Sareddy Gangadhara R, Pratap Uday P, Viswanadhapalli Suryavathi, Venkata Prabhakar Pitta, Nair Binoj C, Krishnan Samaya Rajeshwari, Zheng Siyuan, Gilbert Andrea R, Brenner Andrew J, Brann Darrell W, Vadlamudi Ratna K
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
Neurooncol Adv. 2019 May-Dec;1(1):vdz042. doi: 10.1093/noajnl/vdz042. Epub 2019 Nov 5.
Glioblastoma (GBM) is a deadly neoplasm of the central nervous system. The molecular mechanisms and players that contribute to GBM development is incompletely understood.
The expression of PELP1 in different grades of glioma and normal brain tissues was analyzed using immunohistochemistry on a tumor tissue array. PELP1 expression in established and primary GBM cell lines was analyzed by Western blotting. The effect of PELP1 knockdown was studied using cell proliferation, colony formation, migration, and invasion assays. Mechanistic studies were conducted using RNA-seq, RT-qPCR, immunoprecipitation, reporter gene assays, and signaling analysis. Mouse orthotopic models were used for preclinical evaluation of PELP1 knock down.
Nuclear receptor coregulator PELP1 is highly expressed in gliomas compared to normal brain tissues, with the highest expression in GBM. PELP1 expression was elevated in established and patient-derived GBM cell lines compared to normal astrocytes. Knockdown of PELP1 resulted in a significant decrease in cell viability, survival, migration, and invasion. Global RNA-sequencing studies demonstrated that PELP1 knockdown significantly reduced the expression of genes involved in the Wnt/β-catenin pathway. Mechanistic studies demonstrated that PELP1 interacts with and functions as a coactivator of β-catenin. Knockdown of PELP1 resulted in a significant increase in survival of mice implanted with U87 and GBM PDX models.
PELP1 expression is upregulated in GBM and PELP1 signaling via β-catenin axis contributes to GBM progression. Thus, PELP1 could be a potential target for the development of therapeutic intervention in GBM.
胶质母细胞瘤（GBM）是一种致命的中枢神经系统肿瘤。导致GBM发生发展的分子机制及相关因素尚未完全明确。
利用肿瘤组织芯片免疫组化分析不同级别胶质瘤和正常脑组织中PELP1的表达。通过蛋白质免疫印迹法分析已建立的和原发性GBM细胞系中PELP1的表达。采用细胞增殖、集落形成、迁移和侵袭实验研究PELP1基因敲低的作用。利用RNA测序、逆转录定量聚合酶链反应、免疫沉淀、报告基因检测和信号分析进行机制研究。使用小鼠原位模型对PELP1基因敲低进行临床前评估。
与正常脑组织相比，核受体辅调节因子PELP1在胶质瘤中高表达，在GBM中表达最高。与正常星形胶质细胞相比，已建立的和患者来源的GBM细胞系中PELP1表达升高。敲低PELP1导致细胞活力、存活率、迁移和侵袭能力显著下降。全基因组RNA测序研究表明，敲低PELP1可显著降低参与Wnt/β-连环蛋白信号通路的基因表达。机制研究表明，PELP1与β-连环蛋白相互作用并作为其共激活因子发挥作用。敲低PELP1可显著提高植入U87和GBM患者来源异种移植（PDX）模型小鼠的存活率。
GBM中PELP1表达上调，且PELP1通过β-连环蛋白轴发出的信号促进GBM进展。因此，PELP1可能是GBM治疗干预开发的潜在靶点。
