Int J Biol Sci 2022; 18(3):1288-1302. doi:10.7150/ijbs.66313 This issue

Research Paper

VRK2 activates TNFα/NF-κB signaling by phosphorylating IKKβ in pancreatic cancer

Jionghuang Chen1, Kexiong Qiao1, Chaolei Zhang1, Xinyang Zhou1, Qian Du1, Yuezhen Deng2✉, Liping Cao1✉

1. Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2. Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.

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Citation:
Chen J, Qiao K, Zhang C, Zhou X, Du Q, Deng Y, Cao L. VRK2 activates TNFα/NF-κB signaling by phosphorylating IKKβ in pancreatic cancer. Int J Biol Sci 2022; 18(3):1288-1302. doi:10.7150/ijbs.66313. Available from https://www.ijbs.com/v18p1288.htm

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Abstract

Graphic abstract

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.

Keywords: Pancreatic cancer, VRK2, NF-κB signaling, Phosphorylation, Organoid