文章：

长期严重缺氧适应诱导非经典上皮-间质转化（EMT）及一种新型Wilms瘤1（WT1）异构体

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform 

原文发布日期：2024-07-08 

英文摘要：

The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases. Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol, termed the Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual development of severe hypoxia seen in vivo to mimic conditions observed in primary tumors. Cells subjected to LTHY underwent a non-canonical epithelial to mesenchymal transition (EMT) based on miRNA and mRNA signatures as well as displayed EMT-like morphological changes. Concomitant to this, we report production of a novel truncated isoform of WT1 transcription factor (tWt1), a non-canonical EMT driver, with expression driven by a yet undescribed intronic promoter through hypoxia-responsive elements (HREs). We further demonstrated that tWt1 initiates translation from an intron-derived start codon, retains proper subcellular localization and DNA binding. A similar tWt1 is also expressed in LTHY-cultured human cancer cell lines as well as primary cancers and predicts long-term patient survival. Our study not only demonstrates the importance of culture conditions that better mimic those observed in primary cancers, especially with regards to hypoxia, but also identifies a novel isoform of WT1 which correlates with poor long-term survival in ovarian cancer. 

摘要翻译：

大多数癌症死亡由实体瘤引起，其中四种最常见癌症（乳腺癌、肺癌、结直肠癌和前列腺癌）占比超过总病例的60%。由缺氧等可变癌症微环境驱动的肿瘤细胞异质性是治疗结果的关键决定因素。我们开发了一种称为"长期缺氧（LTHY）时序"的新型培养方案，通过重现体内严重缺氧的渐进发展过程来模拟原发性肿瘤的观测条件。经历LTHY培养的细胞基于miRNA和mRNA特征发生了非经典上皮-间质转化（EMT），并表现出EMT样形态变化。与此同时，我们发现了一种新型WT1转录因子截短亚型（tWt1）——一种非经典EMT驱动因子，其表达由尚未描述的内含子启动子通过缺氧响应元件（HREs）驱动。我们进一步证明tWt1从内含子衍生的起始密码子开始翻译，并保持正确的亚细胞定位和DNA结合能力。类似的tWt1在LTHY培养的人类癌细胞系和原发性癌症中均有表达，且可预测患者长期生存率。我们的研究不仅证明了培养条件更好模拟原发性癌症（特别是在缺氧方面）的重要性，还鉴定出一种与卵巢癌患者长期生存率较差相关的新型WT1亚型。

原文链接：

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform