CYLD deficiency promotes pancreatic cancer development by causing mitotic defects
CYLD deficiency promotes pancreatic cancer development by causing mitotic defects
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CYLD 缺陷通过引起有丝分裂缺陷促进胰腺癌的发展
DOI：
10.1002/jcp.27658
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发表时间：
2019-06-01
影响因子：
5.6
通讯作者：
Liu, Min
中科院分区：
文献类型：
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作者：
Xie, Songbo;Wu, Yuhan;Liu, Min
胰腺癌在各类恶性肿瘤中死亡率最高，数十年来，如何成功治疗胰腺癌一直是肿瘤学家面临的挑战，而早期检测无疑会提高患者的良好预后几率。确定参与胰腺癌进展的蛋白质，可能会找到用于早期检测该疾病的生物标志物。本研究确定了一个潜在候选蛋白——圆柱瘤蛋白（CYLD），这是一种去泛素化酶和微管结合蛋白，在胰腺癌发展过程中发挥抑制作用。在胰腺癌样本中，CYLD基因拷贝数的缺失导致CYLD表达下调；此外，CYLD表达降低与临床病理参数呈负相关。进一步研究表明，CYLD缺失在体外会促进集落形成，在体内会促进胰腺癌生长。机制研究显示，CYLD对纺锤体定向和细胞的正确定向分裂至关重要；CYLD缺失会导致染色体错分离大幅增加。综上所述，这些数据表明CYLD在抑制胰腺癌发生过程中起着关键作用，意味着它有可能成为胰腺癌早期检测的生物标志物以及患者预后的预测指标。
Successful treatment of pancreatic cancer, which has the highest mortality rate among all types of malignancies, has challenged oncologists for decades, and early detection would undoubtedly increase favorable patient outcomes. The identification of proteins involved in pancreatic cancer progression could lead to biomarkers for early detection of this disease. This study identifies one potential candidate, cylindromatosis (CYLD), a deubiquitinase and microtubule‐binding protein that plays a suppressive role in pancreatic cancer development. In pancreatic cancer samples, downregulation of CYLD expression resulted from a loss in the copy number of the CYLD gene; additionally, reduced expression of CYLD negatively correlated with the clinicopathological parameters. Further study demonstrated that CYLD deficiency promoted colony formation in vitro and pancreatic cancer growth in vivo. Mechanistic studies revealed that CYLD is essential for spindle orientation and properly oriented cell division; CYLD deficiency resulted in a substantial increase in chromosome missegregation. Taken together, these data indicate a critical role for CYLD in suppressing pancreatic tumorigenesis, implicating its potential as a biomarker for early detection of pancreatic cancer and a prognostic indicator of patient outcomes.