A novel risk signature with 6 RNA binding proteins for prognosis prediction in patients with glioblastoma

Recent studies suggested that RNA binding proteins (RBPs) were related to the tumorigenesis and progression of glioma. This study was conducted to identify prognostic RBPs of glioblastoma (GBM) and construct an RBP signature to predict the prognosis of GBM.Univariate Cox regression analysis was carried out to identify the RBPs associated with overall survival of GBM in the The Cancer Genome Atlas (TCGA), {"type":"entrez-geo","attrs":{"text":"GSE16011","term_id":"16011"}}GSE16011, and Repository for Molecular Brain Neoplasia data (Rembrandt) datasets, respectively. Overlapping RBPs from the TCGA, {"type":"entrez-geo","attrs":{"text":"GSE16011","term_id":"16011"}}GSE16011, and Rembrandt datasets were selected. The biological role of prognostic RBPs was assessed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction analyses. Least absolute shrinkage and selection operator regression analysis and multivariate Cox regression analysis were used to construct an RBP-related risk signature. The prognostic value of RBP signature was measured by Kaplan–Meier method and time-dependent receiver operating characteristic curve. A nomogram based on independent prognostic factors was established to predict survival for GBM. The CGGA cohort was used as the validation cohort for external validation.This study identified 27 RBPs associated with the prognosis of GBM and constructed a 6-RPBs signature. Kaplan–Meier curves suggested that high-risk score was associated with a poor prognosis. Area under the curve of 1-, 3-, and 5-year overall survival was 0.618, 0.728, and 0.833 for TCGA cohort, 0.655, 0.909, and 0.911 for {"type":"entrez-geo","attrs":{"text":"GSE16011","term_id":"16011"}}GSE16011 cohort, and 0.665, 0.792, and 0.781 for Rembrandt cohort, respectively. A nomogram with 4 parameters (age, chemotherapy, O⁶-methylguanine-DNA methyltransferase promoter status, and risk score) was constructed. The calibration curve showed that the nomogram prediction was in good agreement with the actual observation.The 6-RBPs signature could effectively predict the prognosis of GBM, and our findings supplemented the prognostic index of GBM to a certain extent.     

The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers

Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.Amplification of the chromosomal region 3q26-29 is the most frequent genomic alteration in primary squamous cell lung cancers (1) and occurs in many other cancers (2). The best studied oncogenes of this amplicon include phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (3, 4), TP63 (5), sex-determining region Y box 2 (SOX2) (6), epithelial cell transforming 2 (ECT2) (7), and protein kinase C, iota (PRKCI) (8). In an effort to identify oncogenic drivers in lung cancer associated the 3q26-29 amplicon, we previously integrated genomic and gene expression analysis of multiple lung SCC datasets and identified Fragile X-related 1 (FXR1) as a potential new candidate driver gene (9). FXR1 belongs to a small family of RNA-binding proteins that includes Fragile X mental retardation 1 (FMR1) and Fragile X-related 2 (FXR2) (10). Inactivation of FMR1 expression is the cause of the Fragile X syndrome in humans, whereas alterations of FXR1 are yet to be associated with the pathogenesis of human disease. RNA-binding proteins (RBPs) are essential in RNA metabolism, from synthesis to degradation. RBPs coordinate elaborate networks of RNA–protein and protein–protein interactions that link RNA metabolism to signal transduction pathways (11). Aberrant function of RBPs contributes to the progression of many human diseases including cancer. Nevertheless, few RBPs have been identified as oncogenes or tumor suppressors and clinical implications of these cancer related RBPs is largely unknown. FXR1 is highly expressed in vertebrate muscle cells and FXR1 knockout mice die early during embryogenesis, suggesting an essential role for FXR1 in development (12). In this study, we examined whether RNA binding protein FXR1 is a regulator of tumor progression in nonsmall cell lung cancer (NSCLC) and a driver of the 3q amplicon. We tested this hypothesis across a large number of clinical specimens, in gain- and loss-of-function and mechanistic studies in vitro and in vivo. We investigated the translational relevance of our findings in NSCLC tissue microarrays and in datasets of multiple human cancers available in the public domain.