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Csf1r mediates enhancement of intestinal tumorigenesis caused by inactivation of Mir34a.
Liu, Fangteng; Bouznad, Nassim; Kaller, Markus; Shi, Xiaolong; König, Janine; Jaeckel, Stephanie; Hermeking, Heiko.
Afiliación
  • Liu F; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
  • Bouznad N; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
  • Kaller M; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
  • Shi X; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
  • König J; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
  • Jaeckel S; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
  • Hermeking H; Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University München, Germany.
Int J Biol Sci ; 18(14): 5415-5437, 2022.
Article en En | MEDLINE | ID: mdl-36147476
The CSF1 receptor (CSF1R) encoding mRNA represents a direct target of miR-34a. However, the in vivo relevance of the suppression of CSF1R by miR-34a for intestinal tumor suppression mediated by the p53/miR-34a pathway has remained unknown. Here, Apc Min/+ mice with intestinal-epithelial cell (IEC)-specific deletions of Mir34a showed increased formation of adenomas and decreased survival, whereas deletion of Csf1r decreased adenoma formation and increased survival. In adenomas deletion of Mir34a enhanced proliferation, STAT3 signaling, infiltration with fibroblasts, immune cells and microbes, and tumor stem cell abundance and decreased apoptosis. Deletion of Csf1r had the opposite effects. In addition, homeostasis of intestinal secretory and stem cells, and tumoroid formation were affected in opposite directions by deletion of Mir34a and CSF1R. Concomitant deletion of Csf1r and Mir34a neutralized the effects of the single deletions. mRNAs containing Mir34a seed-matching sites, which encode proteins related to EMT (epithelial-mesenchymal transition), stemness and Wnt signaling, were enriched after Mir34a inactivation in adenomas and derived tumoroids. Netrin-1/Ntn1 and Transgelin/Tagln were characterized as direct targets of Mir34a and Csf1r signaling. Mir34a-inactivation related expression signatures were associated with CMS4/CRISB+D, stage 4 CRCs and poor patient survival. In tumoroids the loss of Mir34a conferred resistance to 5-FU which was mediated by Csf1r. This study provides genetic evidence for a requirement of Mir34a-mediated Csf1r suppression for intestinal stem/secretory cell homeostasis and tumor suppression, and suggests that therapeutic targeting of CSF1R may be effective for the treatment of CRCs with defects in the p53/miR-34a pathway.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenoma / Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos / MicroARNs Límite: Animals Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Australia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenoma / Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos / MicroARNs Límite: Animals Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Australia