Table 2.

Summary of m6A modifications to small RNAs and their cellular functions in homeostasis and human disease

Small RNA	Enzyme	Regulator network (↑ denotes upregulation, ↓ denotes downregulation)	Cellular function	Disease association	Reference
miR-375	METTL14	lncRNA UCA1 ↑ → METTL14↓ → pri-miR-375↑, miR-375↓ → SOX12↑	Promotes cell proliferation and invasion but inhibits apoptosis	Breast cancer	[70]
miR‐181b‐3p	FTO	FTO ↑→ miR‐181b‐3p ↓ → ARL5B ↑	Promotes cell migration and tissue invasion	Breast cancer	[71]
miR-221-3p	METTL3	METTL3 ↑ → m6A-modified pri-miR-221-3p ↑, miR-221-3p ↑ → HIPK2 ↓ →Che-1 ↑	Enhances drug resistance in adriamycin-resistant breast cancer cells	Breast cancer	[72]
miR-374c-5p	Unknown	Cadmium treatment → m6A-modified pri-miR-374c ↓ → pri-miR-374c ↑, miR-374c-5p ↓ → GRM3 ↑	Promotes cell proliferation and metastasis	Breast cancer	[73]
miR-1246	METTL3	METTL3 ↑ → m6A-modified pri-miR-1246 ↑ → pri-miR-1246 ↓, miR-1246 ↑ → SPRED2 ↓ → activates RAF/MEK/ERK pathway	Promotes cancer cell metastasis	Colorectal cancer	[74]
Let-7b-5p	METTL3	Metformin stimulation-METTL3 ↑ → pri-Let-7b ↓, pre-Let-7b↑, Let-7b-5p ↑ → suppresses Notch signaling	Increases sensitivity to Osimertinib therapy in patients with cancer	Lung cancer	[75]
miR-143-3p	METTL3	METTL3 ↑ → m6A-modified pre-miR-143-3p ↑ → pre-miR-143-3p ↓, miR-143-3p ↑ → VASH1 ↓	Triggers epithelial-mesenchymal transition (EMT) in a blood brain barrier model of ell invasion, as well as angiogenesis in the context of lung cancer	Lung cancer	[76]
miR-106b	HNRNPA2/B1	HNRNPA2B1 ↑ → pri-miR-106b ↓, pre-miR-106b ↑, miR-106b-5p ↑ → SFRP2 ↓ → activates Wnt/β-catenin signaling	Promotes cell stemness, proliferation, migration and tumor growth of lung adenocarcinoma cells	Lung cancer	[77]
miR-663	METTL3	METTL3 ↑ → m6A-modified pri-miR-663 ↑ → pri-miR-663 ↓, miR-663 ↑ → SOCS6 ↓	Promotes proliferation, migration and invasion of lung cancer cells	Lung cancer	[78]
miR-486	Unknown	Propofol treatment → m6A-modified pri-miR-486 ↑ → pri-miR-486 ↓, miR-486-5p ↑ → inactivates the RAP1-NF-kappaB signaling axis	Enhances cisplatin-sensitivity	Lung cancer	[79]
miR-576	FTO	FTO ↑ → m6A -modified pri-miR-576 ↓ → pri-miR-576 ↑, miR-576 ↓ → CDK6 ↑	Promotes tumor proliferation and invasion	Bladder cancer	[80]
miR221/222	METTL3	METTL3 ↑ → m6A-modified pri-miR221/222 ↑ → pri-miR221/222 ↓, miR221/222 ↑ → PTEN ↓	Promotes tumor proliferation	Bladder cancer	[81]
miR-146	METTL3	Melittin stimulation → METTL3 ↓ → m6A-modified pri-miR-146 ↓ → pri-miR-146 ↑, miR-146a-5p ↓ → regulates NUMB/NOTCH2 pathway	Induces apoptosis and inhibits tumor growth	Bladder cancer	[82]
miR-125b2	NSun2	PAR2 activation → m6A-modified pre-miR-125b2 in a Nsun2-dependent manner ↑ → miR-125b2 ↓ → Gab2 ↑	Promotes cancer cell migration	Colorectal cancer, lung cancer	[65]
miR-126	METTL14	METTL14 ↓ → m6A-modified pri-miR-126 ↓ → pri-miR-126 ↑, miR-126 ↓	Enhances cell metastasis	Liver cancer	[83]
miR‐589-5p	METTL3	METTL3 ↑ → m6A-modified pri‐miR‐589 ↑ → pri-miR-589 ↓, miR‐589‐5p ↑	Promotes cell viability, migration and invasion	Liver cancer	[84]
miR-194–2 and miR-532	ALKBH5	ALKBH5 ↑ → m6A-modified pri-miR-194 ↓ → miR-194–2 ↓ → RAI1 ↑ → regulates the Hippo pathway	Inhibits cell growth and motility	Esophageal cancer	[85]
miR-99a	METTL14	METTL14 ↓ → m6A-modified pri-miR-99a ↑ → miR-99a ↑ → TRIB2 ↓	Promotes cancer stem cell persistence and radioresistance	Esophageal cancer	[86]
miR-92b	METTL3	Deoxycholic acid treatment → METTL3 dissociation from METTL14 and WTAP complex → m6A-modified pri-miR-92b ↓ → miR-92b ↓ → PTEN ↑ → activates PI3K/AKT signaling	Enhances cell proliferation	Gallbladder cancer	[87]
miR-19a	METTL3	METTL3 ↑ → m6A-modified pri-miR-19a ↑ → miR-19a ↑ → BAMBI ↓	Facilitates nasopharyngeal carcinoma cell proliferation and invasion	Nasopharyngeal carcinoma	[88]
miR-126-5p	METTL3	METTL3 ↑ → m6A-modified pri-miR-126-5p ↑ → miR-126-5p ↑ → PTEN ↓ activates PI3K/Akt/mTOR pathway	Promotes cell proliferation, migration and invasion and inhibits apoptosis	Ovarian cancer	[89]
miR-1246	METTL3	METTL3 ↑ → pri-miR-1246 ↓, miR-1246 ↑ → CCNG2 ↓	Promotes the proliferation and metastasis and inhibits apoptosis	Ovarian cancer	[90]
miR-25-3p	METTL3	Cigarette smoke stimulation → METTL3 ↑, with NKAP as a reader → m6A-modified pri-miR-25 ↑ → pri-miR-25↓, pre-miR-25 ↑, miR-25-3p ↑	Promotes pancreatic cancer cell proliferation, migration and invasion	Pancreatic cancer	[91]
miR-30d	YTHDC1	YTHDC1 ↓ → pri-miR-30d ↑ → miR-30d ↓ → RUNX1 ↑ → SLC2A1 ↑, HK1 ↑	Promotes aerobic glycolysis to potentiate tumor proliferation, metastasis and angiogenesis	Pancreatic cancer	[92]
miR-222-3p	METTL3	METTL3 ↑ → m6A-modified pri-miR-222-3p ↑ → miR-222-3p ↑ → STK4 ↓	Promotes tumor growth and metastasis	Thyroid carcinoma	[93]
miR-143-3p	KIAA1429 and ALKBH5	KIAA1429 ↓, ALKBH5 ↑ → m6A-modified pri-miR-143-3p ↓ → pri-miR-143-3p ↑, miR-143-3p ↓ → DDX6 ↑	Suppresses human aortic smooth muscle cell proliferation, promotes human aortic endothelial cell apoptosis and facilitates aortic dissection progression	Aortic dissection	[94]
miR-19a	METTL14	METTL14 ↑ → m6A-modified pri-miR-19a ↑ → miR-19a ↑	Promotes cardiovascular endothelial cell proliferation and invasion	Atherosclerosis	[95]
miR-25-3p	METTL3	METTL3 ↓ → miR-25-3p ↓ → PTEN ↑ → phosphorylated Akt ↓	Attenuates high-glucose induced retinal pigment epithelium cell pyroptosis	Diabetic retinopathy	[96]
miR-93	METTL3	Cigarette smoke stimulation → METTL3 ↑→ m6A-modified pri-miR-93 ↑ → pri-miR-93 ↓, pre-miR-93 ↑, miR-93 ↑ → miR-93 endocytosed from bronchial epithelial cells into macrophages through extracellular vesicle trafficking ↑ → DUSP2 ↓ → MMP9 ↑, MMP12 ↑, activates JNK pathway	Induces elastin degradation	Emphysema	[97]
miR-126	METTL3	METTL3 ↓ → m6A-modified pri-miR126 ↓ → pri-miR126 ↑, miR126 ↓	Facilitates the migration and invasion of human endometrial stromal cells	Endometriosis	[98]
miR-365-3p	METTL3	METTL3 ↑ → m6A-modified pri-miR-365-3p ↑ → pri-miR-365-3p ↓, miR-365-3p ↑	Produces pain-related behaviors and neuronal sensitization in naive mice	Inflammatory pain	[99]
miR-34-5p	METTL14	METTL14↑ → pri-miR-34 ↓, pre-miR-34 ↑, miR-34a-5p ↑ → SIRT1↓	Promotes cell cycle arrest and senescence	Intervertebral disc degeneration	[100]
miR-221/222	METTL3	Angiotensin II stimulation → METTL3 ↑ → m6A-modified pri-miR-221/222 ↑→ miR-221/222 ↑ → DKK2 ↓ → activates Wnt/β-catenin signaling	Promotes Ang-II-induced cardiac hypertrophy	Myocardial hypertrophy	[101]
miR-143	METTL3	METTL3 ↓ → m6A-modified pri-miR-143 ↓ → pri-miR-143↑, pre-miR-143 ↑, miR-143 ↓ → Yap ↑, Ctnnd1 ↑	Promotes cardiomyocyte proliferation and endogenous cardiac repair after myocardial infarction	Myocardial infarction	[102]
miR-17-3p	METTL3	METTL3 ↑ → increases binding between DGCR8 and pri-miR-17-3p → miR-17-3p ↑	Ameliorates hypoxia-induced decrease in myoproliferative capacity and increase in apoptosis	Myocardial infarction	[103]
miR-150	METTL3	METTL3 ↓, with YTHDF2 as a reader → m6A-modified pri-miR-150 ↓ → miR-150 ↓ → BDNF ↓	Increases the severity of neuropathic pain	Neuropathic pain	[104]
miR‐21	METTL3	METTL3 ↑, with HNRNPA2B1 as a reader → m6A-modified pri‐miR‐21 ↑ → miR‐21‐5p ↑ → activates the SPRY1/ERK/NF‐kB signaling pathway	Promotes inflammation and the development of obstructive renal fibrosis	Obstructive renal fibrosis	[105]
miR-320a-3p	ALKBH5	ALKBH5 ↑ → m6A-modified pri-miR-320a-3p ↓ → pri-miR-320a-3p ↑, miR-320a-3p ↓ → FOXM1↑	Promotes lung fibroblast activation and silica-induced pulmonary fibrosis	Silica-induced pulmonary fibrosis	[61]
miR-335	METTL3	METTL ↑ → m6A-modified pri-miR-335 ↑ → pri-miR-335 ↓, pre-miR-335 ↑, miR-335 ↑→ Erf1 ↓	Promotes stress granule formation and reduces the level of apoptosis in neurons and other cells	Acute ischemic stroke	[106]