Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers

Table 1 MicroRNA dysregulation on gastric cancer stem cells

Function	miRNAs	Validated targets	Pathological process involved	Ref.
Oncogenic (promotion)	miR-17-5p	p21	Enhances the colony-forming ability of GCSCs, regulates the cell cycle of GCSCs, and promotes the drug resistance of GCSCs	[38]
	miR-18	Meis2, HMGB3	Enhances the colony-forming ability of GCSCs and promotes the drug resistance of GCSCs	[39]
	miR-19b	HIPK1, β-catenin	Enhances the colony-forming ability of GCSCs and promotes the drug resistance of GCSCs	[40]
	miR-20a	E2F1, β-catenin	Enhances the colony-forming ability of GCSCs and promotes the drug resistance of GCSCs	[40]
	miR-92a	HIPK1, β-catenin, CDK 4, CDK6, p53	Enhances the colony-forming ability of GCSCs, regulates the cell cycle of GCSCs, and promotes the drug resistance of GCSCs	[41]
	miR-21	Bmi-1, PTEN, p53, AKT	Targets Smad 7, promotes GC metastasis while down-regulating the expression of PTEN and p53 to increase the EMT and invasiveness of GC cells	[47]
	miR-95	DUSP5, ERK, JNK	Promotes GC cell stemness through activation of the DUSP5-mediated MAPK axis	[49]
	miR-106b	Smad 7, TGF-β	Up-regulates EMT markers and TGF-β/Smad signaling pathway to preserve GCSC characteristics	[51]
	miR-132	SIRT1, CREB	Up-regulates the SIRT1/CREB/ABCG2 signaling pathway to promote cisplatin resistance	[53]
	miR-151a-3p	YTHDF3, SUMO1, Smad2/3	Targets YTHDF3, activates Smad 2/3 pathway, and increases GC cell dryness	[56]
	miR-196a-5p	Smad4	Negative regulates Smad4 expression and inhibits GCSC stemness	[58]
	miR-451b	KREMEN1, CASK, LRP5/6, Fzd, AKT, PI3K, PCNA, Bcl-2	Promotes the migration and drug resistance of GCSCs	[59]
	miR-483-5p	Cyclin D1, Bcl-2, matrix metalloproteinase 2	Regulates the Wnt/β-catenin pathway and promotes the proliferation, invasion, and self-renewal of GCSCs	[60]
	miR-492	DNMT3B	Targets DNMT3B to maintain GCSC dryness, reduces the sensitivity of GCSCs to DDP	[61]
	miR-501-5p	BLID, Caspase-9, Caspase-3, AKT, DKK1, NKD1, GSK3β	Targets DKK1, NKD1, and GSK3β, activates the Wnt/β-catenin signaling pathway, maintains self-renewal, and promotes GCSC phenotype	[63,64]
	miR-6778-5p	SHMT1	Up-regulates the stemness of GCSCs and reduces their sensitivity to 5-FU	[65,66]
Tumor-suppressive (inhibition)	miR-7-5p	Smo, Hes1	Inhibits the expression of Smo and Hes1 as well as the stemness and invasion of GCSCs	[67]
	miR-15a-5p	ONECUT2, β-catenin, Cyclin D1	Inhibits the expression of ONECUT2, down-regulates the expression of β-catenin and Cyclin D1, and inhibits the proliferation of GCSCs	[69]
	miR-26a	HOXC9, MMP2	Inhibits EMT and angiogenesis of GCSCs by inhibiting the expression of HOXC9	[70]
	miR-29c	VEGFA, VEGFR2, ERK	Inhibits the migration, invasion, and angiogenesis of GC cells by inhibiting the VEGFA/VEGFR2/ERK pathway	[71]
	miR-34a	Bcl-2, Notch, HMGA2, Caspase-3	Up-regulates the expression of Bcl-2, increases the sensitivity of GCSCs to chemotherapeutic drugs, and inhibits EMT	[74]
	miR-98	BCAT1	Inhibits the stemness of GC cells and the expression of EMT markers, and down-regulates ABCG2 to increase the sensitivity of GCSCs to DDP	[75]
	miR-101	SOCS2, C-myc, CDK2, CDK4, CDK6, CCND2, CCND3, CCNE2, p14, p16, p21, p27	Negatively regulates SOCS2, inhibits the expression of C-myc, CDK2, CDK4, CDK6 and CCNE2, and promotes the expression of cancer inhibitors p14, p16, p21, and p27 to inhibit cell proliferation	[77]
	miR-144-3p	GLI2	Negatively regulates GLI2 expression and inhibits proliferation, invasion, and EMT of GC cells	[79]
	miR-155-5p	-	Down-regulates NF-kB p65 to reprogram BM-MSCs to GC-MSCs	[82,83]
	miR-216a-3p	Wnt3a	BRD4 enhances GC cell stemness by targeting miR-216a-3p and subsequently activating the Wnt/β-catenin pathway	[84]
	miR-345	EPS8	Spheroid-formation ability of GCSCs, inhibits the expression of EPS8, and reduces the migration ability of GCSCs	[85]
	miR-375	SLC7A11	Inhibits the stemness of GC cells while acting on SLC7A11 to induce ferroptosis in GC cells	[86]
	miR-449a	CDK6	Regulates CDK-rb-E2F1 and down-regulates CDK6 protein to inhibit the proliferation of GC cells	[90]
	miR-449c-5p	MYC/Notch1	Regulates MYC/Notch1 and increases GC cell migration or invasion capacity	[88]
	miR-867-3p	TMED3	Negatively regulates TMED3 expression to enhance the sensitivity of GC cells to DDP	[91]

miRNAs: MicroRNAs; GCSCs: Gastric cancer stem cells; GC: Gastric cancer; DUSP5: Dual-specificity phosphatase 5; TGF-β: Transforming growth factor β; EMT: Epithelial–mesenchymal transition; Smo: Smoothened; CDK: Cyclin-dependent kinase; BM-MSCs: Bone marrow-derived mesenchymal stem/stromal cells.