Yang Wei-Feng, Guo Wei-Ming, Luo Qing-Tian, Lu Jingfen, Tan Zhou-Ke, Ye Yuan-Chun, Fan Gang
Department of Urology, Qianhai Shekou Free Trade Zone Hospital, Shenzhen, China.
Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, Guangdong, China.
Cell Death Discov. 2025 Jul 3;11(1):303. doi: 10.1038/s41420-025-02585-8.
TMBIM6, a Ca channel-like protein, shows an increased expression in numerous types of cancer. However, no study has reported its role in bladder cancer. This study aimed to explore the roles and mechanisms of TMBIM6 in bladder cancer. TMBIM6, ferroptosis-related proteins (GPX4, SLC7A11, and FTH1), and calmodulin (CaM) expressions in bladder cancer and paracancerous tissues were obtained by immunohistochemistry. The bladder cells were overexpressed or silenced with TCF3/TMBIM6 with ferroptosis inducer (Erastin)/Ca blocker (BAPTA-AM) to investigate the effects on Ca-dependent ferroptosis and other functions. Finally, tumorigenicity was validated in nude mice. TMBIM6 and ferroptosis-related proteins were up-regulated in bladder cancer tissues, but CaM was downregulated. TMBIM6 overexpression enhanced proliferation, invasion, migration, GSH/GPX4 levels, and ferroptosis resistance while suppressing MDA, Fe²⁺, and lipid ROS in bladder cancer cells, effects reversed by Erastin. TCF3 was up-regulated in cancer and enriched in Ca and ferroptosis-related pathways. TCF3 directly interacted with TMBIM6 and transcriptionally activated TMBIM6 expression. Both TCF3 and TMBIM6 overexpression exhibited comparable effects in modulating ferroptosis and other cellular processes, whereas TMBIM6 knockdown effectively reversed these phenotypic alterations. In addition, silencing TCF3 upregulated Ca and CAM levels, while BAPTA-AM reversed these changes. In vivo, ov-TCF3 promoted tumor volume, weight, and TMBIM6 expression, and inhibited Ca concentration, while Erastin reversed these changes. Our findings demonstrate that TCF3 facilitates bladder cancer progression through the enhancement of TMBIM6-Ca-mediated ferroptosis resistance. Both TCF3 and TMBIM6 emerge as promising biomarkers and therapeutic targets for bladder cancer intervention.
TMBIM6是一种类钙通道蛋白，在多种癌症类型中表达增加。然而，尚无研究报道其在膀胱癌中的作用。本研究旨在探讨TMBIM6在膀胱癌中的作用及机制。通过免疫组织化学检测膀胱癌及癌旁组织中TMBIM6、铁死亡相关蛋白（GPX4、SLC7A11和FTH1）和钙调蛋白（CaM）的表达。用铁死亡诱导剂（埃拉斯汀）/钙阻滞剂（BAPTA-AM）对膀胱细胞进行TCF3/TMBIM6过表达或沉默，以研究其对钙依赖性铁死亡及其他功能的影响。最后，在裸鼠中验证致瘤性。TMBIM6和铁死亡相关蛋白在膀胱癌组织中上调，但CaM下调。TMBIM6过表达增强了膀胱癌细胞的增殖、侵袭、迁移、谷胱甘肽/谷胱甘肽过氧化物酶4水平和铁死亡抗性，同时抑制了丙二醛、铁离子和脂质活性氧，埃拉斯汀可逆转这些作用。TCF3在癌症中上调，并富集于钙和铁死亡相关途径。TCF3直接与TMBIM6相互作用，并转录激活TMBIM6的表达。TCF3和TMBIM6过表达在调节铁死亡和其他细胞过程中表现出相似的作用，而TMBIM6敲低有效地逆转了这些表型改变。此外，沉默TCF3可上调钙和钙调蛋白水平，而BAPTA-AM可逆转这些变化。在体内，过表达TCF3促进肿瘤体积、重量和TMBIM6表达，并抑制钙浓度，而埃拉斯汀可逆转这些变化。我们的研究结果表明，TCF3通过增强TMBIM6-钙介导的铁死亡抗性促进膀胱癌进展。TCF3和TMBIM6均有望成为膀胱癌干预的生物标志物和治疗靶点。
