WDR3 过表达通过与胰腺癌细胞中的 GATA4 相互作用诱导 Hippo 通路的激活。
Overexpressed WDR3 induces the activation of Hippo pathway by interacting with GATA4 in pancreatic cancer.
机构信息
Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, Sichuan, China.
Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 611731, Sichuan, China.
出版信息
J Exp Clin Cancer Res. 2021 Mar 1;40(1):88. doi: 10.1186/s13046-021-01879-w.
BACKGROUND
WD repeat domain 3 (WDR3) is involved in a variety of cellular processes including gene regulation, cell cycle progression, signal transduction and apoptosis. However, the biological role of WDR3 in pancreatic cancer and the associated mechanism remains unclear. We seek to explore the immune-independent functions and relevant mechanism for WDR3 in pancreatic cancer.
METHODS
The GEPIA web tool was searched, and IHC assays were conducted to determine the mRNA and protein expression levels of WDR3 in pancreatic cancer patients. MTS, colony formation, and transwell assays were conducted to determine the biological role of WDR3 in human cancer. Western blot analysis, RT-qPCR, and immunohistochemistry were used to detect the expression of specific genes. An immunoprecipitation assay was used to explore protein-protein interactions.
RESULTS
Our study proved that overexpressed WDR3 was correlated with poor survival in pancreatic cancer and that WDR3 silencing significantly inhibited the proliferation, invasion, and tumor growth of pancreatic cancer. Furthermore, WDR3 activated the Hippo signaling pathway by inducing yes association protein 1 (YAP1) expression, and the combination of WDR3 silencing and administration of the YAP1 inhibitor TED-347 had a synergistic inhibitory effect on the progression of pancreatic cancer. Finally, the upregulation of YAP1 expression induced by WDR3 was dependent on an interaction with GATA binding protein 4 (GATA4), the transcription factor of YAP1, which interaction induced the nuclear translocation of GATA4 in pancreatic cancer cells.
CONCLUSIONS
We identified a novel mechanism by which WDR3 plays a critical role in promoting pancreatic cancer progression by activating the Hippo signaling pathway through the interaction with GATA4. Therefore, WDR3 is potentially a therapeutic target for pancreatic cancer treatment.
背景
WD 重复结构域 3（WDR3）参与多种细胞过程，包括基因调控、细胞周期进程、信号转导和细胞凋亡。然而，WDR3 在胰腺癌中的生物学作用及其相关机制尚不清楚。我们旨在探索 WDR3 在胰腺癌中的免疫无关功能及其相关机制。
方法
通过 GEPIA 在线工具搜索，并进行免疫组织化学检测，以确定胰腺癌患者中 WDR3 的 mRNA 和蛋白表达水平。通过 MTS、集落形成和 Transwell 测定来确定 WDR3 在人类癌症中的生物学作用。通过 Western blot 分析、RT-qPCR 和免疫组化检测来检测特定基因的表达。通过免疫沉淀实验来探索蛋白质-蛋白质相互作用。
结果
我们的研究证明，过表达的 WDR3 与胰腺癌患者的不良生存相关，而 WDR3 沉默显著抑制了胰腺癌的增殖、侵袭和肿瘤生长。此外，WDR3 通过诱导 yes 相关蛋白 1（YAP1）的表达激活 Hippo 信号通路，WDR3 沉默与 YAP1 抑制剂 TED-347 的联合使用对胰腺癌的进展具有协同抑制作用。最后，WDR3 诱导的 YAP1 表达上调依赖于与 YAP1 的转录因子 GATA 结合蛋白 4（GATA4）的相互作用，该相互作用诱导胰腺癌细胞中 GATA4 的核转位。
结论
我们发现了一种新的机制，即 WDR3 通过与 GATA4 相互作用激活 Hippo 信号通路，在促进胰腺癌进展中发挥关键作用。因此，WDR3 可能是治疗胰腺癌的潜在靶点。
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