Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity.
Cystatin SN neutralizes the inhibitory effect of cystatin C on cathepsin B activity.
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DOI：
10.1038/cddis.2013.485
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发表时间：
2013-12-19
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
胱抑素SN(CST1)是与半胱氨酸蛋白酶形成紧密等摩尔复合体的几种唾液胱抑素之一，如组织蛋白。CST1高表达与进展期胃癌pTNM分期相关。然而，CST1在肿瘤发生中的作用尚未阐明。在这项研究中，我们发现CST1在结肠癌组织中高表达，而在非肿瘤组织中表达较高。稳定表达CST1基因的HCT116细胞株(HCT116-CST1)细胞增殖和侵袭能力增强，而CST3基因转染组细胞增殖和侵袭能力增强。我们还证明了CST1过表达的细胞系在裸鼠移植瘤模型中表现出肿瘤生长和转移的增加。有趣的是，在HCT116细胞的胞外空间，CST1与有效的组织蛋白酶B(CTSB)抑制剂半胱氨酸蛋白酶C(CST3)相互作用的亲和力高于CST3与CTSB的相互作用。CST3强烈抑制CTSB介导的细胞侵袭和蛋白降解活性，但在CST1存在下，CTSB活性显著恢复。此外，CST1的结构域图谱表明，CST1的二硫键构象或保守折叠对于其分泌和CST3活性的中和是重要的。这些结果提示，CST1的上调可能参与了大肠肿瘤的发生，并通过中和CST3对CTSB蛋白水解酶活性的抑制而发挥作用。
Cystatin SN (CST1) is one of the several salivary cystatins that form tight equimolar complexes with cysteine proteases, such as the cathepsins. High expression of CST1 is correlated with advanced pTNM stage in gastric cancer. However, the functional role of CST1 in tumorigenesis has not been elucidated. In this study, we showed that CST1 was highly expressed in colon tumor tissues, compared with nontumor regions. Increased cell proliferation and invasiveness were observed in HCT116 cell lines stably transfected with CST1 cDNA (HCT116-CST1) but not in CST3-transfected cells. We also demonstrated that CST1-overexpressing cell lines exhibited increased tumor growth as well as metastasis in a xenograft nude mouse model. Interestingly, CST1 interacted with cystatin C (CST3), a potent cathepsin B (CTSB) inhibitor, with a higher affinity than the interaction between CST3 and CTSB in the extracellular space of HCT116 cells. CTSB-mediated cellular invasiveness and proteolytic activities were strongly inhibited by CST3, but in the presence of CST1 CTSB activities recovered significantly. Furthermore, domain mapping of CST1 showed that the disulfide-bonded conformation, or conserved folding, of CST1 is important for its secretion and for the neutralization of CST3 activity. These results suggest that CST1 upregulation might be involved in colorectal tumorigenesis and acts by neutralizing the inhibition of CTSB proteolytic activity by CST3.
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影响因子：
3.8
作者：
Baron, AC;DeCarlo, AA;Featherstone, JDB
通讯作者：
Featherstone, JDB
DOI：
10.3109/00365519009089165
发表时间：
1990-09-01
影响因子：
2.1
作者：
BUTTLE, DJ;BURNETT, D;ABRAHAMSON, M
通讯作者：
ABRAHAMSON, M
影响因子：
5
作者：
Choi, Eun Hwa;Kim, Jong-Tae;Lee, Hee Gu
通讯作者：
Lee, Hee Gu
影响因子：
11.4
作者：
BODE, W;ENGH, R;TURK, V
通讯作者：
TURK, V
影响因子：
2.2
作者：
Cox, JL;Sexton, PS;Darmani, NA
通讯作者：
Darmani, NA