Serine/arginine protein-specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53
Serine/arginine protein-specific kinase 2 promotes the development and progression of pancreatic cancer by downregulating Numb and p53
复制标题
丝氨酸/精氨酸蛋白特异性激酶 2 通过下调 Numb 和 p53 促进胰腺癌的发生和进展
DOI：
10.1111/febs.14778
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发表时间：
2019-05-01
期刊：
影响因子：
5.4
通讯作者：
Dong, Ming
中科院分区：
文献类型：
--
作者：
Wang, Guosen;Sheng, Weiwei;Dong, Ming
丝氨酸/精氨酸蛋白特异性激酶2 （SRPK2）在一系列不同恶性肿瘤的进展中起着至关重要的作用，包括胰腺癌。然而，人们对其机制知之甚少。先前的研究表明，在肝细胞癌中，SRPK2敲低可导致决定细胞命运的蛋白Numb上调，而在胰腺癌细胞中，Numb敲低可阻止泛素介导的p53降解。在这项研究中，我们研究了SRPK2， Numb和p53在体外化学药物治疗或不治疗胰腺癌发展中的关系。SRPK2在胰腺癌组织中表达上调，并与胰腺癌患者总生存率降低相关，表明该蛋白的表达可作为不良预后的标志。SRPK2的表达与肿瘤T分期和国际癌症控制联盟（UICC）分期呈正相关，与一系列组织切片的Numb表达负相关。在胰腺癌细胞中，SRPK2下调或过表达导致麻木和野生型p53蛋白表达在奥沙利铂治疗下受到调节。此外，这三种内源性蛋白可以作为三重复合物共免疫沉淀。麻木或p53敲低可逆转SRPK2沉默诱导的p53上调。SRPK2过表达促进细胞侵袭和迁移，降低癌细胞对吉西他滨或奥沙利铂治疗的化学敏感性。相反，SRPK2沉默降低细胞侵袭和迁移，增加化学敏感性；通过沉默奥沙利铂治疗的胰腺癌细胞中的p53，这些效应被逆转。我们的数据表明SRPK2在化学药剂处理下通过下调Numb负性调节p53。因此，SRPK2以p53依赖的方式促进胰腺癌的发生和进展。
Serine/arginine protein-specific kinase 2 (SRPK2) plays a vital role in the progression of a range of different malignancies, including pancreatic cancer. However, the mechanisms are poorly understood. Previous studies have shown that in hepatocellular carcinoma, SRPK2 knockdown leads to the upregulation of the cell fate determining protein Numb, and in pancreatic cancer cells, Numb knockdown prevents ubiquitin-mediated degradation of p53. In this study, we investigated the relationship between SRPK2, Numb and p53 in the development of pancreatic cancer with or without chemical agent treatment in vitro. SRPK2 expression was upregulated in pancreatic cancer tissues and associated with decreased overall survival in pancreatic cancer patients, indicating that expression of this protein can be used as a marker of unfavourable prognosis. Expression of SRPK2 was positively associated with tumour T stage and Union for International Cancer Control (UICC) stage, and negatively associated with Numb expression in serial tissue sections. In pancreatic cancer cells, SRPK2 downregulation or overexpression led to modulation of Numb and wild-type p53 protein expression in response to oxaliplatin treatment. Furthermore, these three endogenous proteins could be coimmunoprecipitated as a triple complex. Numb or p53 knockdown reversed the upregulation of p53 that was induced by silencing SRPK2. SRPK2 overexpression promoted cell invasion and migration, and decreased chemosensitivity of cancer cells to gemcitabine or oxaliplatin treatment. Conversely, SRPK2 silencing decreased cell invasion and migration and increased chemosensitivity; these effects were reversed by silencing p53 in oxaliplatin-treated pancreatic cancer cells. Our data suggest that SRPK2 negatively regulates p53 by downregulating Numb under chemical agent treatment. Thus, SRPK2 promotes the development and progression of pancreatic cancer in a p53-dependent manner.