Table 2 Oncogenic signaling pathways modulated by m6A modification regulators
Signaling pathway | Cancer type | m6A regulator(s) | Up/downstream target(s) | Functional outcome/correlation | Reference |
|---|---|---|---|---|---|
Wnt/β-catenin | Hepatoblastoma (HB) | ↑ METTL3 | ↓ miR-186 (upstream of METTL3) | Increased proliferation, vascular invasion, metastasis, tumor recurrence | [29] |
Hepatoblastoma (HB) | ↑ METTL3 | ↑ CTNNB1 | Increased tumor growth | [30] | |
Epithelial ovarian carcinoma (EOC) | ↓ FTO ↓ ALKBH5 ↑ IGF2BP2 | ↑ FZD10 | Resistance to PARP inhibitors (PARPi) | [31] | |
Osteosarcoma (OS) | ↑ METTL3 | ↑ Lymphoid enhancer-binding factor 1 (LEF1) | Increased tumorigenesis | [32] | |
Pancreatic cancer (PC) | ↓ ALKBH5 | ↓Wnt inhibitory factor 1 (WIF-1) | Increased cancer cell proliferation, migration, and invasion Enhanced chemoresistance | [33] | |
Colorectal cancer (CRC) | ↑ YTHDF1 | ↑ FZD9 and WNT6 | Enhanced tumorigenicity and cancer stem cell formation | [34] | |
Gastric cancer (GC) | ↑ YTHDF1 | ↑ FZD7 | Aggressive gastric tumor development | [35] | |
Gastric cancer (GC) | ↓ METTL3 ↓ METTL14 ↑ FTO | ↑ β-Catenin ↑ Axin | Increased proliferation and invasiveness | [36] | |
PI3K/Akt/mTOR | Endometrial cancer | ↓ METTL3 ↓ METTL14 (R298P Mut) | ↓ PHLPP2 ↑ PRR5, PRR5L and mTOR | Increase proliferation and tumorigenicity | [37] |
Endometrial cancer | ↑ FTO | Unspecified | Increased proliferation and invasiveness | [38] | |
Gastric cancer (GC) | ↓ METTL14 ↑ FTO | Unspecified | Increased proliferation and invasiveness | [36] | |
Ovarian cancer | ↑ METTL3 | ↑ miR-126-5p | Increased ovarian cancer cell proliferation, migration and invasion Decreasing apoptosis | [39] | |
GI Cancers (Colorectal, gastric, esophageal, pancreatic, liver) | ↓ METTL14 ↑ FTO | ↑ PTEN, Akt1, PIK3CA and mTOR | Poor overall patient survival | [40] | |
Nasopharyngeal carcinoma (NPC) | ↑ YTHDC2 | ↑ Insulin-like growth factor 1 receptor (IGF1R) | Increased radiation resistance | [41] | |
Renal cell carcinoma (RCC) | ↓ METTL3 | Unspecified | Cancer progression, decreased overall survival | [42] | |
Cervical cancer | ↑ hnRNPA2B1 | Unspecified | Increased proliferation, migration and invasiveness | [43] | |
Breast cancer | ↑ FTO | Unspecified | Increased metabolic activity | [44] | |
High-grade serous ovarian carcinoma (HGSOC) | ↑ WTAP | Unspecified | Increased cell proliferation and migration Decreased apoptosis Poor overall patient survival | [45] | |
Pancreatic cancer (PC) | ↑ YTHDF2 | ↑ GSK3β | Increased cell proliferation | [46] | |
JAK-STAT | Hepatocellular carcinoma (HCC) | ↑ METTL3 ↑ YTHDF2 | ↓ SOCS2 | Increased HCC progression, poor overall and disease-free survival | [47] |
Colorectal cancer (CRC) | ↑ METTL3 | ↓ SOCS2 ↑ LGR5 | Increased stemness and chemoresistance | [48] | |
Gastric cancer (GC) | ↑ METTL3 | ↓ SOCS2 | Increased cancer cell proliferation | [49] | |
MAPK | Â | ||||
ERK1/2 | Renal cell carcinoma (RCC) | ↓ METTL14 ↑ FTO ↓ RBM15B | ↑ P2RX6 | Increased RCC migration and invasion | [50] |
p38/ERK | Colorectal cancer (CRC) | ↓ METTL3 | Unspecified | Increased tumor size, tumor advancement and metastasis | [51] |
Raf/MEK/ERK | Colorectal cancer (CRC) | ↑ METTL3 | Pri-miR-1246 (↑ miR-1246) | Increased invasiveness and metastasis | [52] |
Ras/Raf/ERK | Hepatocellular carcinoma (HCC) | ↑ METTL3 | ↓ RDM1 | Increased tumor progression | [53] |
|  | Gastric cancer (GC) | ↑ METTL3 | ↓ BATF2 | Increased gastric carcinogenesis | [54] |
p38 MAPK | Colorectal cancer (CRC) | ↓ YTHDC2 | Unspecified | Decreased apoptosis | [55] |
|  | High-grade serous ovarian carcinoma (HGSOC) | ↑ WTAP | Unspecified | Increased cell proliferation and migration Decreased apoptosis Poor overall patient survival | [45] |
|  | Hepatocellular carcinoma (HCC) | ↓ YTHDF2 | ↓ EGFR | Increased HCC cell proliferation | [56] |
p53 pathway | Pancreatic cancer (PC) | ↓ ALKBH5 | ↓ PER1 | Increased cell proliferation and invasiveness | [57] |
Clear cell renal cell carcinoma (ccRCC) | ↑ METTL3 ↑ METTL14 | Unspecified | Poor disease prognosis and overall survival | [58] | |
Esophageal carcinoma (ESCA) | ↑ HNRNPC | Unspecified | Activation of cell cycle progression | [59] | |
Colorectal cancer (CRC) | ↑ METTL3 | ↑ mut-p53 mRNA | Increased chemoresistance | [60] | |
Non-small cell lung cancer (NSCLC) | ↑ FTO | ↑ USP7 | Increased cancer cell proliferation | [61] | |
Hepatocellular carcinoma (HCC) | ↑ METTL3 | ↓ RDM1 | Increased tumor progression | [53] | |
Hippo pathway | Non-small cell lung cancer (NSCLC) | ↑ METTL3 ↑ YTHDF1 ↑ YTHDF3 | ↑ YAP1 ↑ MALAT1 (lncRNA) | Increased invasiveness and chemoresistance | [62] |
Non-small cell lung cancer (NSCLC) | ↑ ALKBH5 | ↓ YAP1 | Decreased tumor growth, invasiveness, metastasis and EMT | [63] | |
Lung adenocarcinoma (LUAD) | ↑ METTL3 | ↑ TAZ | Increased cell growth, survival and invasiveness | [64] | |
Colorectal cancer (CRC) | ↓ METTL14 | Pri-miR-375 (↓ miR-375) | Tumor progression Poor overall patient survival | [65] | |
Pancreatic cancer (PC) | ↑ YTHDF2 | ↑ Mob1 | Suppressed migration, invasiveness and EMT | [46] | |
NFκB pathway | Malignant transformed hepatocyte stem-like cells | ↑ METTL3 | CUDR (upstream) SUV39H1 (downstream) | Malignant transformation of hepatocyte stem-like cells | [66] |
MCF7/ADR HepG2/ADR | ↑ METTL3 | ↑ ERRγ | Chemoresistance | [67] | |
Ovarian cancer | ↑ ALKBH5 | ↑ NANOG | Carcinogenesis, increased cancer stem cells | [68] | |
Bladder cancer (BCa) | ↑ METTL3 | ↑ MYC | Increased cancer cell proliferation, migration and decreased apoptosis | [69] | |
Hedgehog pathway | Prostate cancer | ↑ METTL3 | ↑ GLI1 | Increased cancer cell survival, proliferation and invasiveness | [70] |
Notch pathway | Glioma | ↑ METTL3 | ↑ DLL1, DLL3, JAG2, NOTCH1–3 and HES1 | Increased tumorigenesis | [71] |
Snail pathway | Liver cancer | ↑ METTL3 ↑ YTHDF1 | ↑ Snail | Increased tumor progression | [72] |
Hepatocellular carcinoma (HCC) | ↑ METTL3 | ↑ SUMO1 (upstream) ↑ Snail (downstream) | HCC progression | [73] | |