miR-155 Is Downregulated in Familial Adenomatous Polyposis and Modulates WNT Signaling by Targeting AXIN1 and TCF4

: Adenomatous Polyposis Coli (APC) gene mutations are responsible for the onset of familial adenomatous polyposis (FAP) and sporadic colorectal cancer and have been associated with miRNAs dysregulation. The capacity of miR-155, a cancer-related miRNA, to target components of the WNT/β-CATENIN pathway suggests that APC gene mutations, controlling miRNAs expression, may critically regulate WNT/β-CATENIN signaling. To this end, APC gene target sequencing was performed on colonic adenomatous polyps and paired normal mucosa clinical specimens from FAP patients (n = 9) to elucidate the role of miR-155-5p in APC-mutant setting. The expression of selected miRNAs and WNT/β-CATENIN signaling components was characterized in FAP patients and non-FAP control subjects (n = 5). miR-155-5p expression and functional effects on WNT cascade, cell survival, growth, and apoptosis were investigated in different colorectal cancer cell lines. A somatic second hit in the APC gene was found in adenomatous polyps from 6 of 9 FAP patients. Heterozygous APC gene mutations in FAP patients were associated with altered expression of candidate miRNAs and increased levels of AXIN1 and AXIN2 mRNAs. miR-155-5p was downregulated in FAP patients and in the APC and β-CATENIN-mutant colorectal cancer cell lines, and critically regulates WNT/β-CATENIN cascade by targeting both AXIN1 and TCF4. Importantly, miR-155-5p may sustain long-term WNT/β-CATENIN activation in colorectal cancer cells upon WNT3A stimulation. IMPLICATIONS: This study supports a key role of miR-155-5p in modulating WNT/β-CATENIN signaling in colorectal cancer and unravels a new mechanism for AXIN1 regulation which represents a potential therapeutic target in specific tumor subtypes.