title: miR-34aandmiR-34b/cSuppress Intestinal Tumorigenesis.
abstract: The p53-induciblemiR-34aandmiR-34b/cgenes are frequently silenced in colorectal cancer. To address thein vivorelevance ofmiR-34a/b/cfunction for suppression of intestinal tumor formation, we generatedApcMin/+mice with deletions of themiR-34aand/ormiR-34b/cgenes separately or in combination. Combined deletion ofmiR-34a/b/cincreased the number of intestinal stem cells as well as Paneth and Goblet cells, resulting in enlarged intestinal crypts.miR-34a/b/c-deficientApcMin/+mice displayed an increased tumor burden and grade and decreased survival.miR-34a/b/c-deficient adenomas showed elevated proliferation and decreased apoptosis and displayed pronounced bacterial infiltration, which may be due to an observed decrease in infiltrating immune cells and downregulation of barrier proteins. mRNA induction inmiR-34a/b/c-deficient tumors was enriched for miR-34a/b/c seed-matching sites and for mRNAs encoding proteins related to epithelial-mesenchymal transition, stemness, and Wnt signaling. Accordingly, cells explanted frommiR-34a/b/c-deficient adenomas formed tumor organoids at an increased rate. Several upregulated miR-34 targets displayed elevated expression in primary human colorectal cancers that was associated with lymph-node metastases (INHBB, AXL, FGFR1,andPDFGRB) and upregulation ofINHBBandAXLin primary colorectal cancer was associated with poor patient survival. In conclusion, our results show thatmiR-34a/b/csuppress tumor formation caused by loss ofApcand control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs.Cancer Res; 77(10); 2746-58. ©2017 AACR.
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, München, Germany.
authors.forename: Longchang
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, München, Germany. heiko.hermeking@med.uni-muenchen.de.|German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D011379:Prognosis; D034622:RNA Interference; D015203:Reproducibility of Results; D060449:Wnt Signaling Pathway
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs