Related Experiment Videos
miR-34a and miR-34b/c Suppress Intestinal Tumorigenesis
Longchang Jiang1, Heiko Hermeking2,3,4
1Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, München, Germany.
Abstract:
The p53-inducible miR-34a and miR-34b/c genes are frequently silenced in colorectal cancer. To address the in vivo relevance of miR-34a/b/c function for suppression of intestinal tumor formation, we generated ApcMin/+ mice with deletions of the miR-34a and/or miR-34b/c genes separately or in combination. Combined deletion of miR-34a/b/c increased the number of intestinal stem cells as well as Paneth and Goblet cells, resulting in enlarged intestinal crypts. miR-34a/b/c-deficient ApcMin/+ 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 in miR-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 from miR-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, and PDFGRB) and upregulation of INHBB and AXL in primary colorectal cancer was associated with poor patient survival. In conclusion, our results show that miR-34a/b/c suppress tumor formation caused by loss of Apc and control intestinal stem cell and secretory cell homeostasis by downregulation of multiple target mRNAs. Cancer Res; 77(10); 2746-58. ©2017 AACR.
Insights
MicroRNA-34a/b/c (miR-34a/b/c) suppresses intestinal tumor formation by regulating stem cell populations. Deleting these microRNAs in mice increases tumor burden and promotes metastasis, highlighting their tumor-suppressive role in colorectal cancer.
Area of Science:
- Molecular biology
- Oncology
- Genetics
Background:
- The p53-inducible microRNA-34a (miR-34a) and miR-34b/c genes are frequently silenced in colorectal cancer.
- Understanding the in vivo role of miR-34a/b/c in suppressing intestinal tumor formation is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the in vivo relevance of miR-34a/b/c function in suppressing intestinal tumor formation.
- To determine the impact of miR-34a/b/c deletion on intestinal stem cell homeostasis and tumor progression in a mouse model.
Main Methods:
- Generated ApcMin/+ mice with deletions of miR-34a and/or miR-34b/c genes, individually or in combination.
- Assessed intestinal stem cell populations, Paneth and Goblet cell numbers, crypt morphology, tumor burden, and survival.
- Analyzed adenoma proliferation, apoptosis, bacterial infiltration, immune cell presence, barrier protein expression, and mRNA profiles.
Main Results:
- Combined deletion of miR-34a/b/c increased intestinal stem cells, Paneth and Goblet cells, and enlarged crypts.
- miR-34a/b/c-deficient mice exhibited increased tumor burden, higher tumor grade, decreased survival, elevated proliferation, and reduced apoptosis.
- Adenomas showed pronounced bacterial infiltration, decreased immune cells, downregulated barrier proteins, and enrichment of epithelial-mesenchymal transition, stemness, and Wnt signaling pathways.
Conclusions:
- miR-34a/b/c are critical tumor suppressors in Apc-driven intestinal cancer.
- These microRNAs control intestinal stem cell and secretory cell homeostasis by downregulating multiple target mRNAs.
- Upregulated miR-34 targets in human colorectal cancers correlate with lymph-node metastases and poor patient survival.