Zhang Peng, Wang Su, Chen Yuanyuan, Yang Qingbo, Zhou Jian, Zang Wangfu
Department of Cardio-Thoracic Surgery, Shanghai Tenth People's Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, China.
Department of Cardio-Thoracic Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai 200072, China.
Open Med (Wars). 2024 Jan 10;19(1):20230882. doi: 10.1515/med-2023-0882. eCollection 2024.
Overexpression of methyltransferase-like 3 (METTL3) is significantly correlated with the malignancy of lung cancer (LC). In the present study, we demonstrated that METTL3 had higher levels in LC tissues relative to normal tissues. METTL3 showed superior sensitivity and specificity for diagnosis and identification of LC functions. In addition, silencing METTL3 resulted in enhanced ferroptosis sensitivity, whereas overexpression of METTL3 exhibited the opposite effect. Inhibition of METTL3 impeded LC growth in cell-derived xenografts. Further exploratory studies found that METTL3 stimulated the low expression of transferrin receptor (TFRC), which was critical for ferroptosis sensitization in LC cells induced by silenced METTL3, as silencing of TFRC caused a decrease in negative regulators of ferroptosis (FTH1 and FTL) in METTL3 knockdown A549 and PC9 cells. Finally, we confirmed that METTL3 attenuation effectively maintained the stability of TFRC mRNA. In conclusion, we reported a novel mechanism of METTL3 desensitization to ferroptosis via regulating TFRC, and an appropriate reduction of METTL3 might sensitize cancer cells to ferroptosis-based therapy.
甲基转移酶样 3（METTL3）的过表达与肺癌（LC）的恶性程度显著相关。在本研究中，我们证明相对于正常组织，METTL3 在 LC 组织中的水平更高。METTL3 在 LC 功能的诊断和识别方面表现出卓越的敏感性和特异性。此外，沉默 METTL3 导致铁死亡敏感性增强，而 METTL3 的过表达则表现出相反的效果。抑制 METTL3 阻碍了细胞来源异种移植瘤中 LC 的生长。进一步的探索性研究发现，METTL3 刺激转铁蛋白受体（TFRC）的低表达，这对于沉默 METTL3 诱导的 LC 细胞中铁死亡致敏至关重要，因为沉默 TFRC 会导致 METTL3 敲低的 A549 和 PC9 细胞中铁死亡负调节因子（FTH1 和 FTL）减少。最后，我们证实 METTL3 的减弱有效地维持了 TFRC mRNA 的稳定性。总之，我们报道了一种 METTL3 通过调节 TFRC 对铁死亡脱敏的新机制，适当降低 METTL3 可能会使癌细胞对基于铁死亡的治疗敏感。
