Table 1.

Regulation of MICA/ NKG2D by miRNA to influence immune response

Targeted immunity genes	MicroRNAs	Major outcomes	Related Disease/cell Types	References
NKG2D (KLRK1)	miR-181a	miR-181a impaired the differentiation of human γδ T cells into TNF-α associated effector T cells and decreased the expression of NKG2D.	prostate cancer/γδ T cells	[31]
	miR-1245	miR-1245 induced by TGF-β1, targets and downregulates NKG2D expression in NK cells, impairs NK cell functions and immune responses.	NonHodgkin’s lymphoma/Acute myelogenous leukemia/NK cells	[32]
	miR-155 miR-142 Let-7i	Tumour-derived exosomes (tex) with tex-miR-155 enhanced but tex-miR-142 and tex-Let-7i downregulated NKG2D mRNA expression. They induced appropriate immune response maturation by enhancing dendritic cells and impacted on immune suppressed tumour microenvironment.	breast cancer/dendritic cells	[33, 34]
	miR-122-5p miR-451a	Inhibition of miRNA-451a or miRNA-122-5p significantly increased the expression of NKG2D associated with activation in NK cells and may affect the function of circulating NK cells after acute ischemic stroke.	acute ischemic stroke/NK cells	[35]
	miR-30c	miR-30c increased NKG2D protein expression on the surface of NKL cells, enhanced the cytotoxicity.	NKL cells	[36]
	miR-34a	miR-34a targets NKG2D as a major hub in the T cell regulatory network, suggesting that miR-34a acts as an intervention target to regulate T cell immune responses in a wide range of tumour contexts	T cells	[37]
	miR-16	miR-16 targeted NKG2D, overexpression of miR-16 inhibited NKG2D expression in CD8+ T cells. Especially in miR-15-/16- mice, CD8+NKG2D+ T cells were increased, activation and cytotoxicity of T cells.	T cells	[38]
	miR-18a	miR-18a downregulates NKG2D, and impairment of NK cell cytotoxicity.	breast cancer/NK cells	[39]
	miR-182	miR-182 was significantly increased in NK cells from HCV-infected patients, while NKG2D mRNA expression was decreased, and overexpression of miR-182 reduced NKG2D mRNA expression. MiR182 mRNA was positively correlated with NKG2D mRNA in HCC.	NK cells from HCV-infected patients/HCV liver tissues/HCV infected cells/hepatocellular carcinoma	[40, 41]
	miR-29a* miR-155	miR-29a* and miR-155 decreased NKG2D mRNA expression, resulting in a decrease in NK cell lysis function accompanied by an 80% increase in viral load.	NK cells of HCV patients/HCV Huh cell lines	[42]
MICA	HCMV-miR-UL112	HCMV-miR-UL112 may also have binding sites with human cellular miRNAs to regulate MICA expression under certain conditions.	\	[43]
	miR-17-5p miR-20a miR-93 miR-106b miR-373 miR-302d miR-372 miR-520d	Hcmv-miR-UL112 may also have binding sites with human cellular miRNAs (miR-17-5p, miR-20a, miR-93, miR-106b, miR-373 and miR-520d) resulted in down-regulation of MICA and decreased susceptibility of NK cells due to avoid NKG2D-mediated MICA immune recognition in vitro and in vivo. miR-302d and miR-372 no effect on MICA in HeLa cells and DU145 cells.	Hcmv-miR-UL112 infected cells/HeLa cells/DU145 cells/primary human foreskin fibroblast (HFF) cells/human umbilical vein endothelial cells (HUVECs)	[43]
	miR-106b miR-302b miR-372 miR-520b	miR-106b, miR-302b, miR-372 and miR-520b target to MICA 3’-UTR region and dramatically downregulate MICA protein expression. miR-520b was induced by IFN-γ that could be sufficient to reduce the MICA protein and transcript expression.	MelJuSo melanoma and HeLa cell lines	[44]
	miRNA-4448	IFN-γ enhances the expression of MICA mRNA and protein levels by down-regulating miRNA-4448, thereby enhancing cytotoxicity and HCEC apoptosis mediated by NK and CD8+ T cells on corneal epithelium.	human corneal epithelial cells	[45, 46]
	miR-146b-5p	miR-146b-5p target the 3’-UTR of MICA; down-regulation of miR-146b-5p leads to increased expression of MICA in PTC cells and also to increased expression of NKG2D in cancer cells; inhibition of the MICA-NKG2D axis by miR-146b-5p may be one of the ways that PTC cells help tumours evasion immune response.	papillary thyroid carcinoma	[50]
	EBV-miR-BART7	EBV-miR-BART7 suppresses MICA mRNA and protein expression, reducing the sensitivity of NPC cells to NK92MI cells.	nasopharyngeal carcinoma/HK1 cells	[53]
	miR-125b	miR-125b as a tumour suppressor is commonly deregulated in cancer that its overexpression downregulated c-Myc mRNA and IRF4 mRNA but upregulated MICA mRNA and protein expression.	multiple myeloma	[57]
	miR-20a	miR-20a downregulated MICA expression, reduced NK cell cytotoxicity, and was NKG2D dependent in cancer cells to promote tumour growth.	colorectal cancer	[60, 61]
	miR-20a	The regulation of MICA by miR-20a in ovarian cancer is similar to that in colorectal cancer.	ovarian cancer	[62]
	miR-17-92 cluster (miR-20a miR-20b miR-93 miR-106b)	The regulation of MICA by miR-17-92 cluster in breast cancer is similar to that in ovarian and colorectal cancer. Suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA) treatment upregulated the expression of the MICA and typically decreased in the expression of the miR-17-92 cluster, increasing the sensitive of NK cell mediated cytotoxicity.	breast cancer	[64]
	miR-20a	3’-O-acetylvitexin effected cytotoxic and successfully increased MICA expression that had impact on miR-20a validated targets MICA.	triple-negative breast cancer	[67]
	miR-519a-3p	MiR-519a-3p binds to the MICA 3’-UTR and reduces the MICA mRNA levels and surface protein levels, impairs NK cell-mediated killing of BC cells and deregulates apoptosis by downregulating MICA.	breast cancer	[66]
	MiR-25-93-106b cluster (miR-93 miR-106b)	MiR-25-93-106b cluster can regulate sensitivity to NK cells, tumor progression and invasion by regulating the expression level of MICA.	hepatocellular carcinoma	[70]
	miR-17-92 cluster (miR-20a miR-93 miR-106b)	HDACi promoted the protein expression of MICA by inhibition of the transcription of MICA-targeting miRNAs (miR-20a, miR-93, and miR-106b) in HCC.	hepatocellular carcinoma	[71]
	miR-183	Knockdown TGF-β mRNA effectively resulting miR-183 expression was reduced but MICA protein expression was up-regulated. Silencing miR-183 and overexpression MICA contributed to the lysis of tumour cells by activated CD8+ T cells via the MICA-NKG2D pathway.	lung cancer	[74]