Hypoxia-regulated lncRNA CRPAT4 promotes cell migration via regulating AVL9 in clear cell renal cell carcinomas.

Introduction: Long noncoding RNAs (lncRNAs) are proven to be key regulators in cancer biology. Our screening effort for clear cell renal cell carcinoma (ccRCC) prognosis-associated lncRNAs identified a novel lncRNA, ccRCC prognosis-associated transcript 4 (CRPAT4), as one of the top candidates that was previously uncharacterized. The aim of this study was to verify the clinical significance of CRPAT4 in ccRCC patients and to explore its biological role as well as the underlying mechanisms, in ccRCC cell lines. Materials and methods: Quantitative real-time polymerase chain reaction (PCR) was performed to demonstrate that CRPAT4 was differentially expressed between ccRCC and the normal controls and that high CRPAT4 expression significantly associated with advanced Fuhrman nuclear grades. Results: Kaplan-Meier survival analysis with The Cancer Genome Atlas KIRC RNA sequencing data indicated that high CRPAT4 expression was significantly associated with poor overall survival and progression-free survival. Functional studies indicated that CRPAT4 was an HIF-1 alpha regulated gene, and CRPAT4 knockdown significantly inhibited cell migration and proliferation in the absence of HIF-1 alpha. In addition, a mechanistic study revealed that CRPAT4 could regulate the expression of the migration-associated protein AVL9. Conclusion: Collectively, our study first identified CRPAT4 as a hypoxia-regulated lncRNA, acting as an oncogene in ccRCC progression via regulating AVL9 protein, thus expanding our knowledge on the hypoxia pathway in ccRCC biology from a noncoding perspective. Moreover, CRPAT4 has the potential to be a prognostic marker in ccRCC patients.