Department of Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, China.
FEBS J. 2019 May;286(9):1668-1682. doi: 10.1111/febs.14778. Epub 2019 Mar 1.
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.
丝氨酸/精氨酸蛋白特异性激酶 2（SRPK2）在多种恶性肿瘤的进展中发挥着重要作用，包括胰腺癌。然而，其机制尚不清楚。先前的研究表明，在肝细胞癌中，SRPK2 敲低导致细胞命运决定蛋白 Numb 的上调，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 之间的关系，以探讨它们在有无化学药物治疗的体外胰腺癌发展中的作用。SRPK2 在胰腺癌组织中的表达上调，并与胰腺癌患者的总生存期缩短相关，表明该蛋白的表达可作为不良预后的标志物。SRPK2 的表达与肿瘤 T 分期和国际抗癌联盟（UICC）分期呈正相关，与连续组织切片中 Numb 的表达呈负相关。在胰腺癌细胞中，SRPK2 的下调或过表达导致 Numb 和野生型 p53 蛋白表达在奥沙利铂处理时发生变化。此外，这三种内源性蛋白可以作为一个三重复合物被共免疫沉淀。沉默 SRPK2 可引起 Numb 或 p53 的敲低，从而逆转其对 p53 的上调作用。SRPK2 的过表达促进了癌细胞的侵袭和迁移，并降低了对吉西他滨或奥沙利铂治疗的化学敏感性。相反，SRPK2 的沉默降低了癌细胞的侵袭和迁移，并增加了对化学药物的敏感性；在奥沙利铂处理的胰腺癌细胞中，沉默 p53 可逆转这些作用。我们的数据表明，SRPK2 在化学药物处理下通过下调 Numb 来负调控 p53。因此，SRPK2 以 p53 依赖的方式促进了胰腺癌的发生和发展。
