Table 1.
Non-coding (Nc)RNAs, participating in EMT regulation in GC.
| NcRNA | Status in GC | Targets | Mechanism of Action | Functional Role | Reference |
|---|---|---|---|---|---|
| microRNAs: | |||||
| miR-5003-3p | Up | CDH1 | directly targets the 3′UTR of CDH1 at sites A and B | promotes migration, invasion and EMT | [82] |
| miR-200c | Down | ZEB1 | targets ZEB1 and thus increase E-cadherin expression | suppresses invasion and EMT | [72] |
| miR-101 | Down | EZH2 | targets EZH2 and thus increase E-cadherin expression | suppresses EMT | [73] |
| miR-148a | Down | SMAD2 | binds the 3′UTR of the SMAD4 and suppresses TGFβ-induced EMT | suppresses EMT, cell invasion and migration; low expression associated with advanced clinical stage and poor prognosis in GC | [79] |
| miR-29b/c | Down | DNMT3A | targets DNMT3A, thus modulating methylation of CDH1 promoter | suppresses EMT; significantly correlates with the degree of differentiation and invasion of the GC cells | [80] |
| miR-204 | Down | TGFBR2 | targets TGFBR2, regulating TGF-β | suppresses EMT, proliferation, invasion and migration | [81] |
| miR-217 | Up/Down | CDH1, PTPN14 | directly targets the 3′UTR of CDH1; directly targets the 3′UTR of PTPN14 |
promotes cells proliferation; suppresses EMT, low expression is correlated with metastasis | [83,86] |
| miRNA-9 | Up/Down | CDH1, RAB34, NFKB1, CDX-2 | targets 3′UTR of CDH1; being downregulated, target RAB34 and NFKB1, regulating E-cadherin indirectly | triggering cell motility and invasiveness, regulates EMT |
[84] |
| miR-544a | Up | CDH1 | directly targets CDH1 and AXIN2, regulate WNT signaling pathway | promotes EMT, cell motility and invasion; potential therapeutic target for metastatic GC | [85] |
| miR-199a-5p | Up | CDH1 | directly targets the 3′UTR of CDH1 | promotes EMT, cell invasion and metastasis; potential therapeutic targets and biomarkers for GC progression | [87] |
| miR-376a | Down | n/a | n/a | associated with advanced GC and poor prognosis | [88] |
| miR-381 | Down | TMEM16A | targets TMEM16A, thus regulating the TGF-β signaling pathway and EMT | suppresses EMT, decreases cell proliferation, migration and invasion | [89] |
| miRNA-96-5p | Down | FoxQ1 | binds to the 3′UTR of FoxQ1, decreasing the protein level of FoxQ1; upregulates the expression of E-cadherin and downregulates the expression of vimentin | suppresses the proliferation, migration and EMT | [90] |
| miR-574-3p | Down | ZEB1 | bounds 3′-UTR of ZEB1, thus upregulating E-cadherin expression, and concomitantly downregulating the expression of vimentin. | inhibits cancer cell migration, invasion, EMT; modulates cisplatin sensitivity in vitro and in vivo | [91] |
| miR-1254 | Down | SMURF1 | downregulating SMURF1 and thus inhibits EMT and decreases the PI3K/AKT signaling pathway | inhibits proliferation, migration, invasion, and EMT | [92] |
| miR-588 | Down | EIF5A2 | directly binds to 3′-UTR of EIF5A2 | suppresses cell invasion, migration, and progression of EMT | [93] |
| miR-218 | Down | BMI1, WASF3 | inhibits the expression of BMI1 and its downstream targets p-Akt473 and MMPs; directly inhibits expression of WASF3 | inhibits EMT, proliferation, invasion, and migration | [94,95] |
| miR-370 | Down | PAQR4 | directly inhibits expression of PAQR4 | inhibits the proliferation, invasion, and EMT | [96] |
| miR-711 | Down | CD44 | targets CD44 and thus downregulates vimentin expression and upregulates E-cadherin expression | inhibits the invasion, migration, and EMT | [97] |
| miR-543 | Up | SPOP | directly inhibits expression of SPOP | promotes EMT, cell migration, and invasion | [98] |
| miR-361-5p | Down | FOXM1 | suppresses the expression of MMP-3, MMP-9 and VEGF, increases expression of E-cadherin; acting through Wnt/β-catenin pathway; targets FOXM1, acting through the PI3K/Akt/mTOR pathway | inhibits EMT, cell proliferation, and mobility; low expression is correlated with larger tumor size and advanced TNM stage. | [99,100] |
| miR-592 | Up | SPRY2 | targets SPRY2 and acting through PI3K/AKT and MAPK/ERK signaling pathways | promotes proliferation, migration, and invasion, induces the EMT | [101] |
| miR-616-3p | Up | PTEN | directly inhibits expression of PTEN | promotes EMT, angiogenesis and metastasis; high expression is correlated with poor prognosis | [102] |
| miR-495 | Down | TWIST1 | directly inhibits expression of TWIST1 | decreases cell viability and migration, increases apoptosis and inhibits the EMT | [103] |
| miR-1271 | Down | FOXQ1 | directly suppressing FOXQ1 expression | suppressed cell proliferation, invasion, and EMT; correlated with tumor size, tumor stage, lymph node metastasis, and TNM stage | [104] |
| miR-491-5p | Down | SNAIL | directly inhibits SNAIL expression; indirectly inhibits FGFR4, also decreasing the SNAIL level | suppresses EMT and tumor metastasis | [105] |
| miR-338-3p | Down | ZEB2 and MACC1 | targets ZEB2 and MACC1/Met/Akt signaling, thus upregulating the E-cadherin and downregulating the N-cadherin, fibronectin, and vimentin | inhibits EMT, migration, and invasion | [106] |
| miR-124 | Down | SNAIL2 | represses the SNAIL2 expression | inhibits EMT, cell proliferation, and invasion; lower expression is associated with tumor size, lymphatic metastasis, and TNM stage | [107] |
| miR-379 | Down | FAK | directly binds to 3′-UTR of FAK, resulting in suppression of AKT signaling | inhibited cell migration, invasion and EMT; low expression is associated with poor prognosis, lymph node metastasis, and advanced TNM stage | [108] |
| Long non-coding RNAs: | |||||
| HOTAIR | Up | PCR2, miR-34a, c-MET, SNAIL1, CDH1, miR-152 | switching the acetylation of histone H3 lysine 27 to the methylation of the E-cadherin promoter, inducing its transcriptional inhibition; inactivates miR-34a, which activates the HGF/c-MET/SNAIL pathway and thus indirectly inhibits E-cadherin; targets miR-17-5p and thus regulates expression of PTEN | promotes EMT, facilitates viability, proliferation, and metastasis; higher expression correlates with lymphatic metastasis and TNM stage | [109,110,111,112] |
| XLOC_010235 | Up | SNAIL1 | inactivates SNAIL1, thereby upregulating E-cadherin expression | promotes EMT; high expression correlates with metastasis and TNM stage | [113] |
| ZFAS1 | Up | ZEB1 | activates the EMT inducer ZEB1 | promotes EMT | [114,115] |
| MALAT1 | Up | SNAIL, N-cadherin, ZEB1 | targets SNAIL, N-cadherin, and ZEB1, thus decreasing E-cadherin expression | promotes EMT, invasion, angiogenesis, and metastasis | [116,117] |
| FRLnc1 | Up | TWIST, TGFβ-1 | activates the TGFβ-1 and TWIST | promotes EMT, invasion, and migration of cells | [118] |
| LINC00978 | Up | TGFβ/SMAD, TWIST, SLUG | activates the TGF-β/SMAD regulatory pathway, thus decreasing E-cadherin expression | promotes EMT, invasion, and migration of cells, decreases apoptosis | [119] |
| UCA1 | Up | TGFβ | targets TGFβ, decreases the levels of vimentin and SNAIL, thus regulating levels of E-cadherin and ZO-1 | promotes EMT, associated with invasion and metastasis | [120] |
| TUG1 | Up | CDH1 | interacts with PRC2, epigenetically repressing cyclin-dependent kinase inhibitors (P15, P16, P21, and P57); downregulation of E-cadherin | promotes EMT, cell proliferation, and metastases, predicts a poor prognosis | [121,122] |
| Linc00152 | Up | miR-193b-3p | directly inhibits expression of miR-193b-3p, leading additionally to ETS1 upregulation | promotes EMT, proliferation, migration, and invasion | [123] |
| XIST | Up | miR-101 | acts as a sponge for miR-101, and modulates EZH2 expression | promotes EMT, cell proliferation, and invasion | [124] |
| lncRNA-ATB | Up | miR-200 | acts through the TGF-β/miR-200/ZEB regulatory axis, thus decreasing E-cadherin expression | promotes EMT | [125] |
| SNHG1 | Up | miR-140 | acting as a sponge, repress miR-140 expression and thereby elevated its down-stream target ADAM10 | promotes EMT, proliferation, and invasion; linked with poor prognosis in cancer patients. | [126] |
| SNHG6 | Up | miR-101-3p | acts as sponge for miR-101-3p, thereby upregulating ZEB1 at the post-transcriptional level and regulating E-cadherin; epigenetically inactivates P27 through EZH2-dependent histone H3 methylation in the promoter of the P27; activates the JNK pathway and upregulate P21 | promotes EMT, invasion, migration, and metastasis | [65,127] |
| AF147447 | Down | MUC2, miR-34c | acts as sponge for miR-34c, thus regulating MUC2, EGFR, and CD44 expression | suppresses EMT, cell invasion, and proliferation | [128] |
| SNHG5 | Down | MTA2 | provides a cytoplasmic trap for MTA2, directly binding to it and preventing its transfer from the cytoplasm into the nucleus | suppresses EMT, cell invasion, proliferation, and metastases | [129] |
| Linc00261 | Down | SLUG | promotes SLUG degradation | suppresses EMT, cell invasion, and proliferation | [130] |
| AFAP1-AS1 | Up | CDH1 | upregulates E-cadherin and downregulates N-cadherin and vimentin | promotes EMT, invasion, and proliferation, associated with invasion in lymph nodes, distant metastasis, advanced TNM stages, and poor prognosis. |
[131,132] |
| CASC15 | Up | CDH1, miR-33a-5p, EZH2 | targets CHD1; interacts with EZH2 and WDR5, recruits them to the CDKN1A promoter region, and thus modulates CDKN1A expression in the nucleus; acts as a sponge for miR-33a-5p and activates ZEB1 in the cytoplasm | promotes EMT, invasion, and proliferation, associated with poor prognosis | [133] |
| ZEB1-AS1 | Up | miR-335-5p | downregulates miR-335-5p expression by acting as a molecular sponge | promotes EMT, invasion, and proliferation, correlates with lymph node metastasis, TNM stage, and poor overall survival of patients | [134,135] |
| NEAT1 | Up | miR-506, CDH1 | acts through the NEAT1/miR-506/STAT3 regulatory axis; targets CHD1 | promotes EMT, invasion, and migration, correlates with more advanced stages, metastasis, and a low overall survival in patients | [136,137] |
| RP11-789C1.1 | Down | miR-5003-3p | acts as sponge for miR-5003-3p | promotes migration, invasion, and EMT; correlates with metastases | [82,138] |
| LINC00675 | Down | vimentin | regulates vimentin expression | suppresses proliferation, migration, invasion, and EMT | [139] |
| SOX2OT | Up | miR-194-5p | act as sponge for miR-194-5p | promotes EMT, cell proliferation, invasion, and migration | [140] |
| LINC01133 | Down | miR-106a-3p | act as sponge for miR-106a-3p, which specifically targets the APC, and thus inactivates the Wnt/β-catenin pathway | inhibits proliferation, migration, EMT and metastasis | [141] |
| MEG3 | Down | miR-21 | act as sponge for miR-21; downregulating the expression of MMP-3, MMP-9, and VEGF; increases the expression of E-cadherin and downregulates the expression of N-cadherin, Snail, and β-catenin | suppresses EMT and cell mobility | [142] |
| SNHG14 | Up | miR-145 | negatively regulates miR-145 and thus affects its direct target; involved in PI3K/AKT/mTOR pathway | promotes EMT, cell viability, migration, invasion, and inhibits apoptosis | [143] |
n/a—not available, EMT—Epithelial–Mesenchymal Transition.