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.
Highlights
Colorectal cancer is a leading cause of cancer death
The frequency of stem cells at the crypt base was significantly increased in miR-34a/ b/c-deficient mice as determined by detection of the stem cell marker Olfm4 using in situ hybridization (Fig. 1E)
The increase in the pool of intestinal stem cells (ISC) in the miR34a/b/c-deficient mice observed here may underlie the increased rate of tumor formation in ApcMin/þ mice, because ISC were shown to serve as efficient tumor initiating cells during intestinal tumorigenesis [38]
Summary
Colorectal cancer is a leading cause of cancer death. Colorectal cancer is a multistep process driven by mutational activation of several oncogenes and genetic/epigenetic inactivation of tumor suppressors [2]. The majority of colorectal cancers originate from benign adenomas, which are caused by inactivating mutations in the adenomatous polyposis coli (APC) gene. APC mutation leads to the constitutive activation of the Wnt/b-catenin pathway, which results in the increased expression of b-catenin, a critical regulator of intestinal epithelial cell homeostasis [3]. Additional mutations in key oncogenes and tumor suppressor genes, such as p53, are acquired. ApcMin/þ mice inherit a mutant Apc allele that results in a truncation of the APC protein at amino acid 850 [4] and spontaneously lose the wildtype Apc allele, resulting in multiple benign adenomas mainly throughout the small intestine [5].
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