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<p>Introduction: Non-Small Cell Lung Cancer (NSCLC), a predominant subtype of lung cancer, remains a major cause of cancer-related mortality worldwide and continues to present significant clinical challenges. While microRNAs (miRNAs) are established regulators of cellular pathways, their specific involvement in modulating immunometabolic processes in NSCLC remains underexplored. This study aimed to uncover novel regulatory mechanisms in lung adenocarcinoma (LUAD) through an integrative approach combining computational and experimental strategies, with particular emphasis on miRNA, mRNA, and long non-coding RNA (lncRNA) interactions. Methods: By analyzing RNA-Seq datasets, we identified differentially expressed miRNAs, genes, and immune-associated transcripts specific to LUAD. Subsequent enrichment and network analyses highlighted key molecular players involved in immune dysregulation and cancer progression. A competing endogenous RNA (ceRNA) network involving miR-101-3p, the gene CALCRL, and lncRNA NEAT1 were constructed to elucidate regulatory hierarchies. Experimental validation included qRT-PCR, Western blot, and luciferase reporter assays to confirm miRNA-mRNA-lncRNA interactions. Functional assays were conducted to assess cancer cell proliferation, oxidative stress, mitochondrial integrity, and apoptosis. Results: Analysis revealed significant downregulation of miR-101-3p and concurrent upregulation of CALCRL and NEAT1 in LUAD cell lines. Experimental assays confirmed that miR-101-3p directly targets and negatively regulates CALCRL, while NEAT1 enhances CALCRL expression by competitively binding miR-101-3p. Restoration by doing overexpression of miR-101-3p led to reduced cancer cell growth, increased oxidative stress, disrupted mitochondrial function, decreased ATP levels, and increased apoptotic cell death. Conclusion: The study identifies the miR-101-3p/NEAT1/CALCRL regulatory axis as a key mediator of immunometabolic remodeling in LUAD. These findings underscore the potential of targeting this axis for miRNA-guided therapeutic interventions, presenting a novel strategy to counteract tumor progression in NSCLC.</p> Graphical abstract <p></p>

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miR-101-3p overexpression suppresses NSCLC progression through Immune-Related gene CALCRL regulation and lncRNA NEAT1 axis

  • 期刊论文

  • 发表日期：

    2025年9月20日

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  • Gulnaz Tabassum,
  • Shweta Arora,
  • Prithvi Singh,
  • Mohd Mohsin,
  • Salman Khan,
  • Aman Khan,
  • Ravins Dohare,
  • Kapil Dev,
  • Mansoor Ali Syed

摘要

Introduction: Non-Small Cell Lung Cancer (NSCLC), a predominant subtype of lung cancer, remains a major cause of cancer-related mortality worldwide and continues to present significant clinical challenges. While microRNAs (miRNAs) are established regulators of cellular pathways, their specific involvement in modulating immunometabolic processes in NSCLC remains underexplored. This study aimed to uncover novel regulatory mechanisms in lung adenocarcinoma (LUAD) through an integrative approach combining computational and experimental strategies, with particular emphasis on miRNA, mRNA, and long non-coding RNA (lncRNA) interactions. Methods: By analyzing RNA-Seq datasets, we identified differentially expressed miRNAs, genes, and immune-associated transcripts specific to LUAD. Subsequent enrichment and network analyses highlighted key molecular players involved in immune dysregulation and cancer progression. A competing endogenous RNA (ceRNA) network involving miR-101-3p, the gene CALCRL, and lncRNA NEAT1 were constructed to elucidate regulatory hierarchies. Experimental validation included qRT-PCR, Western blot, and luciferase reporter assays to confirm miRNA-mRNA-lncRNA interactions. Functional assays were conducted to assess cancer cell proliferation, oxidative stress, mitochondrial integrity, and apoptosis. Results: Analysis revealed significant downregulation of miR-101-3p and concurrent upregulation of CALCRL and NEAT1 in LUAD cell lines. Experimental assays confirmed that miR-101-3p directly targets and negatively regulates CALCRL, while NEAT1 enhances CALCRL expression by competitively binding miR-101-3p. Restoration by doing overexpression of miR-101-3p led to reduced cancer cell growth, increased oxidative stress, disrupted mitochondrial function, decreased ATP levels, and increased apoptotic cell death. Conclusion: The study identifies the miR-101-3p/NEAT1/CALCRL regulatory axis as a key mediator of immunometabolic remodeling in LUAD. These findings underscore the potential of targeting this axis for miRNA-guided therapeutic interventions, presenting a novel strategy to counteract tumor progression in NSCLC.

Graphical abstract