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

Chen, Yun; Liu, Fangteng; König, Janine; Bouznad, Nassim; Hermeking, Heiko (2026): Myeloid Mir34a suppresses initiation and progression of intestinal and colitis-induced colon cancers in APCmin mice. Cell Death & Disease, 17: 458. ISSN 2041-4889

Abstract

Here we determined whether myeloid Mir34a has a tumor suppressive function in Apc Min/+ mice, a model for intestinal and colon cancer. Myeloid cell-specific deletion of Mir34a in Apc Min/+ mice increased tumor initiation and allowed progression towards invasive carcinomas, which are generally not observed in Apc Min/+ 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 Apc Min/+ 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 + T reg cells increased in myeloid Mir34a -deficient intestinal tumors. Moreover, Apc Min/+ 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 T reg 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.

• Dokumententyp: Artikel (LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Pathologisches Institut
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 314976936
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892