Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, 20057, USA.
Basic and Mechanistic Research Branch, Division of Extramural Research, National Center for Complementary and Integrative Health (NCCAIH), NIH, Bethesda, MD, 20892, USA.
Cell Death Differ. 2020 Jul;27(7):2263-2279. doi: 10.1038/s41418-020-0502-7. Epub 2020 Feb 7.
The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.
胸腺瘤（TET）的发病机制尚未完全阐明。最近，我们报道了 GTF2I 基因在 TET 中经常发生错义突变，并假设 GTF2I 突变可能导致胸腺瘤的发生。突变 TFII-I 的表达改变了正常胸腺上皮细胞的转录组，并上调了几个致癌基因。Gtf2i L424H 敲入细胞表现出细胞转化、非整倍体和在葡萄糖剥夺或 DNA 损伤下增加肿瘤生长和存活。Gtf2i 突变还增加了几个糖酵解酶、环氧化酶-2 的表达，并导致脂质代谢的改变。GTF2I 突变引起的环氧化酶-2 表达升高是代谢应激和胸腺瘤上皮细胞转化存活所必需的。我们的研究结果表明，GTF2I 突变是一种新的致癌驱动基因，负责胸腺瘤上皮细胞的转化。
