Journal of chemotherapy (Florence, Italy) · 2025
E2F1-induced transcriptional activation of MAL2 inhibits sunitinib sensitivity and promotes the malignant progression of bladder cancer.
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Su Mingqiang, Chen Wei, Luo Jingxian, Li Xianyong, Ye Dayong, Han DengJun, Fu Guangqing
Аннотация
BACKGROUND: Mal, T cell differentiation protein 2 (MAL2) has emerged as a potential regulator in the progression of bladder cancer (BCa). Therapeutic resistance to sunitinib poses a significant challenge in BCa treatment. This study investigates the role of MAL2 in modulating BCa malignant development and its influence on sunitinib sensitivity.
METHODS: The mRNA levels of MAL2 and E2F transcription factor 1 (E2F1) were analyzed by quantitative real-time polymerase chain reaction, whereas their protein expression was detected by western blotting. Cell proliferation was analyzed by 5-Ethynyl-2'-deoxyuridine assay. Cell apoptotic rate was quantified by flow cytometry. Cell migration and invasion were analyzed through transwell assays. The sensitivity of BCa cells to sunitinib was analyzed by cell counting kit-8 assay. Fe2+ and malondialdehyde levels were analyzed through colorimetric assays. Reactive oxygen species levels were analyzed through fluorometric assay. The molecular interactions between E2F1 and MAL2 were explored using chromatin immunoprecipitation and dual-luciferase reporter assays. The in vitro findings regarding the effects of E2F1 and MAL2 on the malignant progression of BCa cells were further corroborated in vivo using xenograft mouse models.
RESULTS: The expression of MAL2 was elevated in both BCa tissues and cells. Silencing MAL2 expression led to a suppression of BCa cell proliferation, migration, and invasion, while simultaneously enhancing cell apoptosis and ferroptosis, and increasing sensitivity to sunitinib. E2F1 was identified as a transcriptional activator of MAL2 in T24 and J82 BCa cells, and its overexpression fostered the malignant progression of BCa cells and reduced their responsiveness to sunitinib. Additionally, the adverse effects of E2F1 silencing on BCa cell behavior were mitigated by the overexpression of MAL2 in vitro and in vivo.
CONCLUSION: E2F1-induced transcriptional activation of MAL2 promoted the progression of BCa and inhibited sunitinib sensitivity, offering a potential novel therapeutic approach for BCa patients.
METHODS: The mRNA levels of MAL2 and E2F transcription factor 1 (E2F1) were analyzed by quantitative real-time polymerase chain reaction, whereas their protein expression was detected by western blotting. Cell proliferation was analyzed by 5-Ethynyl-2'-deoxyuridine assay. Cell apoptotic rate was quantified by flow cytometry. Cell migration and invasion were analyzed through transwell assays. The sensitivity of BCa cells to sunitinib was analyzed by cell counting kit-8 assay. Fe2+ and malondialdehyde levels were analyzed through colorimetric assays. Reactive oxygen species levels were analyzed through fluorometric assay. The molecular interactions between E2F1 and MAL2 were explored using chromatin immunoprecipitation and dual-luciferase reporter assays. The in vitro findings regarding the effects of E2F1 and MAL2 on the malignant progression of BCa cells were further corroborated in vivo using xenograft mouse models.
RESULTS: The expression of MAL2 was elevated in both BCa tissues and cells. Silencing MAL2 expression led to a suppression of BCa cell proliferation, migration, and invasion, while simultaneously enhancing cell apoptosis and ferroptosis, and increasing sensitivity to sunitinib. E2F1 was identified as a transcriptional activator of MAL2 in T24 and J82 BCa cells, and its overexpression fostered the malignant progression of BCa cells and reduced their responsiveness to sunitinib. Additionally, the adverse effects of E2F1 silencing on BCa cell behavior were mitigated by the overexpression of MAL2 in vitro and in vivo.
CONCLUSION: E2F1-induced transcriptional activation of MAL2 promoted the progression of BCa and inhibited sunitinib sensitivity, offering a potential novel therapeutic approach for BCa patients.