SKA1 regulates actin cytoskeleton remodelling via activating Cdc42 and influences the migration of pancreatic ductal adenocarcinoma cells
SKA1 regulates actin cytoskeleton remodelling via activating Cdc42 and influences the migration of pancreatic ductal adenocarcinoma cells
复制标题
SKA1通过激活Cdc42调节肌动蛋白细胞骨架重塑并影响胰腺导管腺癌细胞的迁移。
DOI：
10.1111/cpr.12799
复制
发表时间：
2020-03-30
影响因子：
8.5
通讯作者：
Wang, Lifu
中科院分区：
文献类型：
--
作者：
Li, Tong;Liu, Xu;Wang, Lifu
纺锤体和着丝点相关蛋白1（SKA1）最初被认为是染色体正确分离所必需的蛋白质，最近被认为与多种恶性肿瘤有关。本研究旨在探讨SKA1在胰腺癌发生中的生物学、临床作用及分子机制。材料与方法应用免疫组化方法检测145例胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）中SKA1的表达。生物学行为测定用于确定SKA1在体内和体外PDAC进展中的作用。使用等压标签进行相对和绝对定量（iTRAQ），检测SKA1的下游蛋白。此外，利用细胞松弛素B和ZCL278研究ska1诱导的信号传导和细胞形态的变化，并通过免疫印迹和免疫荧光实验进一步证实。结果PDAC组织中SKA1表达升高与肿瘤大小、细胞分化程度显著相关。此外，SKA1水平升高反映了较短的总生存期（P = 0.019）。生物学行为方面，SKA1在PDAC中作为肿瘤启动子，SKA1过表达促进细胞在体内外的增殖、迁移和侵袭。在机制上，我们证明SKA1通过激活Cdc42抑制G2/M阻滞和调节肌动蛋白细胞骨架组织来增强胰腺癌的侵袭性。结论本研究揭示了SKA1在PDAC细胞中作为肌动蛋白细胞骨架组织和癌基因的重要调节因子的新作用，这可能为开发新的治疗方法提供见解。
Objectives Spindle and kinetochore-associated protein 1(SKA1), originally identified as a protein essential for proper chromosome segregation, has been recently linked to multiple malignancies. This study aimed to explore the biological, clinical role and molecular mechanism of SKA1 in pancreatic carcinogenesis.Materials and Methods SKA1 expression was detected in 145 pancreatic ductal adenocarcinoma (PDAC) specimens by immunohistochemistry. Biological behaviour assays were used to determine the role of SKA1 in PDAC progression in vitro and in vivo. Using isobaric tags for relative and absolute quantitation (iTRAQ), SKA1's downstream proteins were examined. Moreover, cytochalasin B and ZCL278 were used to explore the changes of SKA1-induced signalling and cell morphology, with further confirmation by immunoblotting and immunofluorescence assays.Results Increased SKA1 expression was significantly correlated with tumour size and cellular differentiation degree in PDAC tissues. Furthermore, elevated levels of SKA1 reflected shorter overall survival (P = .019). As for biological behaviour, SKA1 acted as a tumour promotor in PDAC, overexpression of SKA1 facilitates cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, we demonstrated that SKA1 enhanced pancreatic cancer aggressiveness by inhibiting G2/M arrest and regulating actin cytoskeleton organization via activating Cdc42.Conclusions This study revealed novel roles for SKA1 as an important regulator of actin cytoskeleton organization and an oncogene in PDAC cells, which may provide insights into developing novel therapeutics.