Gain-of-function mutations and overexpression of KIT are characteristic features of gastrointestinal stromal tumors (GIST). Dysregulation in miRNA expression may lead to KIT overexpression and tumorigenesis. Researchers recently utilized miRNA microarray technology and real-time PCR to determine the miRNA expression profiles in a cohort of 69 clinical samples including 50 CD117IHC+/KITmutation GISTs and 19 CD117IHC−/wild-type GISTs. GO enrichment and KEGG pathway analyses were performed to reveal the predicted targets of the dysregulated miRNAs. Of the dysregulated miRNAs whose expression was inversely correlated with that of KIT miRNAs were predicted by bioinformatics analysis and confirmed by luciferase reporter assay.

Of the six miRNAs whose expression was inversely correlated with that of KIT, scientists found that miR-148b-3p was significantly downregulated in the CD117IHC+/KITmutation GIST cohort. This miRNA was subsequently found to inhibit proliferation, migration and invasion of GIST882 cells. Mechanistically, miR-148b-3p was shown to regulate KIT expression through directly binding to the 3’-UTR of the KIT mRNA. Restoration of miR-148b-3p expression in GIST882 cells led to reduced expression of KIT and the downstream effectors proteins ERK, AKT and STAT3. However, overexpression of KIT reversed the inhibitory effect of miR-148b-3p on cell proliferation, migration and invasion. Furthermore, we found that reduced miR-148b-3p expression correlated with poor overall survival (OS) and disease-free survival (DFS) in GIST patients.

miR-148b-3p functions as an important regulator of KIT expression and a potential prognostic biomarker for GISTs.

LC Sciences

A network of the dysregulated miRNAs and their predicted target genes. Red/blue, miRNAup/down-regulated in CD117IHC+/KITmutation GISTs compared to CD117IHC-/wild type GISTs

 

Reference
Y. Wang, J. Li, D. Kuang, H. Cheng, Q. Zhao, Y. Duan, G. Wang et al. (2018) miR-148b-3p functions as a tumor suppressor in GISTs by directly targeting KIT Cell Communications and Signaling doi: 10.1186/s12964-018-0228-z [article]

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