Abstract Introduction: PIWI-interacting RNAs (piRNAs) constitute a distinct class of small non-coding RNAs initially described for their roles in germline transposon silencing. Recent evidence implicates somatic piRNAs in cancer-associated gene regulation; however, their mechanistic contribution to lung tumor progression remains poorly defined. In this study, we identify piRNA-5939 as a novel oncogenic regulator that enhances lung cancer cell proliferation and migration via PIWIL3-mediated post-transcriptional modulation of gene expression. Methods: Human lung adenocarcinoma cell lines (A549, ABC1, and H522) were transfected with antisense oligonucleotides targeting piRNA-5939. Proliferation was assessed by MTT, Click-iT™ EdU incorporation, and colony formation assays; migration and invasion were analyzed by wound-healing and transwell assays; and apoptosis was quantified using Annexin V Alexa Fluor™ 488/Propidium Iodide flow cytometry. Global transcriptomic changes following piRNA-5939 knockdown were examined by RNA sequencing, and key targets were validated using qRT-PCR and Western blotting. Cytoplasmic and nuclear RNA fractionation determined piRNA-5939 subcellular localization and its impact on PIWIL family (PIWIL1-4) expression profiles. Results: Subcellular fractionation revealed heterogeneous cytoplasmic and nuclear distribution of piRNA-5939 across lung cancer cell lines. Baseline profiling demonstrated that PIWIL3 transcripts are preferentially localized to the cytoplasm, and piRNA-5939 silencing led to a significant downregulation of PIWIL3 mRNA and protein expression. Functionally, loss of piRNA-5939 markedly reduced cell proliferation (∼40%) and migration (∼55%) relative to controls (p 0.01). Transcriptomic analyses highlighted suppression of oncogenic signaling pathways, including those governing cell cycle progression, cytoskeletal remodeling, and RNA stability—all consistent with attenuated PIWIL3 activity. Conclusions: These findings identify piRNA-5939 as a functional oncogenic piRNA that promotes lung cancer progression through PIWIL3-dependent post-transcriptional regulation of key growth and migration pathways. The piRNA-5939/PIWIL3 axis represents a previously unrecognized regulatory mechanism and a potential therapeutic vulnerability in lung cancer. Citation Format: Sudhir Kumar Rai, Yuanyuan Fu, Masaki Nasu, Zhuokun Feng, Li Ma, Asmita Pandey, Lauren Higa, Hua Yang, Youping Deng. piRNA-5939 drives lung cancer progression via PIWIL3-mediated post-transcriptional regulation 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 5897.
Rai et al. (Fri,) studied this question.
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