Table 2.
Validated and potential mechanisms of metastasis mediating cell-free miRNAs
| Invasion & Migration | Activity | Targets | Target cell | Reference |
|---|---|---|---|---|
| miR-10b | Enhances invasion/migration, metastasis in vivo | HOXD10† | TC | [106, 247, 248] |
| miR-21† | Enhances invasion/migration, metastasis in vivo | SERPINB5, TMP1, PDCD4, MARCKS | TC | [88, 93, 95–97] |
| miR-126† | Decreases migration/invasion, enhances cell adhesion | CRK1 | TC | [108, 109] |
| miR-145 (exo‡) | Decreases invasion/migration, metastasis in vivo | AKT3 | TC | [249] |
| miR-155† | Promotes EMT | RHOA | TC | [250] |
| miR-221/222† | Enhance invasion/migration in vitro | PTEN, TIMP3 | TC | [251] |
| miR-373† | Enhances invasion/migration, metastasis in vivo | CD44 | TC | [107, 252, 253] |
| let-7c† | Decreases invasion/migration, metastasis in vivo | MMP11, PBX3 | TC | [254] |
| Intra-& Extravasation | Activity | Targets | Target cell | Reference |
|
| ||||
| miR-105 (exo) | Inhibits tight junctions, enhances vascular leakiness, metastasis in vivo | ZO-1 | EC | [167] |
| MET | Activity | Targets | Target cell | Reference |
|
| ||||
| miR-145 (exo‡) | Decreases E-cadherin expression in vitro | AKT3 | TC | [249] |
| miR-200 family† (miR-141 also exo) | Promote MET, enhance metastasis in vivo | ZEB1, ZEB2 | TC | [115, 116, 210] |
| miR-203† | Promotes MET | ZEB2, SMAD4 | TC | [255] |
| ECM & niche | Activity | Targets | Target cell | Reference |
|
| ||||
| miR-9 (exo) | Promotes angiogenesis and tumor growth in vivo | SOCS5 | EC | [173] |
| miR-17/92† | Promotes angiogenesis | TSP1, E2F1, CTGK | EC, TC | [256–259] |
| miR-21† | Establishes pro-metastatic niche | RECK, TIMP3, PTEN | [89, 97] | |
| miR-21, miR-29a (exo) | Induce pro-metastatic inflammatory response, enhance metastasis in vivo | TLR 7, TLR8 | IC | [147] |
| miR-27a† | Promotes EC-mediated angiogenesis | ZBTB10, SEMA6A | EC | [260, 261] |
| miR-29c† | Inhibits ECM (laminin & collagen) deposition | Collagens, LAMC1 | [262, 263] | |
| miR-126† | Promotes EC-mediated angiogenesis | SPRED1, PIK3R2, VEGFA, PIK3R2 | EC | [264–266] |
| miR-130† | Promotes EC-mediated angiogenesis | GAX, HOXA5 | EC | [267] |
| miR-145 (exo‡) | Decreases VEGF secretion and angiogenesis in vitro & in vivo | AKT3 | [249] | |
| miR-155† | Promotes angiogenesis | AT1R | EC | [268, 269] |
| miR-192 (exo) | Inhibits angiogenesis and metastasis in vivo | ICAM-1, IL-8, CXCL1 | EC | [270] |
| miR-210 (exo) | Promotes EC-mediated angiogenesis in vitro | EFNA3 | EC | [271] |
| miR-221/222† | Reduce EC-mediated angiogenesis | c-kit, eNOS* | EC | [272, 273] |
| miR-221/222† | Promote tumor induced angiogenesis | P27/KIP1 | TC | [274] |
| miR-378† | Promotes tumor induced angiogenesis | Sufu, Fus-1 | TC | [275] |
| miR-494, miR-542-3p (exo) | Establish pro-metastatic niche, enhance metastasis in vivo | Mal, Cdh17, Traf4 | LN stroma, lung fibroblasts | [276] |
| Renal CSC-derived exosomes | Promote EC-mediated angiogenesis | EC | [277] | |
| Stemness & growth | Activity | Targets | Target cell | Reference |
|
| ||||
| miR-21† | Promotes survival | BCL2 | TC | [98] |
| miR-21† | Promotes tumor growth | PTEN, BTG2, SPR2, P12/CDK2AP1 | TC | [132, 278, 279] |
| miR-126† | Decreases cell proliferation | CRK1 | TC | [264, 265] |
| miR-145 (exo‡) | Decreases cell proliferation, stemness in vitro | AKT3 | TC | [249] |
| miR-200 family (miR-141 also exo)† | Promotes survival and metastasis | Sec23a | TC | [115, 116, 210] |
| miR-221/222† | Promotes cell proliferation and tumor growth | p27/KIP1 | TC | [274, 280] |
| miR-375† | Decreases cell proliferation | SEC23A | TC | [210] |
| let-7 family† | Decrease cell proliferation, inhibit stemness | RAS, HMGA2, MYC | TC | [101–105] |
†
Studies entirely done on tumor miRNAs. Activity and targets potentially similar of cell-free miRNAs.
‡
Effects of miRNA were not tested in exosomes, but by overexpression/knockdown in tumor cells
EC, endothelial cell; EMT, epithelial-mesenchymal transition; exo, exosomal; IC, immune cell; LN, lymph node; TC, tumor cell