Abstract：
P53 and DNA damage-regulated gene1 (PDRG1) is overexpressed in diverse carcinomas. Here, we discover that PDRG1 is overexpressed in glioblastoma multiforme (GBM). However, the clinical significance, biological role, and underlying molecular mechanisms of PDRG1 in GBM remain unclear. PDRG1 was aberrantly overexpressed in glioma, especially prevalent in GBM, and correlated with poor clinicopathologic features of glioma. The risk score, operational feature curve analysis, Kaplan-Meier curve, and univariate and multivariate Cox regression analysis indicated that PDRG1 was an independent prognostic indicator and significantly correlates with disease progression of glioma. A prognostic nomogram was constructed to predict the survival risk of individual patients. The function and pathway enrichment analysis of PDRG1 in The Cancer Genome Atlas cohort was performed. PDRG1 knockdown significantly inhibited the migration and proliferation of GBM cells in vitro and in vivo. Transcriptome sequencing analysis of PDRG1 knockdown U-118 MG(U118) cells indicated that biological regulation adhesion, growth and death, cell motility, cell adhesion molecular and proteoglycans in cancer were significantly enriched. Importantly, we found that the expression of adhesion molecule cluster of differentiation 44 (CD44) was regulated by PDRG1 in GBM. We found that PDRG1 promoted the migration and proliferation of GBM cells via the mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinase (ERK)/CD44 pathway. Our findings provide proof that PDRG1 upregulation predicts progression and poor prognosis in human gliomas, especially in isocitrate dehydrogenase (IDH) wt glioma patients. The study provides new evidence that PDRG1 regulates the expression of CD44 in GBM cells and might promote the migration and proliferation via the MEK/ERK/CD44pathway. PDRG1 might be a novel diagnostic indicator and promising therapeutic target for GBM.
摘要：
P53和DNA损伤调节基因1（PDRG1）在多种癌中过表达。这里,我们发现PDRG1在多形性胶质母细胞瘤（GBM）中过度表达。然而,临床意义，生物学作用,PDRG1在GBM中的潜在分子机制仍不清楚。PDRG1在胶质瘤中异常过度表达，特别是在GBM中普遍存在，并与胶质瘤的不良临床病理特征相关。风险评分，运行特征曲线分析,卡普兰-迈耶曲线,单因素和多因素Cox回归分析显示，PDRG1是一个独立的预后指标，与胶质瘤的疾病进展显著相关。构建预后列线图以预测个体患者的生存风险。在癌症基因组图谱队列中进行PDRG1的功能和途径富集分析。PDRG1敲低可显著抑制GBM细胞的体内外迁移和增殖。PDRG1敲低U-118MG(U118)细胞的转录组测序分析表明,成长与死亡,细胞运动性,细胞黏附分子和蛋白聚糖在癌症中显著富集。重要的是,我们发现GBM中PDRG1的表达受分化粘附分子簇44（CD44）的调控。我们发现PDRG1通过丝裂原活化蛋白激酶激酶（MEK）/细胞外调节蛋白激酶（ERK）/CD44途径促进GBM细胞的迁移和增殖。我们的研究结果证明，PDRG1上调可预测人脑胶质瘤的进展和不良预后。特别是在异柠檬酸脱氢酶（IDH）wt胶质瘤患者中。该研究为PDRG1调控GBM细胞CD44的表达提供了新的证据，并可能通过MEK/ERK/CD44途径促进细胞的迁移和增殖。PDRG1可能是一种新的GBM诊断指标和有希望的治疗靶点。
