Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Medical & Biological Computing Laboratory, School of Bio-Sciences & Technology, Vellore Institute of Technology, Vellore, India.
J Med Virol. 2023 Jun;95(6):e28856. doi: 10.1002/jmv.28856.
NFX1-123 is a splice variant isoform of the NFX1 gene. It is highly expressed in cervical cancers caused by HPV, and NFX1-123 is a protein partner with the HPV oncoprotein E6. Together, NFX1-123 and E6 affect cellular growth, longevity, and differentiation. The expression status of NFX1-123 in cancers beyond cervical and head and neck cancers, and its potential as therapeutic target, have not been investigated. TSVdb of TCGA was used to quantify NFX1-123 expression in 24 cancers compared with normal tissues. The NFX1-123 protein structure was predicted and then submitted to retrieve suitable drug molecules. The top four compounds, found to bind in silico to NFX1-123, were tested experimentally to determine their effects on NFX1-123-related cellular growth, survival, and migration. 46% of cancers (11 of 24 had significant differences in NFX1-123 expression, with nine having had greater NFX1-123 expression, when compared with adjacent normal tissues. Bioinformatics and proteomic predictive analysis modeled the three-dimensional structure of NFX1-123, and drug libraries were screened for high-binding affinity compounds using this modeled structure. Seventeen drugs with binding energies ranging from -1.3 to -10 Kcal/mol were identified. The top four compounds were used to treat HPV- and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1-123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1-123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1-123 a potential novel therapeutic target.
NFX1-123 是 NFX1 基因的剪接变异体同工型。它在 HPV 引起的宫颈癌中高度表达，NFX1-123 是 HPV 癌蛋白 E6 的蛋白伴侣。NFX1-123 和 E6 一起影响细胞生长、寿命和分化。NFX1-123 在宫颈癌以外的癌症中的表达状态及其作为治疗靶点的潜力尚未被研究。TCGA 的 TSVdb 用于定量比较 24 种癌症与正常组织中的 NFX1-123 表达。预测了 NFX1-123 蛋白结构，然后提交以检索合适的药物分子。在计算机上发现与 NFX1-123 结合的前四种化合物进行了实验测试，以确定它们对 NFX1-123 相关细胞生长、存活和迁移的影响。在 24 种癌症中，有 46%（11 种）的 NFX1-123 表达存在显著差异，与相邻正常组织相比，有 9 种癌症的 NFX1-123 表达更高。生物信息学和蛋白质组学预测分析对 NFX1-123 的三维结构进行建模，并使用该建模结构对药物库进行筛选，以寻找具有高结合亲和力的化合物。鉴定出 17 种结合能范围为-1.3 至-10 Kcal/mol 的药物。前四种化合物用于治疗 HPV-和 HPV+宫颈癌细胞系，其中三种（Ropitoin、R428 和酮康唑）降低了 NFX1-123 蛋白水平，抑制了细胞生长、存活和迁移，并增强了顺铂的细胞毒性。这些发现强调了表达高水平 NFX1-123 的癌症，以及针对它的药物，可能会降低细胞生长、存活和迁移，使 NFX1-123 成为一个潜在的新的治疗靶点。
