The lncRNA, CyKILRb acts as a ceRNA for tumor suppressive microRNA to augment oncogenic phenotype via induction of...

The lncRNA CyKILR produces two splice variants with antagonistic roles in lung tumorigenesis. While its nuclear counterpart functions as a tumor suppressor, we revealed that the cytoplasmic variant, CyKILRb, is a potent oncogenic driver that activates the PI₃K/AKT signaling axis. Specifically, downregulation of CyKILRb induced the loss of the PI₃K activator PIK3R2 and the tumor promoter RPS6KB2, while simultaneously increasing the tumor suppressors, p21 and p27. CyKILRb ectopic expression produced the contrasting effect, and suppression of either PIK3R2, PI₃K, or AKT attenuated CyKILRb-induced cell proliferation and clonogenicity. Combinatorial expression studies oriented the pathway from CyKILRb→↑PIK3R2→PI₃K→AKT→enhanced oncogenicity. An in silico analysis comparing predicted microRNA response elements (MREs) across the CyKILRb and PIK3R2 transcripts identified shared contiguous complementary miRNA binding sequences. Of these miRs, miR-3151-5p, a tumor suppressor and known PIK3R2 regulator, was identified. This miR associated with both RNAs in cells, and treatment of NSCLC cells with a miR-3151-5p mimic reduced PIK3R2 and clonogenicity. Ectopic expression of CyKILRb containing a mutated MRE for miR-3151-5p showed an inability to upregulate PIK3R2 and tumor-promoting phenotypes in contrast to WT CyKILRb. These findings define a novel role for CyKILRb as a competing endogenous RNA for tumor suppressive miRs, which induces the PI3K/AKT axis.