Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Oncogene. 2022 Feb;41(6):838-851. doi: 10.1038/s41388-021-02140-6. Epub 2022 Jan 3.
Pancreatic cancer is regarded as the most lethal solid tumor worldwide. Deregulated and constitutively activated NF-κB signaling is one of the major characteristics of pancreatic cancer. The total expression level and subcellular localization of RelA/p65 have been shown to determine the activation of canonical NF-κB signaling in pancreatic cancer. FGD3, which is involved in regulating the actin cytoskeleton and cell shape, has been reported to inhibit cancer cell migration and predict a favorable prognosis in multiple types of cancer. However, the specific role of FGD3 in pancreatic cancer is still unknown. In this study, we conducted a systematic investigation of the cancer-related role of FGD3 in pancreatic cancer. We demonstrated that FGD3 was abnormally downregulated in pancreatic cancer tissues and that low expression of FGD3 was associated with unfavorable prognosis in patients with pancreatic cancer. Then, we showed that FGD3 inhibited pancreatic cancer cell proliferation, invasion and metastasis in vivo and in vitro. Moreover, we revealed that FGD3 silencing activated the NF-κB signaling pathway by promoting HSF4 nuclear translocation and increasing p65 expression in pancreatic cancer cells. Therefore, our results identified a novel and targetable FGD3/HSF4/p65 signaling axis in pancreatic cancer cells.
胰腺癌被认为是全球最致命的实体肿瘤。NF-κB 信号的失调和持续激活是胰腺癌的主要特征之一。RelA/p65 的总表达水平和亚细胞定位已被证明决定了胰腺癌细胞中经典 NF-κB 信号的激活。FGD3 参与调节肌动蛋白细胞骨架和细胞形状，据报道可抑制癌细胞迁移，并预测多种类型癌症的预后良好。然而，FGD3 在胰腺癌中的具体作用尚不清楚。在这项研究中，我们对 FGD3 在胰腺癌中的癌症相关作用进行了系统研究。我们证明 FGD3 在胰腺癌组织中异常下调，并且 FGD3 的低表达与胰腺癌患者的不良预后相关。然后，我们表明 FGD3 在体内和体外抑制了胰腺癌细胞的增殖、侵袭和转移。此外，我们揭示了 FGD3 沉默通过促进 HSF4 核易位和增加胰腺癌细胞中 p65 的表达来激活 NF-κB 信号通路。因此，我们的研究结果确定了胰腺癌细胞中一个新的、可靶向的 FGD3/HSF4/p65 信号轴。
