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Altered Atlas of Exercise-Responsive MicroRNAs Revealing miR-29a-3p Attacks Armored and Cold Tumors and Boosts

Jie Mei1,2, Zhiwen Luo3, Yun Cai4

  • 1Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Research (Washington, D.C.)
|January 23, 2025
PubMed

Insights

Physical exercise suppresses cancer by regulating microRNAs (miRNAs). This study identifies miR-29a-3p as a key exercise-responsive miRNA that inhibits tumor growth by targeting B7-H3, offering a potential new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Physical exercise demonstrates significant anti-cancer effects, with exercise-responsive microRNAs (miRNAs) playing a crucial role in tumor suppression.
  • Understanding the specific roles of these miRNAs in various cancers is essential for developing novel therapeutic strategies.

Purpose of the Study:

  • To investigate the expression and prognostic significance of exercise-responsive miRNAs in breast cancer (BRCA) and other cancer types.
  • To elucidate the tumor-suppressive mechanisms of miR-29a-3p, focusing on its targets and impact on the tumor microenvironment (TME).
  • To evaluate the therapeutic potential of restoring miR-29a-3p in cancer treatment.

Main Methods:

  • Analysis of exercise-responsive miRNA expression and prognostic value in BRCA and pan-cancer cohorts.
  • In vitro assays using macrophages, fibroblasts, and tumor cells, alongside in vivo models to study miR-29a-3p function.
  • Mechanistic studies involving B7 homolog 3 (B7-H3) targeting, single-cell RNA sequencing (scRNA-seq), and cytometry by time-of-flight (CyTOF) to assess TME modulation.
  • Development and testing of liposome-encapsulated miR-29a-3p (lipo@miR-29a-3p) in a mouse model.

Main Results:

  • miR-29a-3p was found to be downregulated in tumor tissues and associated with poor prognosis in BRCA.
  • miR-29a-3p was identified as an exercise-responsive miRNA that targets macrophages, fibroblasts, and tumor cells, leading to the downregulation of B7-H3 expression.
  • scRNA-seq and CyTOF analyses revealed that miR-29a-3p converts "armored" and "cold" tumors into an immuno-hot TME.
  • Lipo@miR-29a-3p demonstrated significant antitumor effects and good biocompatibility in a mouse model.

Conclusions:

  • miR-29a-3p is a critical exercise-responsive miRNA with potent tumor-suppressive functions.
  • By inhibiting B7-H3 expression, miR-29a-3p effectively targets "armored" and "cold" tumors, reshaping the TME to enhance anti-tumor immunity.
  • Restoration of miR-29a-3p presents a promising alternative therapeutic strategy for cancer treatment.

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