared between the control and sivelestat-treated xenografts. We found that more infiltrated neutrophils and an increased NE expression were detected in the cancerous tissues compared to the normal tissues. The serum NE concentration in CRC patients was statistically higher than that in the healthy controls (0.56±0.08 μg/ml vs. 0.22±0.03ug/ml) (p<0.05), indicating that serum NE can potentially be a putative marker of CRC. To characterize the role of NE in tumorigenesis, the NE avtivity was detected in HCT-15-xenografts using in vivo imaging system (IVIS). Compare to normal mice, the amounts of active NE in xenografts are significantly higher than normal control animals. In the therapeutic characterizing studies, we found that sivelestat can inhibit tumor growth in the HCT-15-induced xenografts. This study suggests that NE is not only as a putative diagnostic biomarker of CRC, but also a potential therapeutic target for patients suffered with CRC.
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影响因子：
6
作者：
Tazawa, H;Okada, F;Hosokawa, M
通讯作者：
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9.3
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影响因子：
82.9
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通讯作者：
Shapiro, Steven D.