{"doi":"10.1101/2025.10.13.682173","title":"The long non-coding RNA, CyKILRb, augments oncogenic phenotypes via induction of PIK3R2 and activation of the PI <sub>3</sub> K/AKT axis","abstract":"ABSTRACT Our laboratory recently identified a novel long noncoding RNA termed CyKILR that has two splice variants with distinct cellular localizations and opposing roles in tumorigenesis. The cytoplasmic variant, CyKILRb (exon 3 exclusion), promotes tumorigenesis, whereas the nuclear variant, CyKILRa (exon 3 inclusion), functions as a tumor suppressor. In this study, the molecular mechanism of the tumorigenic role of CyKILRb was characterized. Specifically, deep RNA sequencing analysis revealed that CyKILRb regulated the PI 3 K/AKT signaling pathway to block downstream tumor suppressors. In particular, downregulation of CyKILRb induced the loss of PIK3R2, an activator of PI 3 K, as well as RPS6KB2 and GNB2, two implicated tumor promotors, with a concomitant increase in the tumor suppressors, CDKN1A (p21) and CDKN1B (p27). In contrast, CyKILRb ectopic expression produced the opposite effect, and suppression of either PIK3R2, PI 3 K or AKT attenuated CyKILRb-induced cell proliferation and clonogenic survival. CyKILRb negatively regulated CyKILRa expression, which was blocked by inhibition of either PI 3 K or AKT. PIK3R2 ectopic expression overcame the cellular effects of CyKILRb downregulation, but not PI 3 K or AKT inhibition orienting the signaling pathway from CyKILRb→↑PIK3R2→PI3K→AKT→↓CyKILRa→enhanced oncogenicity. These findings highlight the critical role of CyKILRb in tumorigenesis and define a novel feed-forward regulatory mechanism linked to alternative RNA splicing.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":577910,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":862338,"name":"H. Patrick MacKnight","orcid":"0000-0003-3232-6155","position":1,"is_corresponding":false},{"id":1285723,"name":"Amy L. Lu","orcid":null,"position":2,"is_corresponding":false},{"id":489008,"name":"Charles E. Chalfant","orcid":"0000-0002-5844-5235","position":3,"is_corresponding":false},{"id":501378,"name":"Xiujie Xie","orcid":"0000-0002-3424-7939","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:58:16.148027Z","pmid":"41279506","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}