High expression of the cysteine proteinase legumain in colorectal cancer - Implications for therapeutic targeting
High expression of the cysteine proteinase legumain in colorectal cancer - Implications for therapeutic targeting
复制标题
DOI：
10.1016/j.ejca.2014.10.020
复制
发表时间：
2015-01-01
影响因子：
8.4
通讯作者：
Flatmark, Kjersti
中科院分区：
文献类型：
--
作者：
Haugen, Mads H.;Boye, Kjetil;Flatmark, Kjersti
背景：半胱氨酸蛋白酶豆蛋白在肿瘤中高表达。Legumain是一种潜在的生物标志物，已被建议用于癌症治疗中的前药物激活。然而，为了确定豆蛋白是否适合用于这一目的，有必要详细了解肿瘤组织中特定细胞类型和亚细胞表达以及蛋白分解活性模式。方法：采用免疫组织化学方法检测277例结直肠癌(CRC)患者原发肿瘤中豆蛋白的表达。对豆类肿瘤(胞浆弥漫性、胞浆颗粒性和胞核)和间质细胞的表达进行量化，并分析其与临床病理参数和预后的关系。此外，对正常结肠组织和自发性小鼠肿瘤组织进行豆胺染色。结果：在肿瘤和间质细胞中豆蛋白高表达。核豆蛋白在30%的肿瘤中被检测到。在结肠癌患者中，在单因素和多因素分析中，豆蛋白的高表达与总的无转移生存期(OS；MFS)相关。在结肠癌亚组中，核豆蛋白与OS不良有关，但与MFS无关。胞浆颗粒化或弥漫性表达与OS或MFS无关。结论：豆蛋白是结肠癌中高表达的一种蛋白水解酶，与结肠癌的预后有关。肿瘤和间质细胞中豆蛋白表达的多样化表明结直肠癌具有多种功能，这既是一种挑战，也是一种用于治疗靶向的机会。(C)2014爱思唯尔有限公司。保留所有权利。
Background: The cysteine proteinase legumain is highly expressed in cancer. Legumain is a potential biomarker and has been suggested to be utilised for prodrug activation in cancer therapy. However, to define the suitability of legumain for such purposes, detailed knowledge of cell type-specific and subcellular expression together with proteolytic activity patterns in tumour tissue is necessary.Methods: Expression of legumain was examined in a panel of 277 primary tumours from colorectal cancer (CRC) patients using immunohistochemistry. Tumour (cytoplasmic diffuse, cytoplasmic granulated, and nuclear) and stromal cell expression of legumain was quantified, and associations with clinicopathological parameters and outcome were analysed. Additionally, normal colon tissue and spontaneous mouse tumours were stained for legumain.Results: Legumain was highly expressed in tumour and stromal cells. Nuclear legumain was detected in 30% of the tumours. In colon cancer patients, high legumain expression was associated with overall and metastasis-free survival (OS; MFS) in uni- and multivariate analysis. Nuclear legumain was associated with poor OS, but not MFS in the colon cancer subgroup. Cytoplasmic granulated or diffuse expression was not associated with OS or MFS. Normal epithelial cells exhibited granulated legumain mainly at the apical pole, and legumain was highly expressed in CD68 positive macrophages.Conclusions: Legumain is a highly expressed proteinase in CRC and associated with poor outcome in colon cancer. Diversified localisation of legumain expression in tumour and stromal cells suggests multiple functions in CRC, representing both a challenge and an opportunity for use in therapeutic targeting. (C) 2014 Elsevier Ltd. All rights reserved.