Overexpression of CD98 in intestinal epithelium dysregulates miRNAs and their targeted proteins along the ileal villus-crypt axis

Moon K. Han, Mark Baker, Yuchen Zhang, Chunhua Yang, Mingzhen Zhang, Pallavi Garg, Emilie Viennois, Didier Merlin
2018 Scientific Reports  
CD98 has been implicated in the experimental model of inflammatory bowel disease. We have previously shown that IEC-specific overexpression of CD98 mediates intestinal inflammation and intestinal epithelial barrier dysfunction. Mice overexpressing CD98 exhibited severe colitis and a greater susceptibility to CAC. Here we demonstrated CD98 overexpression to dysregulate homeostatic gradient profile of miRNA and protein expression along the ileal villus-crypt axis. Using miRNA-target gene
more » ... arget gene prediction module, we observed differentially expressed miRNAs to target proteins of villus and crypt profoundly affected by CD98 overexpression. We have utilized online bioinformatics as methods to further scrutinize the biological meanings of miRNA-target data. We identified significant interactions among the differentially regulated proteins targeted by altered miRNAs in Tg mice. The biological processes affected by the predicted targets of miRNAs deviate from the homeostatic functions of the miRNA-gene-protein axis of the wildtype mice. Our results emphasize a dynamic perturbation of miRNA and protein expression in villus-crypt axis contributing to potential biological consequences of altering CD98 expression. Our findings also suggest the need for a consideration of arrays of interacting biological entities (i.e. miRNAs-mRNAs, protein-protein interaction) or a combination comparison for a better understanding of the disease pathology which is necessary for an effective therapeutic target development. CD98, a heterodimer of an L-type amino acid transporter (LAT) and β-integrin 1 , has been implicated in the experimental colitis model that mirrors the clinical symptoms of inflammatory bowel disease (IBD). Initially detected in activated immune cells 2,3 , CD98 is constitutively expressed on the epithelial cells of various tissues 4-7 . During chronic intestinal inflammation, a greater number of CD98-positive mononuclear cells 8 and higher CD98 mRNA levels are found in circulation 9 . Moreover, increased CD98 protein expression 10,11 is detected in the colonic biopsies of IBD patients. We previously reported that mice with intestinal epithelial cell (IEC)-specific overexpression of CD98 exhibited an exacerbations of colitis and increased susceptibility to colonic tumorigenesis compared to the wild-type mice (WT) 12,13 . This augmented expression of CD98 in the intestinal epithelium (IE) increased intestinal barrier permeability, upregulated pro-inflammatory cytokines, elevated the phosphorylation of proteins associated with β-integrin signaling, and enhanced the expressions of proliferation markers in the small intestine and colonic epithelium 13 . In addition, CD98 overexpression in IE resulted in the aggressive formation of larger and more numerous tumors, suggesting that CD98 may be involved in oncogenesis 14 . In a mouse model that spontaneously develops intestinal carcinomas, greater CD98 expression in IECs enhanced the incidences of small intestinal and colonic tumors, increased cell proliferation, and decreased cell apoptosis 15 . We speculate the dysregulation of protein expression along the IE upon changes in CD98 expression to be facilitated by microRNAs (miRNAs), which have been implicated in regulating the inflammatory conditions of IBD and various cancers [16] [17] [18] . miRNAs are small-noncoding RNAs that target 3′ end of the untranslated regions of their target mRNAs to destabilize gene and protein expression 19, 20 . Studies of colonic mucosa of IBD patients Published: xx xx xxxx OPEN www.nature.com/scientificreports/
doi:10.1038/s41598-018-34474-9 fatcat:w4hcikxoa5g4tdck5oxzdxtrlq