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Heparin-binding EGF-like growth factor via miR-126 controls tumor formation/growth and the proteolytic niche in murine models of colorectal and colitis-associated cancers

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  • معلومة اضافية
    • بيانات النشر:
      Nature Publishing Group, 2024.
    • الموضوع:
      2024
    • Collection:
      LCC:Cytology
    • نبذة مختصرة :
      Abstract MicroRNAs, including the tumor-suppressor miR-126 and the oncogene miR-221, regulate tumor formation and growth in colitis-associated cancer (CAC) and colorectal cancer (CRC). This study explores the impact of the epithelial cytokine heparin-binding epidermal growth factor (HB-EGF) and its receptor epidermal growth factor receptor (EGFR) on the pathogenesis of CAC and CRC, particularly in the regulation of microRNA-driven tumor growth and protease expression. In murine models of CRC and CAC, lack of miR-126 and elevated miR-221 expression in colonic tissues enhanced tumor formation and growth. MiR-126 downregulation in colon cells established a pro-tumorigenic proteolytic niche by targeting HB-EGF-active metalloproteinase-7, -9 (MMP7/MMP9), disintegrin, and metalloproteinase domain-containing protein 9, and modulating chemokine-mediated recruitment of HB-EGF-loaded inflammatory cells. Mechanistically, downregulation of HB-EGF and EGFR in the colon suppressed miR-221 and enhanced miR-126 expression via activating enhancer-binding protein 2 alpha. Reintroducing miR-126 reduced tumor development and HB-EGF expression. Combining miR-126 reintroduction, which targets specific HB-EGF-active proteases but not ADAM17, with MMP inhibitors like Batimastat or Marimastat effectively suppressed tumor growth. This combination normalized protease expression and balanced miR-126 and miR-221 levels in developing and growing tumors. These findings demonstrate that suppressing HB-EGF and EGFR1 shifts the balance from oncogenic miR-221 to tumor-suppressive miR-126 action. Consequently, normalizing miR-126 expression could open new avenues for treating patients with CAC and CRC, and this normalization is intertwined with the anticancer efficacy of MMP inhibitors.
    • File Description:
      electronic resource
    • ISSN:
      2041-4889
    • Relation:
      https://doaj.org/toc/2041-4889
    • الرقم المعرف:
      10.1038/s41419-024-07126-2
    • الرقم المعرف:
      edsdoj.2c2328a0a522480a97a3d4d1e728982e