Ho Ai-Sheng, Chen Chien-Hsin, Cheng Chun-Chia, Wang Chia-Chi, Lin Hua-Ching, Luo Tsai-Yueh, Lien Gi-Shih, Chang Jungshan
Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, Taiwan.
Oncotarget. 2014 Jan 30;5(2):473-80. doi: 10.18632/oncotarget.1631.
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 ± 0.03 μg/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 activity 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.
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，在癌症进展过程中促进肿瘤侵袭和转移。已有充分报道称，结直肠癌组织周围区域通常有中性粒细胞的积累或聚集增加，同时NE的沉积/表达也更高。因此，我们假设结直肠癌（CRC）患者中NE表达水平升高可能是CRC的一种潜在生物标志物。本研究的目的是通过测量CRC患者血清和组织中NE的表达水平来评估和验证我们的假设。此外，我们还提出了一种潜在的治疗策略，即使用西维来司他阻断NE的酶活性，以抑制肿瘤发展进程。对CRC患者标本组织中的中性粒细胞浸润数量以及血清中NE的分泌形式进行了定量测量和比较。为了评估血清NE作为CRC患者潜在生物标志物之一，绘制了受试者工作特征（ROC）曲线，以确定血清中NE用于确诊CRC的临界值。为了评估NE作为CRC的治疗靶点，使用了NE抑制剂西维来司他，并将其施用于CRC异种移植瘤。测量并比较了对照组和西维来司他治疗的异种移植瘤中NE表达水平和肿瘤体积。我们发现，与正常组织相比，癌组织中检测到更多浸润的中性粒细胞和NE表达增加。CRC患者的血清NE浓度在统计学上高于健康对照组（0.56±0.08μg/ml对0.22±0.03μg/ml）（p<0.05），表明血清NE可能是CRC的一种潜在标志物。为了表征NE在肿瘤发生中的作用，使用体内成像系统（IVIS）在HCT-15异种移植瘤中检测了NE活性。与正常小鼠相比，异种移植瘤中活性NE的量显著高于正常对照动物。在治疗特性研究中，我们发现西维来司他可以抑制HCT-15诱导的异种移植瘤的生长。本研究表明，NE不仅是CRC的一种潜在诊断生物标志物，也是CRC患者的一种潜在治疗靶点。
