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Kidney renal clear cell carcinoma (KIRC), as one of the most angiogenically active urological tumors, has not yet been fully elucidated its molecular mechanisms. Molecules interacting with CasL-Like 2 (MICAL-L2), a unique oxidoreductase, is known to be involved in cytoskeletal regulation. However, its role and mechanism in tumor angiogenesis remain unclear. This study aims to reveal the specific mechanism by which MICAL-L2 regulates KIRC angiogenesis through cytoskeletal dynamics and to explore its clinical translational value and significance. Bioinformatics database analysis showed that MICAL-L2 was significantly overexpressed in various solid tumors and was closely associated with shorter overall survival in KIRC patients. Gene set enrichment analysis demonstrated that MICAL-L2 expression was significantly correlated with members of the hypoxia-inducible factor (HIF) family and was closely related to angiogenesis pathways. Analysis of human KIRC cell lines revealed that the upregulation of MICAL-L2 stimulated the release of various pro-angiogenic cytokines, primarily through the activation of a novel mTOR/HIF1α/VEGF pathway, promoting tumor angiogenesis. Further studies using cultured KIRC cell lines unveiled that MICAL-L2 co-localized with F-actin in the cytoplasm and promoted tumor angiogenesis remodeling in vitro. Additionally, analysis of clinical datasets indicated that high expression of MICAL-L2 was associated with drug resistance to various anti-angiogenic agents and actin inhibitors in cancer. This study reveals a new mechanism in which MICAL-L2, under the tumor hypoxic environment, promotes KIRC angiogenesis and progression by activating the "cytoskeletal remodeling-mTOR/HIF1α/VEGF signaling pathway" using integrated analysis of clinical samples and cell models, providing new theoretical evidence and potential intervention targets for the development of combination therapies targeting the tumor microenvironment.