E2F1-induced transcriptional activation of MAL2 inhibits sunitinib sensitivity and promotes the malignant progression of bladder cancer.

IF 1.8 4区医学 Q3 INFECTIOUS DISEASES

Journal of Chemotherapy Pub Date : 2025-09-26 DOI:10.1080/1120009X.2025.2561275

Mingqiang Su, Wei Chen, Jingxian Luo, Xianyong Li, Dayong Ye, DengJun Han, Guangqing Fu

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引用次数: 0

Abstract

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.

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e2f1诱导MAL2转录激活抑制舒尼替尼敏感性，促进膀胱癌恶性进展。

背景：T细胞分化蛋白2 （MAL2）已成为膀胱癌（BCa）进展的潜在调节因子。对舒尼替尼的治疗耐药性对BCa治疗提出了重大挑战。本研究探讨MAL2在调节BCa恶性发展中的作用及其对舒尼替尼敏感性的影响。方法：采用实时荧光定量聚合酶链式反应分析MAL2和E2F转录因子1 (E2F1) mRNA表达水平，western blotting检测其蛋白表达。用5-乙基-2′-脱氧尿苷法分析细胞增殖情况。流式细胞术测定细胞凋亡率。transwell法分析细胞迁移和侵袭。采用细胞计数试剂盒-8法分析BCa细胞对舒尼替尼的敏感性。通过比色法分析Fe2+和丙二醛水平。通过荧光法分析活性氧水平。利用染色质免疫沉淀法和双荧光素酶报告基因法研究了E2F1和MAL2之间的分子相互作用。E2F1和MAL2对BCa细胞恶性进展影响的体外研究结果在体内异种移植小鼠模型中得到进一步证实。结果：MAL2在BCa组织和细胞中的表达均升高。沉默MAL2表达可抑制BCa细胞的增殖、迁移和侵袭，同时增强细胞凋亡和铁凋亡，增加对舒尼替尼的敏感性。E2F1在T24和J82 BCa细胞中被鉴定为MAL2的转录激活因子，其过表达促进了BCa细胞的恶性进展，降低了它们对舒尼替尼的反应性。此外，体外和体内MAL2的过表达可以减轻E2F1沉默对BCa细胞行为的不良影响。结论：e2f1诱导的MAL2转录激活促进BCa的进展，抑制舒尼替尼的敏感性，为BCa患者提供了一种潜在的新型治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Chemotherapy 医学-药学

CiteScore

3.70

自引率

0.00%

发文量

144

审稿时长

6-12 weeks

期刊介绍： The Journal of Chemotherapy is an international multidisciplinary journal committed to the rapid publication of high quality, peer-reviewed, original research on all aspects of antimicrobial and antitumor chemotherapy. The Journal publishes original experimental and clinical research articles, state-of-the-art reviews, brief communications and letters on all aspects of chemotherapy, providing coverage of the pathogenesis, diagnosis, treatment, and control of infection, as well as the use of anticancer and immunomodulating drugs. Specific areas of focus include, but are not limited to: · Antibacterial, antiviral, antifungal, antiparasitic, and antiprotozoal agents; · Anticancer classical and targeted chemotherapeutic agents, biological agents, hormonal drugs, immunomodulatory drugs, cell therapy and gene therapy; · Pharmacokinetic and pharmacodynamic properties of antimicrobial and anticancer agents; · The efficacy, safety and toxicology profiles of antimicrobial and anticancer drugs; · Drug interactions in single or combined applications; · Drug resistance to antimicrobial and anticancer drugs; · Research and development of novel antimicrobial and anticancer drugs, including preclinical, translational and clinical research; · Biomarkers of sensitivity and/or resistance for antimicrobial and anticancer drugs; · Pharmacogenetics and pharmacogenomics; · Precision medicine in infectious disease therapy and in cancer therapy; · Pharmacoeconomics of antimicrobial and anticancer therapies and the implications to patients, health services, and the pharmaceutical industry.