Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer.
Functional significance and therapeutic implication of ring-type E3 ligases in colorectal cancer.
复制标题
环型E3连接酶在结直肠癌中的功能意义和治疗意义。
作者：
Liu L;Wong CC;Gong B;Yu J
累积研究表明，E3泛素连接酶在结直肠癌中具有重要作用。结直肠癌（CRC）的开始和进展的致病机制是复杂且异质的，涉及体细胞突变，基因融合异常，缺失或扩增以及表观遗传改变，这可能会导致CRC中E3连接酶的异常表达或改变。据报道，E3连接酶的缺陷参与了CRC的分子病因和发病机理。异常表达的E3连接酶可以根据CRC中的泛素化靶标底物的肿瘤基因或肿瘤抑制剂作用。最近，我们了解E3连接酶介导的泛素化在结直肠癌发生中的潜在作用方面取得了长足的进步。人类中主要有两个亚型的E3泛素连接酶的两个亚型，这是由Hect结构域或环手指域的存在定义的。大多数与癌症相关的E3连接酶都参与调节细胞周期，凋亡，基因转录，细胞信号传导和DNA修复，这是CRC肿瘤发生的关键部分。在这篇综述中，我们提供了异常表达的E3连接酶及其在CRC中相关的关键机理效应的全面摘要。特别是，我们强调了环型E3泛素酶在调节癌症信号通路，免疫力和肿瘤微环境中在CRC发育和进展中的功能；它们在CRC中的作用机制涉及泛素化依赖性和泛素化的效应；环E3连接酶是预测患者预后和作为CRC治疗靶标的分子生物标志物的潜力。对CRC发展涉及的E3连接酶介导的底物的泛素化的更好理解将为CRC的病理生理机制提供新的见解，并揭示了新型的CRC预后标记和治疗策略。
Accumulative studies revealed that E3 ubiquitin ligases have important roles in colorectal carcinogenesis. The pathogenic mechanisms of colorectal cancer (CRC) initiation and progression are complex and heterogeneous, involving somatic mutations, abnormal gene fusion, deletion or amplification and epigenetic alteration, which may cause aberrant expression or altered function of E3 ligases in CRC. Defects of E3 ligases have been reported to be involved in the molecular etiology and pathogenesis of CRC. The aberrant expressed E3 ligases can function as either oncogenes or tumor suppressors depending on ubiquiting target substrates in CRC. Recently, considerable progress has been made in our understanding of the potential roles of E3 ligase-mediated ubiquitylation in colorectal carcinogenesis. There are mainly two subtypes of E3 ubiquitin ligases in humans, as defined by the presence of either a HECT domain or a RING finger domain on the basis of structural similitude. Most cancer-associated E3 ligases participate in regulating the cell cycle, apoptosis, gene transcription, cell signaling and DNA repair, the critical parts of CRC tumorigenesis. In this review, we have provided a comprehensive summary of abnormally expressed E3 ligases and their related pivotal mechanistic effects in CRC. In particular, we have highlighted the function of RING-type E3 ubiquitin enzymes in modulating cancer signaling pathways, immunity and tumor microenvironment in CRC development and progression; their mechanism(s) of action in CRC involving both ubiquitylation-dependent and ubiquitylation-independent effects; and the potential of RING E3 ligases as molecular biomarkers for predicting patient prognosis and as therapeutic targets in CRC. A better understanding of E3 ligase-mediated substrates' ubiquitylation involved in the development of CRC will provide new insights into the pathophysiology mechanisms of CRC, and unravel novel prognostic markers and therapeutic strategies for CRC.
登录
查看更多内容
影响因子：
10.5
作者：
de Lau W;Peng WC;Gros P;Clevers H
通讯作者：
Clevers H
影响因子：
5.3
作者：
Ding, Qingqing;He, Xianghuo;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
3.4
作者：
Chen, Haijin;Mo, Xiaodong;Gao, Liping
通讯作者：
Gao, Liping
影响因子：
64.5
作者：
Ceccarelli, Derek F.;Tang, Xiaojing;Sicheri, Frank
通讯作者：
Sicheri, Frank
影响因子：
11.4
作者：
Aberle, H;Bauer, A;Kemler, R
通讯作者：
Kemler, R