Abstract 1371: POLR1B-derived circular RNA hsa-POLR1B_0014 orchestrates RNA polymerase I transcription and oncogenic hallmarks in lung adenocarcinoma through miR-181b-5p-mediated regulatory networks.

Abstract RNA Polymerase I (Pol I) transcription is hyperactive in lung adenocarcinoma (LUAD), underpinning various hallmarks of cancer, including therapeutic resistance. However, the molecular mechanisms, particularly the role(s) of non-coding RNAs, that couple the Pol I transcriptional machinery to oncogenic pathways remain poorly defined. Here, we identify hsa-POLR1B_0014, a circRNA derived from POLR1B gene encoding the core subunit of Pol I, is up-regulated in LUAD in concert with its parent gene. RNA-sequencing analysis of a stable hsa-POLR1B_0014 knockdown LUAD cell line (A549) revealed upregulation of several miRNAs associated with oncogenic pathways. Among these, miR-181b-5p emerged as a key effector predicted to regulate LUAD-relevant malignant networks. Consistently, integrative analyses of public transcriptomic datasets, and LUAD tissues confirmed miR-181b-5p downregulation in LUAD. Furthermore, back-splice junction pull-down and AGO2-RNA immunoprecipitation assays validated a direct interaction between hsa-POLR1B_0014 and miR-181b-5p, with circRNA knockdown enhancing miRNA enrichment, thereby confirming its miRNA-decoy function. Functionally, loss of hsa-POLR1B_0014 elevated miR-181b-5p levels, leading to suppression of TAF1A, an essential Pol I transcription factor, thereby diminishing rRNA synthesis. This reveals a positive feedback circuit in which a Pol I-derived circRNA sustains Pol I output through sequestration of an inhibitory miRNA. Notably, miR-181b-5p also directly targets mTOR, a master regulator of Pol I transcription and malignant proliferation, inducing G1/S cell cycle arrest, apoptosis, and downregulation of Bcl2. Furthermore, miR-181b-5p suppression of ZEB1 attenuates migration, invasion, and enhances chemosensitivity to doxorubicin and cisplatin. In vivo, xenografts derived from hsa-POLR1B_0014-depleted LUAD cells exhibited markedly reduced tumor burden, rRNA synthesis, and Ki-67 expression, and increased apoptosis. Our findings uncover a previously unrecognized Pol I-derived circRNA-miRNA regulatory axis that coordinates ribosome biogenesis, cell growth, and therapeutic resistance in LUAD. By linking Pol I machinery to multiple oncogenic pathways, hsa-POLR1B_0014 emerges as both a driver and a vulnerability within the cancer Pol I network. These results highlight circRNA-mediated regulation of Pol I transcription as a central node controlling cancer hallmarks and a promising therapeutic target in LUAD. Citation Format: DEEPIKA ANTIL, Mansi Sharma, Srivatsava karmakar Arpita, Naidu. POLR1B-derived circular RNA hsa-POLR1B_0014 orchestrates RNA polymerase I transcription and oncogenic hallmarks in lung adenocarcinoma through miR-181b-5p-mediated regulatory networks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1371.