VRK2 promotes colorectal cancer growth and impedes immunotherapy and 5-FU treatment efficacy.

Vaccinia-Related Kinase 2 (VRK2), a member of the vaccinia virus-related protein kinase family, is crucial in regulating apoptosis and tumor cell growth signaling pathways. Despite its established roles in various cancers, investigations into its functions in colorectal cancer have been relatively limited. Utilizing The Cancer Genome Atlas and Genotype-Tissue Expression databases, this study assesses VRK2 expression across 33 cancer types, highlighting significant upregulation and diagnostic relevance, particularly in colorectal cancer, where it marks poor prognosis. VRK2's influence extends across multiple cancer-related signaling pathways, with focused experiments confirming its vital role in the E2F signaling pathway through transcriptomic sequencing and dual-luciferase reporter assays. Deletion of VRK2 markedly inhibits proliferation, cell cycle progression, migration, and tumorigenesis in colorectal cancer cells, whereas overexpression enhances these oncogenic traits. Additionally, VRK2 expression correlates with genomic instability and the tumor microenvironment, influencing antitumor immunity and response to immunotherapy. Importantly, our analysis reveals that VRK2 modulates the chemosensitivity of tumor cells, specifically enhancing resistance to the chemotherapeutic agent 5-FU. These findings underscore VRK2's multifaceted role in promoting colorectal cancer development and suggest its potential as a therapeutic target.