BACKGROUND: Inflammation triggers stem cell proliferation to repair the tissue damage, while abnormal gene expression can transform temporary hyperplasia into a fertile ground for tumorigenesis. We investigated the role and mechanism of microRNA miR-34a deficiency in inflammation-induced colon tumorigenesis. METHODS: We treated wildtype and miR-34a-/- mice with DSS or infected them with Citrobacter rodentium and examined how miR-34a deficiency affects inflammation-induced colon tumorigenesis. We analyzed type and level of T helper cells infiltrated in infected colon. We investigated how Th17 cells and IL-17 regulate colon organoid growth. We systemically analyzed and validated miR-34a targets involved in Th17 cell infiltration, colon organoid growth and tumorigenesis. RESULTS: miR-34a deficiency leads to colon tumorigenesis after DSS treatment or Citrobacter rodentium infection. miR-34a targets both immune and epithelial stem cells to restrain inflammatory cytokine-induced stem cell proliferation (Fig. 1). miR-34a targets Interleukin 6 receptor (IL-6R) to suppress T helper 17 (Th17) cell differentiation, targets Interleukin 23 receptor (IL-23R) to block Th17 cell expansion and IL-17 production, targets chemokine CCL22 production to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) in colon stem cells to inhibit IL-17 induced stem cell proliferation. IP injection of IL-17 neutralizing antibody abrogates stem cell proliferation. Deletion of miR-34a in either colon epithelial cells alone (by generating a Lgr5-EGFP-CreERT2/miR-34aflox/flox strain) or in immune cells alone (bone marrow transplantation from miR-34a-/- mice) promoted tumorigenesis at much lower incidence rates. CONCLUSION: miR-34a acts as a central safeguard to protect the inflammatory colon stem cell niche by targeting both Th17 cells and colon epithelial stem cells during IBD reparative regeneration (Fig. 2).
