VRK2 activates TNFa/NF-KB signaling by phosphorylating IKKss in pancreatic cancer

NF-KB 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-KB signaling is important for the treatment of pancreatic cancer. In this study, the regulation of TNFa/NF-KB 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-KB 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 IKKss, phosphorylating its Ser177 and Ser181 residues and thus activating the TNFa/NF-KB signaling pathway. An IKKss 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 TNFa/NF-KB signaling pathway, suggesting that VRK2 is a potential therapeutic target for pancreatic cancer.

Automated summary

NF-KB signaling is active in pancreatic cancer and plays a crucial role in its progression. This study demonstrates that VRK2 regulates TNFa/NF-KB signaling by interacting with IKKss and activating the pathway. VRK2 overexpression promotes the growth of pancreatic cancer cells and organoids. Inhibition of IKKss abolishes the promotive effect of VRK2. These findings suggest that VRK2 may serve as a potential therapeutic target for pancreatic cancer.