Li Kang, Yi Yuxuan, Ling Rongsong, Zhang Caihua, Zhang Zhihui, Wang Yue, Wang Ganping, Chen Jie, Cheng Maosheng, Chen Shuang
Otorhinolaryngology Hospital, Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Clin Transl Med. 2025 Apr;15(4):e70286. doi: 10.1002/ctm2.70286.
Oesophageal squamous cell carcinoma (OSCC) represents a highly aggressive malignancy with limited therapeutic options and poor prognosis. This study uncovers PCIF1 as a critical driver of OSCC progression via m6Am RNA modification, leading to translational repression of the tumour suppressor MTF2. Our results demonstrate that PCIF1 selectively suppresses MTF2 translation, activating oncogenic pathways that promote OSCC growth. In vitro and in vivo models confirm that PCIF1 knockdown reduces OSCC progression, whereas MTF2 knockdown counteracts this effect, highlighting the importance of the PCIF1-MTF2 axis. Clinical analyses further reveal that high PCIF1 expression and low MTF2 expression correlate with advanced tumour stage, poor treatment response and decreased overall survival. Furthermore, in a preclinical mouse model, PCIF1 knockout enhanced the efficacy of anti-PD1 immunotherapy, reducing tumour burden and improving histological outcomes. Notably, flow cytometry analysis indicated that PCIF1 primarily exerts its effects through tumour-intrinsic mechanisms rather than direct modulation of the immune microenvironment, distinguishing its mode of action from PD1 blockade. These findings establish PCIF1 and MTF2 as promising prognostic markers and therapeutic targets for OSCC, offering new avenues for treatment strategies and patient stratification. KEY POINTS: PCIF1 promotes OSCC progression via m6Am methylation at the MTF2 mRNA 5' cap. m6Am methylation suppresses MTF2 translation, enhancing tumour cell proliferation and invasion. Targeting PCIF1 holds therapeutic potential for OSCC treatment.
食管鳞状细胞癌（OSCC）是一种侵袭性很强的恶性肿瘤，治疗选择有限且预后较差。本研究发现PCIF1是OSCC进展的关键驱动因子，它通过m6Am RNA修饰导致肿瘤抑制因子MTF2的翻译抑制。我们的结果表明，PCIF1选择性抑制MTF2的翻译，激活促进OSCC生长的致癌途径。体外和体内模型证实，敲低PCIF1可降低OSCC的进展，而敲低MTF2可抵消这种作用，突出了PCIF1-MTF2轴的重要性。临床分析进一步显示，PCIF1高表达和MTF2低表达与肿瘤晚期、治疗反应差和总生存期降低相关。此外，在临床前小鼠模型中，敲除PCIF1可增强抗PD1免疫治疗的疗效，减轻肿瘤负担并改善组织学结果。值得注意的是，流式细胞术分析表明，PCIF1主要通过肿瘤内在机制发挥作用，而非直接调节免疫微环境，这使其作用模式有别于PD1阻断。这些发现确立了PCIF1和MTF2作为OSCC有前景的预后标志物和治疗靶点，为治疗策略和患者分层提供了新途径。要点：PCIF1通过在MTF2 mRNA 5'帽处进行m6Am甲基化促进OSCC进展。m6Am甲基化抑制MTF2翻译，增强肿瘤细胞增殖和侵袭。靶向PCIF1对OSCC治疗具有潜在治疗价值。
