Abstract
Background: The SENEX gene, encoding the protein ARHGAP18, is thought to be involved in the development of various diseases. Previous studies have shown that the SENEX gene may trigger tumor cell senescence and is highly expressed in relapsed and refractory lymphoma. However, the mechanism of action of the SENEX gene in Burkitt's lymphoma remains unclear. Methods: We verified the effect of SENEX gene-induced cellular senescence on RAJI cell through a series of functional experiments, including senescence-associated-β-galactosidase(SA-β-Gal) staining, cell proliferation, apoptosis and Transwell assays. The effects of SENEX gene-triggered senescence on the expression levels of senescence-related proteins, EMT-related proteins and WNT/β-catenin signaling pathway star proteins were detected by Western blot experiments. In addition, we established an immunodefic ient mice model of subcutaneous xenografts to observe the effects of SENEX gene-triggered tumor cell senescencehe biological characteristics and survival of lymphoma in vivo. Results:Chemotherapy-induced SIPS significantly improves the SENEX gene and senescence-associated proteins, promoting resistance to apoptosis and leading to drug resistance. Through in vitro experiments, we found that SENEX gene-mediated SIPS affects the levels of senescence-associated proteins, enhances tumor cell apoptosis resistance, and increases tumor invasiveness via epithelial-mesenchymal transition (EMT) and the WNT/β-catenin pathway. In vivo experiments revealed that both chemotherapy-induced and SENEX gene-mediated SIPS promote malignant growth of mouse xenografts and reduce survival time. The mechanisms involve resistance to apoptosis through cellular senescence, tumor invasion and metastasis promotion via the WNT/β-catenin signaling pathway, and tumor progression through alterations in the tumor microenvironment. Conclusion: Our study reveals that the SENEX gene can regulate the apoptosis signaling pathway, stem cell signaling activation and reprogram the tumor microenvironment to promote tumorigenicity and invasiveness of Burkitt's lymphoma cells both in vitro and in vivo. The SENEX gene may be a potential therapeutic target for Burkitt's lymphoma.
Published Version
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