Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer
Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer
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WD重复结构域54作为结直肠癌癌基因的临床意义和生物学功能
DOI：
10.1002/ijc.31736
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发表时间：
2019-04-01
影响因子：
6.4
通讯作者：
Zheng, Shangyong
中科院分区：
文献类型：
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作者：
Yuan, Yuncang;Qi, Guoxiang;Zheng, Shangyong
近年来，蛋白质-蛋白质相互作用已成为确定各种疾病的生物标志物和药物靶点的有吸引力的候选者。然而，WD 40重复（WDR）结构域蛋白，一些最丰富的蛋白质相互作用的介质，在很大程度上是未开发的。在我们的研究中，361个已知的WDR蛋白中的57个被鉴定为枢纽节点，并且选择在结直肠癌（CRC）中具有升高的mRNA的枢纽（WDR 54）用于进一步研究。来自945例患者的标本的免疫组化证实了CRC中WDR 54的表达升高，我们发现WDR 54高肿瘤患者的疾病特异性生存期（DSS）通常比WDR 54低肿瘤患者短，特别是对于没有分化良好的肿瘤的亚组。多变量分析显示，WDR 54高肿瘤是DSS的独立风险因素，风险比为2.981（95%置信区间，1.425-6.234; p = 0.004）。敲低WDR 54显著抑制CRC细胞的生长和侵袭性，并减少异种移植模型中的肿瘤生长。发现每种WDR 54同种型（a、B和c）逆转WDR 54敲低的抑制作用;然而，仅表现出最高表达的同种型c在CRC细胞中增加。在CRC细胞中一致地发现WDR 54敲低对SHP 2抑制剂的敏感性，并且潜在的机制涉及它们在调节AKT和ERK信号传导中的共同功能。总之，本研究首次探讨了WDR 54在癌症中的意义，并得出结论，WDR 54在CRC中作为癌基因，可能是潜在的预后标志物和治疗靶点。
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In our study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target.