Background and aims: Hippo signalling is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, survival, apoptosis, and stem cell self-renewal. In addition, Hippo signalling is profoundly implicated in intestinal regeneration and cancer. However, its roles in the pathogenesis of Crohn's disease [CD] remain largely unexplored.
Methods: Quantitative reverse transcription-polymerase chain reaction [qRT-PCR] was performed to identify the deregulated molecules in Hippo signalling. Expression of the highly upregulated Yes-associated protein 1 [YAP] was subsequently examined by qRT-PCR, western blotting, and immunohistochemistry in the intestinal tissues of CD patients and the colons of 2,4,6-trinitrobenzene sulphonic acid [TNBS]-induced colitis mice. The microRNAs [miRNAs] predicted to target YAP were explored by transfection of miR-590-5p mimics or inhibitors and analyzed by luciferase reporter assay. The roles of the miR-590-5p/YAP axis in CD and colorectal cancer were studied in experimental colitis mice and colorectal cancer cell lines.
Results: YAP mRNA was significantly upregulated in intestinal epithelial cells in CD patients and TNBS-induced colitis mice. MiR-590-5p suppressed YAP expression by directly targeting the YAP 3'-untranslated region in Caco-2 cells and SW620 cells. Upregulation of miR-590-5p in colon reduced YAP level and its downstream targets in intestinal epithelial cells [IECs]. Treatment of miR-590-5p or YAP inhibitor Verteporfin alleviated experimental colitis. Targeting the miR-590-5p/YAP axis inhibited cell proliferation and invasiveness of colorectal cancer [CRC] cells in vitro.
Conclusions: Our results suggest that miR-590-5p inhibits intestinal inflammation in mouse colon and tumourigenesis of colorectal cancer cells by inhibiting YAP. The miR-590-5p/YAP axis may be an important novel mechanism in the pathogenesis of CD and colorectal cancer.