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<p>Here we determined whether myeloid <i>Mir34a</i> has a tumor suppressive function in <i>Apc</i><sup><i>Min/+</i></sup> mice, a model for intestinal and colon cancer. Myeloid cell-specific deletion of <i>Mir34a</i> in <i>Apc</i><sup><i>Min/+</i></sup> mice increased tumor initiation and allowed progression towards invasive carcinomas, which are generally not observed in <i>Apc</i><sup><i>Min/+</i></sup> mice. Loss of <i>Mir34a</i> facilitated the polarization of tumor-associated macrophages (TAMs) towards a pro-tumorigenic M2-like state, implying that <i>Mir34a</i> is required to maintain TAMs in a tumor-suppressive state. Also, <i>Mir34a</i>-deficient, bone-marrow-derived macrophages (BMDMs) from <i>Apc</i><sup><i>Min/+</i></sup> mice were polarized towards a pro-tumorigenic, M2-like state and displayed enhanced migration when compared to <i>Mir34a</i>-proficient BMDMs. Intestinal tumors in myeloid <i>Mir34a</i>-deficient mice showed elevated expression of several known <i>Mir34a</i> target mRNAs, including <i>Csf1r, Pd-l1, Mmp9, Ccl22</i>, and <i>c-Myc</i>. In addition, the number of immuno-suppressive, pro-tumorigenic CD4<sup>+</sup>Foxp3<sup>+</sup> T<sub>reg</sub> cells increased in myeloid <i>Mir34a</i>-deficient intestinal tumors. Moreover, <i>Apc</i><sup><i>Min/+</i></sup> mice with myeloid-specific deletion of <i>Mir34a</i> had a significantly diminished survival rate. Following the induction of inflammatory colitis, these mice showed enhanced colon cancer initiation and progression towards invasive carcinomas with an increase in M2-like TAMs, N2-like neutrophils and T<sub>reg</sub> cells. These findings imply that myeloid <i>Mir34a</i> suppresses tumor formation and progression by maintaining myeloid and T-cells in an anti-tumorigenic state. Therefore, the p53-<i>miR-34a</i> axis has a central role in non-tumor cell mediated suppression of intestinal and colon cancers.</p>

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Myeloid Mir34a suppresses initiation and progression of intestinal and colitis-induced colon cancers in APCmin mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月15日

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  • Yun Chen,
  • Fangteng Liu,
  • Janine König,
  • Nassim Bouznad,
  • Heiko Hermeking

摘要

Here we determined whether myeloid Mir34a has a tumor suppressive function in ApcMin/+ mice, a model for intestinal and colon cancer. Myeloid cell-specific deletion of Mir34a in ApcMin/+ mice increased tumor initiation and allowed progression towards invasive carcinomas, which are generally not observed in ApcMin/+ mice. Loss of Mir34a facilitated the polarization of tumor-associated macrophages (TAMs) towards a pro-tumorigenic M2-like state, implying that Mir34a is required to maintain TAMs in a tumor-suppressive state. Also, Mir34a-deficient, bone-marrow-derived macrophages (BMDMs) from ApcMin/+ mice were polarized towards a pro-tumorigenic, M2-like state and displayed enhanced migration when compared to Mir34a-proficient BMDMs. Intestinal tumors in myeloid Mir34a-deficient mice showed elevated expression of several known Mir34a target mRNAs, including Csf1r, Pd-l1, Mmp9, Ccl22, and c-Myc. In addition, the number of immuno-suppressive, pro-tumorigenic CD4+Foxp3+ Treg cells increased in myeloid Mir34a-deficient intestinal tumors. Moreover, ApcMin/+ mice with myeloid-specific deletion of Mir34a had a significantly diminished survival rate. Following the induction of inflammatory colitis, these mice showed enhanced colon cancer initiation and progression towards invasive carcinomas with an increase in M2-like TAMs, N2-like neutrophils and Treg cells. These findings imply that myeloid Mir34a suppresses tumor formation and progression by maintaining myeloid and T-cells in an anti-tumorigenic state. Therefore, the p53-miR-34a axis has a central role in non-tumor cell mediated suppression of intestinal and colon cancers.