Center for Childhood Cancer Research, The Abigail Wexner Research Institute, Nationwide Children's Hospital, 575 Children's Crossroad, Columbus, OH, 43215, USA.
Department of Molecular Genetics, The Ohio State University, Columbus, OH, 43210, USA.
Sci Rep. 2024 Sep 5;14(1):20773. doi: 10.1038/s41598-024-71227-3.
The study of cooperating genes in cancer can lead to mechanistic understanding and identifying potential therapeutic targets. To facilitate these types of studies, we developed a new dual-inducible system utilizing the tetracycline- and cumate-inducible systems driving HES3 and the PAX3::FOXO1 fusion-oncogene, respectively, as cooperating genes from fusion-positive rhabdomyosarcoma. With this model, we can independently induce expression of either HES3 or PAX3::FOXO1, as well as simultaneously induce expression of both genes. This new model will allow us to further investigate the cooperation between HES3 and PAX3::FOXO1 including the temporal requirements for genetic cooperation. Functionally, we show that dual-induction of PAX3::FOXO1 and HES3 modifies sphere formation in a HEK293T-based system. More broadly, this lentiviral dual-inducible system can be adapted for any cooperating genes (overexpression or knockdown), allowing for independent, simultaneous, or temporally controlled gene expression.
研究癌症中的合作基因可以帮助我们深入了解癌症的发生机制，并确定潜在的治疗靶点。为了促进这类研究，我们开发了一种新的双诱导系统，该系统利用四环素和棒曲霉素诱导系统分别驱动 HES3 和 PAX3::FOXO1 融合癌基因，这些基因均来自融合阳性横纹肌肉瘤。利用该模型，我们可以分别独立诱导 HES3 或 PAX3::FOXO1 的表达，也可以同时诱导这两个基因的表达。这个新模型将使我们能够进一步研究 HES3 和 PAX3::FOXO1 之间的合作关系，包括遗传合作的时间要求。从功能上看，我们发现 PAX3::FOXO1 和 HES3 的双重诱导改变了基于 HEK293T 的系统中的球体形成。更广泛地说，这种慢病毒双诱导系统可以适用于任何合作基因（过表达或敲低），从而实现独立、同时或时间控制的基因表达。
