文章目录

小眼畸形相关转录因子参与胃肠道间质瘤的生长

The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth

原文发布日期：2022-10-14

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小眼畸形相关转录因子参与胃肠道间质瘤的生长

The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth

原文发布日期：2022-10-14

英文摘要：

Gastrointestinal stromal tumors (GISTs) are the most common neoplasms of mesenchymal origin, and most of them emerge due to the oncogenic activation of KIT or PDGFRA receptors. Despite their relevance in GIST oncogenesis, critical intermediates mediating the KIT/PDGFRA transforming program remain mostly unknown. Previously, we found that the adaptor molecule SH3BP2 was involved in GIST cell survival, likely due to the co-regulation of the expression of KIT and Microphthalmia-associated transcription factor (MITF). Remarkably, MITF reconstitution restored KIT expression levels in SH3BP2 silenced cells and restored cell viability. This study aimed to analyze MITF as a novel driver of KIT transforming program in GIST. Firstly, MITF isoforms were characterized in GIST cell lines and GIST patients’ samples. MITF silencing decreases cell viability and increases apoptosis in GIST cell lines irrespective of the type of KIT primary or secondary mutation. Additionally, MITF silencing leads to cell cycle arrest and impaired tumor growth in vivo. Interestingly, MITF silencing also affects ETV1 expression, a linage survival factor in GIST that promotes tumorigenesis and is directly regulated by KIT signaling. Altogether, these results point to MITF as a key target of KIT/PDGFRA oncogenic signaling for GIST survival and tumor growth.

摘要翻译：

胃肠道间质瘤（GIST）是间叶来源的最常见肿瘤，其发生多源于KIT或PDGFRA受体的致癌性激活。尽管这些受体在GIST肿瘤发生中具有重要作用，但介导KIT/PDGFRA转化程序的关键中间介质仍大多未知。我们先前发现衔接蛋白SH3BP2参与GIST细胞存活，这可能源于其对KIT与小眼畸形相关转录因子（MITF）表达的协同调控。值得注意的是，MITF的重表达可在SH3BP2沉默细胞中恢复KIT表达水平并挽救细胞活力。本研究旨在分析MITF作为GIST中KIT转化程序的新型驱动因子。首先，我们在GIST细胞系和患者样本中对MITF异构体进行了表征。MITF沉默可降低GIST细胞系活力并增加细胞凋亡，且不受KIT原发性或继发性突变类型的影响。此外，MITF沉默会导致细胞周期阻滞并削弱体内肿瘤生长。值得注意的是，MITF沉默还会影响ETV1表达——这是GIST中促进肿瘤发生且受KIT信号直接调控的谱系生存因子。这些结果共同表明，MITF是KIT/PDGFRA致癌信号促进GIST存活和肿瘤生长的关键靶点。