Abstract
Long noncoding RNAs (lncRNAs) are implicated in renal cell carcinoma (RCC), but remain largely unclear. Using publicly available transcriptome sequencing data from renal cancer (n = 703) and integrating bioinformatics analyses, we screened and identified a valuable lncRNA, EGFR-AS1. In our validation cohort (n = 204), EGFR-AS1 was significantly upregulated in RCC tissues (P < 0.001). Gain-of-function and loss-of-function studies showed that EGFR-AS1 promoted cell proliferation and invasion in vitro and in vivo. Based on previous studies and sequence complementarity of EGFR with EGFR-AS1, we demonstrated that EGFR-AS1 directly bound to EGFR mRNA and inhibited its degradation. Furthermore, RNA pull-down and mass spectrometry analyses showed that EGFR-AS1 interacted with HuR, which was responsible for the mRNA stability of EGFR. Multivariate analysis suggested that higher EGFR-AS1 expression predicted a poor prognosis in RCC patients (high vs low: P = 0.018, HR = 2.204, 95% CI: 1.145–4.241). In conclusion, EGFR-AS1 enhances the malignant phenotype of RCC cells by enhancing HuR-mediated mRNA stability of EGFR. Our data also provide biological rationales for EGFR-AS1 as a prognostic biomarker and a potential therapeutic target for RCC.
Highlights
Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system and the second leading cause of urinary cancer-related death[1]
LncRNA Epidermal growth factor receptor (EGFR)-AS1 is upregulated in human RCC tissues First, we analyzed the differential long noncoding RNAs (lncRNAs) expression between RCC tissues and normal tissues in four GEO datasets (GSE40911, GSE61763, GSE76207, and GSE82122) and the TCGA database (577 tumor tissues and 126 normal tissues; Fig. 1a)
After qRT-polymerase chain reaction (PCR) analysis of these lncRNAs in our own samples, we focused on three upregulated lncRNAs (EGFR-AS1, CTC-327F10.4, and RP11-142A23.1) (Fig. 1a)
Summary
Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system and the second leading cause of urinary cancer-related death[1]. Recent research has shown that lncRNAs play important roles in tumor progression and metastasis. These noncoding RNAs can affect the transcription and translation of coding genes via multiple mechanisms, such as chromosome remodeling, transcriptional activation, or Inhibition, protein inhibition, and post-transcriptional modification. The use of high-throughput sequencing has led to the discovery of many lncRNAs associated with renal cancer[4,5,6,7,8], such as the lncRNA HOTAIR, which is targeted and regulated by miR-141 in renal carcinoma cells[4]. Hirata et al.[5] reported that MALAT1 promotes invasion in renal cancer by binding to EZH2, which is regulated by miR-205. Some noncoding RNAs have been reported to be involved in the development and metastasis of renal cancer, the roles and mechanisms of these lncRNAs in renal cancer remain unclear
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