Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
Int J Biol Sci. 2022 Jan 9;18(3):1288-1302. doi: 10.7150/ijbs.66313. eCollection 2022.
NF-κB signaling is active in more than 50% of patients with pancreatic cancer and plays an important role in promoting the progression of pancreatic cancer. Revealing the activation mechanism of NF-κB signaling is important for the treatment of pancreatic cancer. In this study, the regulation of TNFα/NF-κB signaling by VRK2 (vaccinia-related kinase 2) was investigated. The levels of VRK2 protein were examined by immunohistochemistry (IHC). The functions of VRK2 in the progression of pancreatic cancer were examined using CCK8 assay, anchorage-independent assay, EdU assay and tumorigenesis assay. The regulation of VRK2 on the NF-κB signaling was investigated by immunoprecipitation and invitro kinase assay. It was discovered in this study that the expression of VRK2 was upregulated in pancreatic cancer and that the VRK2 expression level was significantly correlated with the pathological characteristics and the survival time of patients. VRK2 promoted the growth, sphere formation and subcutaneous tumorigenesis of pancreatic carcinoma cells as well as the organoid growth derived from the pancreatic cancer mouse model. Investigation of the molecular mechanism indicated that VRK2 interacts with IKKβ, phosphorylating its Ser177 and Ser181 residues and thus activating the TNFα/NF-κB signaling pathway. An IKKβ inhibitors abolished the promotive effect of VRK2 on the growth of organoids. The findings of this study indicate that VRK2 promotes the progression of pancreatic cancer by activating the TNFα/NF-κB signaling pathway, suggesting that VRK2 is a potential therapeutic target for pancreatic cancer.
NF-κB 信号在超过 50%的胰腺癌患者中活跃，并在促进胰腺癌的进展中发挥重要作用。揭示 NF-κB 信号的激活机制对于胰腺癌的治疗至关重要。在这项研究中，研究了 VRK2（牛痘相关激酶 2）对 TNFα/NF-κB 信号的调节。通过免疫组织化学（IHC）检查 VRK2 蛋白水平。使用 CCK8 测定、非依赖性附着测定、EdU 测定和肿瘤发生测定来检查 VRK2 在胰腺癌进展中的功能。通过免疫沉淀和体外激酶测定研究了 VRK2 对 NF-κB 信号的调节。本研究发现，VRK2 在胰腺癌中的表达上调，并且 VRK2 表达水平与患者的病理特征和生存时间显著相关。VRK2 促进了胰腺癌细胞的生长、球体形成和皮下肿瘤生成，以及源自胰腺癌小鼠模型的类器官生长。分子机制研究表明，VRK2 与 IKKβ 相互作用，磷酸化其 Ser177 和 Ser181 残基，从而激活 TNFα/NF-κB 信号通路。IKKβ 抑制剂消除了 VRK2 对类器官生长的促进作用。这项研究的结果表明，VRK2 通过激活 TNFα/NF-κB 信号通路促进胰腺癌的进展，表明 VRK2 是胰腺癌的潜在治疗靶点。
