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miRNA-Mediated Signaling Networks in Non-Small Cell Lung Cancer: Linking Tumor Progression to Sarcopenia

Swati Goswami1,2, Pooja Gulhane1, Shailza Singh1,2

  • 1Systems Medicine Laboratory, BRIC-National Centre for Cell Science, National Centre for Cell Science Complex, SPPU Campus, Ganeshkhind, Pune 411007, India.

International Journal of Molecular Sciences
|June 12, 2026
PubMed

Insights

This study reveals how microRNAs (miRNAs) drive non-small cell lung cancer (NSCLC) progression and inflammation, leading to muscle wasting. Novel RNA-based therapies could improve survival and metabolic health in NSCLC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Systems Biology

Background:

  • Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality, with the tumor microenvironment (TME) crucial for tumor progression and immune evasion.
  • Despite advances, NSCLC outcomes remain poor, necessitating deeper understanding of underlying molecular mechanisms.
  • The TME influences systemic metabolism and immune responses, contributing to cancer-associated morbidity.

Purpose of the Study:

  • To investigate the role of differentially expressed microRNAs (miRNAs) in NSCLC signaling networks using integrative analysis.
  • To identify key regulatory nodes and pathways influenced by miRNAs in NSCLC pathogenesis.
  • To explore the link between NSCLC progression, inflammation, and systemic metabolic dysfunction, specifically cancer-associated sarcopenia.

Main Methods:

  • Integrative analysis of differentially expressed miRNAs in NSCLC.
  • Mathematical modeling and regression-based reduction to identify regulatory nodes (FOXO1, ULK2).
  • Analysis of modulated signaling pathways (PI3K/AKT/mTOR, NF-κB, JAK-STAT3) and cytokine secretion (IL-6, TNF-α, IL-1β).
  • Investigation of E3 ubiquitin ligases (TRIM63, FBXO32) in muscle protein degradation.
  • Quasipotential landscape analysis for dynamic phenotypic transitions.

Main Results:

  • hsa-miR-486-5p identified as a key differentially expressed miRNA.
  • FOXO1 and ULK2 identified as critical regulatory nodes integrating oncogenic signaling and homeostasis.
  • Aberrant hsa-miR-486-5p expression modulates PI3K/AKT/mTOR, NF-κB, and JAK-STAT3 pathways, promoting tumor progression and inflammation.
  • NSCLC-induced cytokines activate muscle-specific protein degradation via TRIM63 and FBXO32, linking cancer to sarcopenia.
  • Dynamic phenotypic transitions observed, highlighting tumor-host interaction adaptability.

Conclusions:

  • miRNA-mediated networks drive NSCLC progression, inflammation, and systemic muscle wasting (cancer-associated sarcopenia).
  • Dysregulated miRNAs contribute to metabolic complications and poor survival in NSCLC.
  • Novel therapeutic strategies, including RNA-based interventions, are needed to overcome resistance and improve patient outcomes.
Keywords:
FOXO1NSCLCTMEcancermiRNAsarcopenia

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