Wei Huifang, Zhao Dengyun, Zhi Yafei, Wu Qiong, Ma Jing, Xu Jialuo, Liu Tingting, Zhang Jing, Wang Penglei, Hu Yamei, He Xinyu, Guo Fangqin, Jiang Ming, Zhang Dandan, Nie Wenna, Yang Ran, Zhao Tongjin, Dong Zigang, Liu Kangdong
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, China-US (Henan) Hormel Cancer Institute, Chest Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Adv Sci (Weinh). 2025 Feb;12(8):e2406220. doi: 10.1002/advs.202406220. Epub 2025 Jan 5.
Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of esophageal cancer cases. The lack of effective therapeutic targets makes it difficult to improve the overall survival of patients with ESCC. Reticulon 4 Interacting Protein 1 (RTN4IP1) is a novel mitochondrial oxidoreductase. Here, a notable upregulation of RTN4IP1 is demonstrated, which is associated with poor survival in patients with ESCC. RTN4IP1 depletion impairs cell proliferation and induces apoptosis of ESCC cells. Furthermore, c-Myc regulates RTN4IP1 expression via iron regulatory protein 2 (IRP2) at the post-transcriptional level. Mechanistically, RTN4IP1 mRNA harbors functional iron-responsive elements (IREs) in the 3' UTR, which can be targeted by IRP2, resulting in increased mRNA stability. Finally, RTN4IP1 depletion abrogates amino acid uptake and induces amino acid starvation via downregulation of the amino acid transporters SLC1A5, SLC3A2, and SLC7A5, indicating a possible pathway through which RTN4IP1 contributes to ESCC carcinogenesis and progression. In vivo studies using cell-derived xenograft and patient-derived xenograft mouse models as well as a 4-nitroquinoline 1-oxide-induced ESCC model in esophageal-specific Rtn4ip1 knockout mice demonstrate the essential role of RTN4IP1 in ESCC development. Thus, RTN4IP1 emerges as a key cancer-promoting protein in ESCC, suggesting therapeutic RTN4IP1 suppression as a promising strategy for ESCC treatment.
食管鳞状细胞癌（ESCC）约占食管癌病例的90%。缺乏有效的治疗靶点使得提高ESCC患者的总生存率变得困难。网状蛋白4相互作用蛋白1（RTN4IP1）是一种新型的线粒体氧化还原酶。在此，研究表明RTN4IP1显著上调，这与ESCC患者的不良生存相关。RTN4IP1缺失会损害细胞增殖并诱导ESCC细胞凋亡。此外，c-Myc在转录后水平通过铁调节蛋白2（IRP2）调节RTN4IP1的表达。机制上，RTN4IP1 mRNA在3'UTR中含有功能性铁反应元件（IREs），可被IRP2靶向，从而导致mRNA稳定性增加。最后，RTN4IP1缺失通过下调氨基酸转运蛋白SLC1A5、SLC3A2和SLC7A5消除氨基酸摄取并诱导氨基酸饥饿，这表明RTN4IP1促进ESCC发生和进展的可能途径。使用细胞来源的异种移植和患者来源的异种移植小鼠模型以及食管特异性Rtn4ip1基因敲除小鼠中的4-硝基喹啉1-氧化物诱导的ESCC模型进行的体内研究证明了RTN4IP1在ESCC发展中的重要作用。因此，RTN4IP1成为ESCC中一种关键的促癌蛋白，提示抑制RTN4IP1作为ESCC治疗的一种有前景的策略。
