Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis.
Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis.
复制标题
组织蛋白酶B促进结直肠肿瘤发生，细胞侵袭和转移。
DOI：
10.1002/mc.22312
复制
发表时间：
2016-05
影响因子：
4.6
通讯作者：
Rivard N
中科院分区：
文献类型：
--
作者：
Bian B;Mongrain S;Cagnol S;Langlois MJ;Boulanger J;Bernatchez G;Carrier JC;Boudreau F;Rivard N
组织蛋白酶B是一种半胱氨酸蛋白酶，主要作为正常细胞内溶酶体内的内肽酶发挥作用。然而，在肿瘤扩张过程中，组织蛋白酶B的调节可以在多个水平上发生改变，从而导致其过度表达并输出到细胞外。这可能表明组织蛋白酶B在导致癌症进展的改变中可能起到作用。本研究的目的是确定细胞内和细胞外组织蛋白酶B在结直肠癌(CRC)细胞生长、肿瘤发生和侵袭中的作用。结果表明，组织蛋白酶B在人腺瘤和各期癌组织中的表达和活化水平均升高。用高选择性和非穿透性组织蛋白酶B抑制剂Ca074处理CRC细胞，发现细胞外组织蛋白酶B对人CRC细胞的侵袭有积极的促进作用，但对其在软琼脂中的生长并不是必需的。组织蛋白酶B在人结直肠癌细胞中被RNAi沉默，抑制了它们在软琼脂中的生长，以及它们在免疫缺陷小鼠中的侵袭能力、肿瘤扩张和转移扩散。在组织蛋白酶B缺陷的肿瘤中，细胞周期抑制物p27Kip1的水平较高，细胞周期蛋白B1的水平也较高。最后，组织蛋白酶B与p27Kip1共定位在溶酶体中，有效地降解了抑制物。综上所述，目前的数据表明，组织蛋白酶B在结直肠癌的发生、侵袭和转移扩散中是一个重要的因子，因此可能成为结直肠癌治疗的潜在药理靶点。©2015作者。《分子癌变》，由Wiley期刊出版公司出版。
Cathepsin B is a cysteine proteinase that primarily functions as an endopeptidase within endolysosomal compartments in normal cells. However, during tumoral expansion, the regulation of cathepsin B can be altered at multiple levels, thereby resulting in its overexpression and export outside of the cell. This may suggest a possible role of cathepsin B in alterations leading to cancer progression. The aim of this study was to determine the contribution of intracellular and extracellular cathepsin B in growth, tumorigenesis, and invasion of colorectal cancer (CRC) cells. Results show that mRNA and activated levels of cathepsin B were both increased in human adenomas and in CRCs of all stages. Treatment of CRC cells with the highly selective and non‐permeant cathepsin B inhibitor Ca074 revealed that extracellular cathepsin B actively contributed to the invasiveness of human CRC cells while not essential for their growth in soft agar. Cathepsin B silencing by RNAi in human CRC cells inhibited their growth in soft agar, as well as their invasion capacity, tumoral expansion, and metastatic spread in immunodeficient mice. Higher levels of the cell cycle inhibitor p27Kip1 were observed in cathepsin B‐deficient tumors as well as an increase in cyclin B1. Finally, cathepsin B colocalized with p27Kip1 within the lysosomes and efficiently degraded the inhibitor. In conclusion, the present data demonstrate that cathepsin B is a significant factor in colorectal tumor development, invasion, and metastatic spreading and may, therefore, represent a potential pharmacological target for colorectal tumor therapy. © 2015 The Authors. Molecular Carcinogenesis, published by Wiley Periodicals, Inc.