PDRG1 promotes the proliferation and migration of GBM cells by the MEK/ERK/CD44 pathway

• Published in: Cancer science 2022-02, Vol.113 (2), p.500-516
• Main Authors: Sun, Jinmin, Xu, Yixin, Liu, Jia, Cui, Huiyue, Cao, Haowei, Ren, Jing
• Format: Article
• Language: English
• Subjects: Animals; Bioinformatics; Brain cancer; Cancer therapies; Carcinoma; CD44 antigen; Cell adhesion; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Chemotherapy; Committees; Correlation analysis; Datasets; Disease Progression; DNA damage; DNA methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Extracellular regulated protein kinase; Extracellular signal-regulated kinase; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genomes; Genotype & phenotype; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma multiforme; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Humans; Hyaluronan Receptors - metabolism; Isocitrate dehydrogenase; Kinases; Laboratory animals; Lung cancer; Male; MAP Kinase Signaling System; Medical prognosis; Mice; Middle Aged; migration; Molecular modelling; Original; P53 and DNA damage‐regulated gene1; p53 Protein; Patients; Prognosis; proliferation; Protein kinase; Proteins; Proteoglycans; Radiation; Reagents; Sequence analysis; Signal Transduction; Software; Therapeutic targets; Transcriptomes
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15214

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. Our study provides the evidence that aberrantly expressed P53 and DNA damage‐regulated gene1 (PDRG1) might be a negative prognosticator in glioma. We characterized the roles of PDRG1 in proliferation and migration of GBM cells, and delineated the underlying molecular mechanism that PDRG1 functions via the MEK/extracellular regulated protein kinase/cluster of differentiation 44 pathway. Our data provide evidence that PDRG1 might serve as a valuable prognostic marker. Inhibition of PDRG1 may be a plausible strategy for the development of