Role, mechanism, and application of N6-methyladenosine in hepatobiliary carcinoma

Table 1 The roles and mechanism of N6-methyladenosine modification in hepatobiliary carcinoma

Tumor typed role	Regulators	m6A-relate	Functions	Mechanisms	Ref.
Hepatocellular carcinoma	METTL3	m6A writers	Promotes HCC cell proliferation, migration, and tumorigenicity	Accelerates the degradation of SOCS2	[66]
			Promotes HCC progression	Modulates MAPK cascade	[78]
			Promotes the formation of vasculogenic mimicry	Enhances the translation efficiency of YAP1 mRNA	[133]
	METTL14	m6A writers	Inhibits tumor invasion and metastasis	Regulates the pri-microRNA 126 processing	[69]
			Inhibits HCC progression	Inhibits the EGFR/PI3K/AKT signaling pathway	[74]
			Inhibits HCC tumor growth	Regulates degradation of SLC7A11 mRNA	[75]
			Boosts the differentiation of liver CSCs and repress HCC growth	Maintains the stability of HNF3γ mRNA	[76]
			Impairs the metabolic reprogramming of HCC cells	Stabilizes USP48 mRNA	[77]
Pancreatic cancer	METTL3	m6A writers	Promotes tumorigenesis and chemoradiation tolerance	Modulates MAPK cascade	[52]
	METTL14	m6A writers	Promotes PC proliferation and migration	Induces PERP mRNA degradation	[81,82]
			Inhibits PC cells apoptosis and autophagy, and enhances chemotherapy tolerance	Facilitates AMPKα, ERK1/2, and mTOR pathways	[83]
			Enhances PC cells chemotherapy tolerance	Maintains CDA mRNA stability	[84]
			Inhibits PC progression	Induces PIK3CB mRNA degradation	[85]
	ALKBH5	m6A erasers	Inhibits the initiation and progression of PC	Reduce WIF-1 mRNA methylation and down-regulate the Wnt pathway	[86]
			Prevents PC tumorigenesis	Activates PER1 via YTHDF2-dependent manner	[87]
	FTO	m6A erasers	Promotes PC progression	Stabilizes proto-oncogene MYC mRNA	[88]
	YTHDF2	m6A readers	Inhibits PC progression	Curtails cell invasion and migration via the YAP pathway	[89]
			Accelerating the growth of PC cells	Activates Akt/GSK3b/CyclinD1 pathway	[89]
Gallbladder carcinoma	IGF2BP3	m6A readers	Promotes the aggressive progression of GBC	Stabilizes CLDN4 mRNA	[93]
			Promotes GBC progression	Stabilizes KLK5 mRNA	[94]
	YTHDF2	m6A readers	Promotes GBC progression and chemoresistance	Decreases DAPK3 mRNA stability	[95]
	METTL3	m6A writers	Promotes GBC cell proliferation, migration, and tumorigenicity	Destabilizes DUSP5 mRNA	[96]
			Promotes GBC progression	Regulates miR-92b-3p expression	[97]
Cholangiocarcinoma	METTL3	m6A writers	Facilitates glycolysis and CCA progression	Increase AKR1B10 expression via m6A-dependent manner	[101]
			Promotes CCA progression	Mediates IFIT2 mRNA degradation	[102]
			Facilitates iCCA proliferation and metastasis	Stabilizes NFAT5 mRNA	[103]
	METTL5	m6A writers	Promotes CCA progression	Mediating 18S rRNA m6A methylation	[104]
	METTL14	m6A writers	Promotes CCA progression	Disrupts Siah2 mRNA stability	[105]
	METTL16	m6A writers	Promotes ICC proliferation and metastasis	Up-regulates PRDM15-mediated FGFR4 expression	[106]
	VIRMA	m6A writers	Facilitates the malignant development of iCCA	Enhances the abundance of TMED2	[107]
			Facilitates the malignant development of iCCA	Enhances the abundance of PARD3B	[107]
			Promotes CCA progression	Activates the downstream target SIRT1	[108]
	IGF2BP1	m6A readers	Promotes iCCA progression	Activates the c-Myc/p16 and ZIC2/PAK4/AKT/MMP2 pathways	[109]
	YTHDF1	m6A readers	Induces CCA growth and metastasis	Regulates EGFR mRNA translation	[110]
			Induces CCA growth and metastasis	Mediating the m6A methylation of lncRNA CTBP1-AS2	[111]
	YTHDF2	m6A readers	Facilitates iCCA progression and chemoresistance	Destabilizes CDKN1B mRNA	[112]
	ALKBH5	m6A erasers	Promotes the malignant development of CCA	Increases the expression of PD-L1 to facilitate immune evasion	[113]

m6A: N6-methyladenosine; GBC: Gallbladder carcinoma; HCC: Hepatocellular carcinoma; PC: Pancreatic cancer; CCA: Cholangiocarcinoma.