Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer
Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer
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肺癌中 CUL4A 和 CUL4B 泛素连接酶的失调
DOI：
10.1074/jbc.m116.765230
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发表时间：
2017-02-17
影响因子：
4.8
通讯作者：
Zhou, Pengbo
中科院分区：
文献类型：
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作者：
Jia, Lei;Yan, Fan;Zhou, Pengbo
库林环泛素连接酶4(CRL4)参与控制细胞周期、DNA损伤修复和检查点反应，基于对细胞系和小鼠模型的研究。CRL4蛋白，包括CUL4A和CUL4B，通常在人类恶性肿瘤中高度积聚。CRL4的升高减弱了DNA损伤修复，并增加了基因组的不稳定性，这被认为有助于肿瘤的发生。然而，这还有待在人类癌症患者身上进行评估。在我们的研究中，352例来自亚洲的肺癌和62例正常肺标本被构建成四种不同肺癌亚型的组织芯片。用免疫组织化学方法检测CUL4A、CUL4B及其底物的表达，并对其预后价值及与DNA损伤反应和基因组不稳定性的关系进行统计学分析。结果表明，CUL4A和CUL4B在大多数肺癌(P-CUL4A<；0.001和P-CUL4B<；0.001)中高表达，且与肿瘤大小(P-CUL4A<；0.001和P-CUL4B=0.002)、淋巴侵袭(P-CUL4A=0.004和P-CUL4B<；0.001)、转移(P-CUL4A=0.019和P-CUL4B=0.006)、分期(P-CUL4A和P-CUL4B<；0.001和P-CUL4B<；)显著相关。0.001)，这与基因扩增和典型的WNT信号的异常激活平行。此外，CUL4A的过度表达与吸烟显著相关，而与作为CUL4A底物的XPC和P21呈负相关(P-CUL4A=0.019和P-CUL4B=0.006)。CUL4A或CUL4B水平较高与患者的总体生存显著相关(P-CUL4A
The Cullin-RING ubiquitin ligase 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair, and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B, are often highly accumulated in human malignancies. Elevated CRL4 attenuatesDNAdamage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human patients with cancer. In our study, 352 lung cancer and 62 normal lung specimens of Asian origin were constructed into tissue microarrays of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B, and their substrates was detected by immunohistochemistry and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability. Our results show that both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (P-CUL4A < 0.001 and P-CUL4B < 0.001) and significantly associated with tumor size (P-CUL4A < 0.001 and P-CUL4B = 0.002), lymphatic invasion (P-CUL4A = 0.004 and P-CUL4B < 0.001), metastasis (P-CUL4A = 0.019 and P-CUL4B = 0.006), and advanced TNM stage (P-CUL4A < 0.001 and P-CUL4B < 0.001), which parallels gene amplification and abnormal activation of the canonical WNT signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (p = 0.01) and is inversely correlated withXPC and P21, both of which are substrates ofCUL4A(P-CUL4A = 0.019 and P-CUL4B = 0.006). Higher levels of CUL4A or CUL4B are significantly associated with the overall survival of patients(P-CUL4A