Abstract
The treatment of cancer through the induction of natural killer group 2, member D (NKG2D) ligands is of interest, but understanding of mechanisms controlling expression of individual ligand is limited. The major histocompatibility complex (MHC) class I chain related protein B (MICB) is a member of NKG2D ligands. We aimed to investigate the role of 3′-untranslated (3′-UTR) and 5′-untranslated regions (5′-UTR) in post-transcriptional regulation of MICB. Nine novel microRNAs (miRNAs) predicted to interact with 3′-UTR and 5′-UTR using TargetScan, RNAhybrid and miBridge were identified. Their regulation of 3′-UTR, 5′-UTR and both 3′- and 5′-UTR sequences of MICB were indicated by the reduction of luciferase activities of luciferase reporter constructs. Mutations of miRNA binding sites at 3′- and 5′-UTRs resulted in increased luciferase activities confirming the regulation of nine candidate miRNAs. In addition, overexpression of candidate miRNAs also down-regulated the expression of reporter constructs. Consequently, the overexpression and inhibition of candidate miRNAs lead to the decreased and increased. MICB protein expressions on the cells tested, respectively. This study has identified a new role of miRNAs in regulation of MICB expression via both 3′-UTR and 5′-UTR sequences applicable for cancer immunotherapy.
Highlights
The natural killer group 2, member D (NKG2D) system consists of the NKG2D receptor expressed on natural killer (NK) cells, cluster of differentiation 8+ (CD8+) thymus (T)-cells and natural killer thymus (NKT) cells and NKG2D ligands (NKG2D-Ls), frequently upregulated in stressed cells such as viral or bacterial infected cells and tumor cells [1]
Several studies reported that MHC class I chain related protein B (MICB) expression was controlled by various miRNAs via binding at the 30 -untranslated regions (UTRs) of MICB leading to repression of protein expression [16,17,31,32]
We have identified novel miRNAs regulating MICB expression via both30 -UTR and 50 -UTR sequences
Summary
The natural killer group 2, member D (NKG2D) system consists of the NKG2D receptor expressed on natural killer (NK) cells, cluster of differentiation 8+ (CD8+) thymus (T)-cells and natural killer thymus (NKT) cells and NKG2D ligands (NKG2D-Ls), frequently upregulated in stressed cells such as viral or bacterial infected cells and tumor cells [1] They are restrictively expressed on normal cells [1,2]. Numerous reports demonstrated that different cells and tissues expressed messenger RNAs (mRNAs) for NKG2D-Ls but lacked any expression of the corresponding proteins. These observations suggest that at least some of the NKG2D-Ls are regulated at post-transcriptional level [9]
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