Long non-coding RNA SOX2-OT enhances cancer biological traits via sponging to tumor suppressor miR-122-3p and miR-194-5p

Sep 24, 2026

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Long non-coding RNA SOX2 overlapping transcript (SOX2-OT) acts as a miRNA-decay system that sequesters tumor suppressor miRNAs, but its molecular function in most cancers including lung cancer remained unclear. Using RNA interference in A549 and Calu-3 lung cancer cell lines, SOX2-OT knockdown reduced SOX2-OT expression and altered downstream regulators. Down-regulating miRNAs miR-122-3p and miR-194-5p increased, with corresponding changes in FOXO1 and FOXA1. Functional assays including proliferation, metastasis, and apoptosis showed that cellular phenotypes were affected after knockdown, supporting SOX2-OT as an oncogenic driver via miR-122-3p/FOXO1 and miR-194-5p/FOXA1 pathways.

LanguageEnglish

CategoryResearch & Report

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Pages11

Reading Time28 min

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Introduction

Results

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Long non‑coding RNA SOX2‑OT enhances cancer biological traits via sponging to tumor suppressor miR‑122‑3p and miR‑194‑5pin non‑small cell lung carcinoma Fatemeh Dodangeh, Zahra Sadeghi, Parichehr Maleki & Jamshid Raheb * The oncogenic role of long non‑coding RNA SOX2 overlapping transcript (SOX2‑OT) has been demonstrated as a miRNA decay system that sponges tumor suppressor miRNA, including miR‑ 122‑3p in glioblastoma and miR‑194‑5p in glioblastoma, gastric, and colorectal cancers. However, the molecular function of SOX2‑OT remains unknown in most cancers, including lung cancer. In the current study, we aimed to evaluate the downstream regulatory function of SOX2‑OTinA549 and Calu‑3 lung cancer cell lines. We knocked down SOX2‑OT expression using an RNA interference system, which significantly decreased expression inA549 and Calu‑3 cells. The expression of down‑ regulating miRNAs (miR‑122‑3p and miR‑194‑5p) was evaluated, revealing increased expression of miR‑122‑3p and miR‑194‑5p. Additionally, the expression of miRNAs downstream mRNA, including FOXO1 (Forkhead Box O1) and FOXA1 (Forkhead Box O1), changed. Recently, critical roles of FOXO1 and FOXA1 proteins in pathways involved in proliferation, metastasis and apoptosis have been demonstrated. Downstream changes in cellular traits were assessed using MTT, flow cytometry, metastasis and apoptosis assays. These assessments confirmed that the biological behaviors of lung cancer cells were influenced after SOX2‑OT knockdown. In summary, the present study highlights the oncogenic role of SOX2‑OTthrough the regulation of miR‑122‑3p/FOXO1 and miR‑194‑5p/FOXA1 pathways. Lung cancer is the second most common cancer cases that lead to the highest rank of mortality among all cancers worldwide1,2. Non-Small Cell Lung Cancer (NSCLC) includes about 80–85 percent of lung cancer cases1. Despite advanced in diagnosis and treatment, most lung cancer cases have poor prognoses. Therefore, the recognition of biomarkers as new strategies for early detection and treatment of lung cancer seems essential2–5. Long noncoding RNAs (lncRNAs) are mRNA-like transcripts longer than 200 nucleotides without protein-coding capability6. Recently, the regulatory function of lncRNAs in various biological and pathological processes has been discovered and reported that LncRNAs dysregulation could affect various biological pathways leading to development of cancers7,8. The lncRNA SOX2-OT is mapped to human the chromosome 3q26.3 (Chr3q26.3) locus9. Recently, it has been made clear that some SOX2-OT variants play an oncogenic role in cancer and stem cell-related pathways10. The oncogenic role of SOX2-OT has been reported in various types of cancer, including lung cancer11, breast cancer12, ovarian cancer13, gastric cancer14, glioblastoma15, colorectal cancer16, hepatocellular carcinoma17. One of the lncRNA’s functions is gene expression regulation through the sponging to miRNAs that decoy miRNAs, leading to the effect of miRNA downstream mRNA targets18. Recently, numerous studies have demonstrated the oncogenic roles of SOX2-OTin regulating malignancy traits in cancers by sponging miRNAs, including miR-194-5p in gastric cancer19, miR-200 family members in pancreatic ductal adenocarcinoma20 and miR-146b-5p in nasopharyngeal carcinoma21. Su et al. indicated that SOX2-OT knockdown inhibits glioblastoma malignancy behaviors by up-regulating miR-194-5p/SOX3 and miR-122/SOX3, affecting the JAK/STAT signaling pathway15. Wang et al. demonstrated that FOXO1 protein functions as a tumor suppressor in the suppression of proliferation, metastasis and induction of apoptosis via miR-122-3p/FOXO1 axis in lung cancer22. Also, transcription factor FOXA1 has been demonstrated to be associated with poor overall survival in lung Department of Molecular Medicine, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran. *[email: Ja

FAQs

What is the main function of SOX2-OT investigated in lung cancer cells?

SOX2-OT is investigated as an oncogenic long non-coding RNA that regulates tumor suppressor miRNAs by acting through miRNA sponging and downstream pathway modulation.

How was SOX2-OT expression reduced in the study?

SOX2-OT expression was knocked down using an RNA interference system with SOX2-OT siRNAs in A549 and Calu-3 cell lines.

Which downstream axes linked to cellular traits were highlighted after SOX2-OT knockdown?

The study highlights regulation through the miR-122-3p/FOXO1 axis and the miR-194-5p/FOXA1 axis, supported by changes in miRNA and downstream mRNA levels and functional assays.

Sep 24, 2026

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