Table 1.
Epi-miRs as potential cancer therapeutics.
| Epi-miRNA | mRNA Target | Cell Lines | Methods | Animal Study | Results | References |
|---|---|---|---|---|---|---|
| Breast cancer | ||||||
| miR-34a |
HDAC1
HDAC7 |
MCF-7, MDA-MB-231, BT-20, T47-D, PC3, DU-145, LNCaP, NIH:OVCAR, SK-OV-3, HeLa and non-transformed mammary MCF-10A cells | miR-34a mimics; luciferase reporter assay (in MCF-7, PC3, and MDA-MB-231 cells) | ND | miR-34a expression negatively correlates with tumor grades; transfection of miR-34a mimic reduces cell survival and increases the cytotoxicity of chemotherapy drugs; re-expression of miR-34a inhibits the tumorigenic activity of cancer stem cells (CSCs). | [82] |
| miR-101 | EZH2 | SKBR3 | pre-miR-101; luciferase reporter assay (in SKBr3 cells) | ND | miR-101 overexpression in SKBr3 attenuates cell proliferation, migration and inhibits the invasive potential. | [83] |
| miR-128 | BMI1 | SK-3rd, MCF-7 and SKBR3 | lentivirus vector miR-128; luciferase reporter assay (in SK-3rd and MCF-7 cells) | ND | Ectopic expression of miR-128 decreases cell viability and increases apoptosis and DNA damage in the presence of doxorubicin; ectopic miR-128 expression sensitizes BT-ICs (breast tumor–initiating cells) to doxorubicin enhancing the DNA damage and pro-apoptotic effects. | [84] |
| miR-148a | SMAD2 | MDA-MB-231 and Hs-578T | miR-148a mimics; luciferase reporter assay (in MDA-MB-231 cells) | BALB/c nude mice; MDA-MB-231 cells were injected s.c.; glabridin (GLA) was administered intragastrically each day. | GLA enhances the expression of miR-148a; GLA-treated tumors have increased expression of miR-148a and decreased expressions of SMAD2. | [75] |
| miR-185 | DNMT1 | MDA-MB-231, MDA-MB-361, MDA-MB-435, MDA-MB-468, MCF-7, T47D, BT-474, BT-20 and BT-483; normal mammary epithelial cell lines (HBL-100, 184A1 and MCF-10A) | miR-185 mimics | Nude mice; MDA-MB-231 cells were injected s.c.; intratumoral injection of miR-185 mimics. | Ectopic expression of miR-185 inhibits cell proliferation and induces apoptosis; inhibits tumor growth in vivo. | [85] |
| miR200b | SUZ12 | MCF-10A cells containing the ER-Src fusion gene, MCF7, SKBR3, MDAMB-231, MDA-MB-435, NSCCs (non-stem cancer cells) | miR-200b; luciferase reporter assay (in ER-Src cells) | Athymic nude mice; CSCs were pretreated with miR-200b and injected s.c.; ER-Src (treated and untreated with tamoxifen) were injected s.c. and then doxorubicin or combination doxorubicin and miR-200b was administered i.p. | miR-200b overexpression affects CSCs growth and reduces cell invasiveness; pretreatment of CSCs with miR-200b blocked tumor formation in vivo; combinatorial therapy (doxorubicin with miR-200b) causes regression of tumor growth and prevents relapse of the disease. | [72] |
| Bladder cancer | ||||||
| miR-101 | EZH2 | T24, UM-UC-3 and TCCSUP | vector pcDNA3.1 with pre-miR-101; luciferase reporter assay (in UM-UC-3 cells) | ND | Restored miR-101 expression inhibits cell proliferation, suppresses colony formation and hinders EZH2-mediated neoplastic progression. | [86] |
| miR-124 | UHRF1 | J82, T24, HEK 293 and SV-HUC-1 | miR-124 mimics; luciferase reporter assay (in HEK-293cells) | Male BALB/C-A mice; T24 cells were injected s.c. and then intratumoral injection was performed with miR-124 mimics. | miR-124 overexpression attenuates cell proliferation, migration, invasion and vasculogenic mimicry; inhibits tumor growth in vivo. | [87] |
| miR-144 | EZH2 | T24 | vector pcDNA–miR-144; luciferase reporter assay (in HEK293 cells) | ND | miR-144 overexpression inhibits cell proliferation; decreases EZH2 protein levels. | [88] |
|
miR-145-5p
miR-145-3p |
UHRF1 | T24 and BOY | pre-miR-145-5p and pre-miR-145-3p; luciferase reporter assay (in T24 and BOY cells) | ND | Ectopic expression of either miR-145-5p or miR-145-3p suppresses cancer cell growth, migration and invasion and induces apoptosis. | [89] |
| miR-148a | DNMT1 | SV-HUC-1, T24, TCCSUP, J82 and UM-UC-3 | miR-148a mimics; cisplatin or doxorubicin treatment | ND | miR-148a overexpression reduces cell viability by promoting apoptosis; combinatorial therapy (miR-148a/cisplatin or miR-148a/doxorubicin) enhanced apoptosis. | [71] |
| Colorectal cancer | ||||||
| miR-9 | UHRF1 | HCT116 and HT29 | miR-9 oligonucleotides; lentivirus vector miR-9; luciferase reporter assay (in HCT116 and HT29 cells) | ND | miR-9 overexpression attenuates CRC cell proliferation and promotes cell apoptosis; reduces UHRF1 expression. | [90] |
| miR-143 | DNMT3A | 228, CaCO2, Clone A, HCT116, HT-29, MIP101 and SW480 | pre-miR-143; luciferase reporter assay (in 228 and SW480 cells) | ND | Ectopic expression of miR-143 inhibits cell growth, reduces clone formation; restored miR-143 expression decreases tumor cell growth and soft-agar colony formation, and downregulates DNMT3A expression. | [91] |
| miR-342 | DNMT1 | SW480, HT29, HCT116 and HEK293T | miR-342 oligonucleotides; lentivirus vector miR-342; luciferase reporter assay (in SW480 cells) | Female athymic BABL/c nude mice; cell lines stably expressing miR-342 were injected s.c. | Enhanced miR-342 expression inhibits cell proliferation and invasion; miR-342 overexpression leads to demethylation and induction of tumor suppressor genes through blocking DNMT1 expression; miR-342 overexpression inhibits tumor growth and lung metastasis in vivo. | [92] |
| Endometrial cancer | ||||||
| miR-101 | EZH2 | SPAC-1-L and SPAC-1-S; HEC-50 and HOUA-I cell lines were derived from poorly-differentiated endometrioid EC (endometrial carcinoma) | vector with pre-miR-101-3p; luciferase reporter assay (in SPAC-1-L and HOUA-I cells) | ND | Ectopic overexpression of miR-101 suppresses cell proliferation, attenuates the epithelial-mesenchymal transition associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. | [93] |
| Esophageal cancer | ||||||
| miR-203 | BMI1 | EC9706 and KYSE150 | lentivirus vector miR-203; luciferase reporter assay (in EC9706 cells) | Female nude mice and nonobese diabetic/severe combined immunodeficient mice; freshly prepared cells were injected s.c. | miR-203 overexpression reduces colony formation, tumorigenicity ability and self-renewal of esophageal cancer stem-like cells; increases sensitivity to cisplatin. | [94] |
| Gastric cancer | ||||||
| miR-29b/c | DNMT3A | AGS and BGC-823 | miR-29b/c mimics; luciferase reporter assay (in BGC-823 cells) | ND | miR-29b/c overexpression decreases migration and reduces invasive ability; miR-29b/c suppresses the expression of DNMT3A. | [95] |
|
miR-146a
miR-146b |
UHRF1 | GC9811, GC9811-P, MKN28NM and MKN28M | pre-miR-146a/b; lentivirus vector miR-146a/b; luciferase reporter assay (in HEK293T and GC9811 cells) | Nude mice; metastasis assay: GC9811-P cells infected with miR-146a/b were injected into the tail vein. | Restored expression of miR-146a/b reduces the expression of UHRF1; upregulation of miR-146a/b suppresses metastasis. | [96] |
| miR-148a | DNMT1 | SGC-7901, BGC-823 and GES-1 (human gastric epithelium-immortalized cell line) | miR-148a mimics | ND | miR-148a mimics suppresses cell proliferation; miR-148a overexpression decreases DNMT1 expression and induces the overexpression of MEG3 (lncRNA). | [97] |
| miR-206 | HDAC4 | SGC-7901, BGC-823, AGS, non-malignant gastric cell line GES-1 and HEK293T | miR-206 mimics; vector with miR-206 | Nude mice; SGC-7901 cells carrying P2GM-miR-206 was injected s.c. | Ectopic expression of miR-206 represses cell proliferation, colony formation, invasion and migration; miR-206 promotes myogenic differentiation and blocks tumor growth in vivo. | [98] |
| Glioblastoma | ||||||
| miR-128 | Bim-1 | U87MG, U251MG and U373MG | pre-miR-128 mimics; lentivirus vector pri-miR-128-1; luciferase reporter assay (in U87, U251, and U373 cells) | Athymic mice; U87 cells stably expressing miR-128 were implanted s.c. | miR-128 expression reduces glioma cell proliferation, self-renewal in vitro and glioma xenograft growth in vivo. | [99] |
| miR-128 |
SUZ12
BMI1 |
U87 malignant glioma (MG) and U251MG glioblastoma cells | pre-miR-128; lentivirus vector miR-128; luciferase reporter assay (in HEK293 cells) | Mut3 mice (hGFAP-cre; Nf1flox/+; Trp532/+). | miR-128 overexpression reduces proliferative potential and colony formation; reestablishment of miR-128 expression impairs glioma stem-like cells self-renewal and increases their radiosensitivity. | [100] |
| Head and neck squamous cell carcinoma | ||||||
| miR-874 | HDAC1 | SAS, FaDu, HSC3, IMC-3, human fibroblast and MRC-5 | mature miR-874; luciferase reporter assay (in SAS cells) | ND | Restoration of miR-874 inhibits cell proliferation, induces cell cycle arrest and apoptosis. | [101] |
| Hepatobiliary cancer | ||||||
|
miR-152
miR-148a |
DNMT1 | KMCH-1, Mz-ChA-1, TFK-1 and H69; Mz-IL-6 (KMCH-1 stably transfected with IL-6) | pre-miR-152 and pre-miR-148a; luciferase reporter assay (in Mz-ChA-1 cells) | Male athymic nu/nu mice; Mz-IL-6 cells were injected s.c. | pre-miR-148a and pre-miR-152 decreases DNMT-1 protein expression and reduces cell proliferation; miR-148a and miR-152 expression was reduced in tumor cell xenografts in vivo. | [102] |
| Hepatocellular carcinoma | ||||||
| miR-22 | HDAC4 | Hep3B and SMMC7721 | miR-22 mimics; luciferase reporter assay (in Hep3B cells) | Male BALB/c athymic nude mice; miR-22 mimics transfected Hep3B or SMMC7721 cells were injected s.c. | Restoration of miR-22 expression suppresses cell proliferation and endogenous expression of HDAC4 protein; miR-22 transfection delays tumor formation and reduces tumor size in vivo. | [103] |
|
miR-29a
miR-185 |
DNMT3A
DNMT3B |
HepG2 and HuH-7 | dendrosomal curcumin (DNC) treatment | ND | Overexpression of miR-29a and miR-185 after dendrosomal curcumin (DNC) treatment, down-regulates the expression of DNMT1, 3A and 3B. | [74] |
| miR-145 | HDAC2 | Hep3B, HepG2, SNU-182, SNU-449 and PLC/PRF/5 | miR-145 mimics; vector with miR-145; luciferase reporter assay (in SNU-449 cells) | Male athymic nude mice; Hep3B cells transfected with miR-145 were injected s.c. | Ectopic expression of miR-145 inhibits cell growth and HDAC2 expression; inhibits tumor growth in vivo. | [104] |
| miR-200a | HDAC4 | SMMC-7721 and HepG2 | miR-200a mimics; lentivirus vector miR-200a; luciferase reporter assay (in SMMC-7721 cells) | Nude mice; HepG2 cells stably transfected with miR-200a were implanted s.c. | miR-200a inhibits cell proliferation and migration both in vivo and in vitro; miR-200a overexpression induces up-regulation of global acetyl-histone H3. | [105] |
| Acute myeloid leukemia | ||||||
| miR-29b |
DNMT3A
DNMT3B |
AML cell lines, Kasumi-1, MV4-11 and K562 | pre-miR-29b; lentivirus vector miR-29b; luciferase reporter assays (in K562 cells) | ND | Enforced expression of miR-29b in AML cells reduces of the expression of DNMT1, DNMT3A, and DNMT3B; pre-miR-29b overexpression induces partial differentiation of AML blasts. | [79] |
| miR-29b | DNMT3B | primary AML blasts, K562 and Kasumi-1 | synthetic miR-29b | Female nude mice; synthetic miR-29b oligonucleotides were injected directly into the tumors. | Restoring miR-29b expression, induces apoptosis and dampens cell growth in AML cells. | [106] |
| miR-193a-3p |
DNMT3A
HDAC3 |
HL60, U937, U937-A/E-HA, Kasumi-1, SKNO-1, SKNO-1-siA/E-RNA and KG1 | miR-193a mimics; lentivirus vector miR-193a; luciferase reporter assay (in 293T cells) | Nude mice; SKNO-1 cells were injected s.c.; intratumor injection of miR-193a. | Enhanced miR-193a levels induce G1 arrest, apoptosis, and restores leukemic cell differentiation; decreases tumor size in vivo. | [107] |
| Chronic myeloid leukemia | ||||||
| miR-217 | DNMT3A | Bcr/Abl-expressing K562 cells | lentivirus vector miR-217; luciferase reporter assay (in K562DR cells) | Female immune deficient BALB/c nude mice; K562 cells were injected s.c.; drug administration: dasatinib or 5-AzadC or a combination of both dasatinib and 5-AzadC. | Forced expression of miR-217 inhibits expression of DNMT3A and sensitizes cells to growth inhibition mediated by the tyrosine kinase inhibitors (prevents drug resistance). | [108] |
| Multiple myeloma | ||||||
| miR-29b |
DNMT3A
DNMT3B |
MM cell lines | pre-miR-29b mimics (formulated with a Neutral Lipid Emulsion (NLE) delivery system); lentivirus vector miR-29b; luciferase reporter assay (in INA-6 cells) | Male CB-17 severe combined immunodeficient (SCID) mice; MM cells were inoculated s.c.; miR-29b mimics were administered intratumorally and systemically via tail vein. | miR-29b mimics impair cell cycle progression and potentiate the growth-inhibitory effects induced by the demethylating agent 5-azacitidine; miR-29b mimics induce anti-tumor effects in vivo. | [70] |
| Leukemia | ||||||
| miR-143 | DNMT3A | AML (HL-60, NB4 and U937), CML (K562), acute erythroleukemia (HEL), T lymphocytic leukemia (Jurkat and CEM), B-cell lymphoma (CA46, Raji cells of Burkitt’s lymphoma) and multiple myeloma (U266) | lentivirus vector miR-143 | ND | miR-143 overexpression decreases DNMT3A mRNA and protein expression, reduces cell proliferation, colony formation and cell cycle progression as well as induces apoptosis. | [109] |
| Lung cancer | ||||||
| miR-29a, -b, -c |
DNMT3A
DNMT3B |
A549 and H1299 | pre-miR-29a, -29b-1, -29c oligonucleotides; luciferase reporter assay (in A549 cells) | Female nude mice; A549 cells transfected with pre-miR-29a, -29b, or -29c, were injected s.c. | Enforced expression of miR-29s restores normal patterns of DNA methylation, induces re-expression of methylation-silenced tumor suppressor genes and inhibits tumorigenicity in vitro and in vivo. | [68] |
|
miR-193a-3p
miR-193a-5p |
UHRF1 | SPC-A-1, SPC-A-1sci, A549, H1299, LC-21, H358 and HEK-293T | miR-193a-3p/5p mimics; lentivirus vector miR-193a-3p/5p; luciferase reporter assay (in HEK293T cells) | BALB/C-nu/nu nude male mice; metastasis assays: SPC-A-1sci cells stably expressing the miR-193a-3p/5p-mimic were injected into the tail vein. | miR-193a-3p/5p overexpression inhibits cell proliferation, migration, invasion and epithelial–mesenchymal transition (EMT); lung metastasis formation in vivo. | [110] |
| Lymphoma | ||||||
| miR-26a | EZH2 | human BL cell lines; murine MYC-induced lymphoma cell lines | vectors with mature miR-26a; luciferase reporter assay (in HEK-293 cells) | ND | miR-26a overexpression reduces cell numbers and results in an anti-proliferative effect. | [111] |
| Melanoma | ||||||
| miR-200c | BMI1 | WM35, WM793, WM115A, M3523A, 1205Lu and 293T | lentivirus vector miR-200c; vector pEZX-miR-200c | Male athymic nu/nu mice; miR-200c–WM115A cells were injected s.c. | miR-200c overexpression decreases cell proliferation, colony formation and migratory capacity as well as drug resistance and increases sensitivity to various chemotherapeutic agents (including cisplatin); inhibits melanoma xenograft growth and metastasis in vivo. | [112] |
| Neuroblastoma | ||||||
| miR-137 | EZH2 | Mouse Neuro-2a (N-2a); human SH-SY5Y | miR-137 mimics; resveratrol (RSV) treatment; luciferase reporter assay (in HEK293 cells) | ND | miR-137 expression is up-regulated after RSV treatment; miR-137 inhibits EZH2 expression after RSV treatment; miR-137 regulates the EZH2-mediated apoptosis after RSV treatment. | [73] |
| miR-124 | EZH2 | Neural Stem Cells (NSCs) and HEK293T | mature miR-124 | ND | miR-124 overexpression down-regulates expression of Ezh2 and up-regulates neuron-specific Ezh2 target genes; promotes neuronal differentiation. | [113] |
| miR-137 | KDM1A | IMR-32, SHEP, SKN-BE and HEK-293 | pre-miR-137; luciferase reporter assay (in SHEP and HEK293 cells) | ND | Re-expression of miR-137 increases apoptosis, decreases cell viability and proliferation, induces neuronal differentiation; downregulates KDM1A. | [114] |
| miR-152 | DNMT1 | SK-N-BE, SH-SY5Y, SK-N-AS and Kelly | pre-miR-152; luciferase reporter assay (in Kelly cells) | ND | Ectopic upregulation of miR-152 declines cell invasiveness and anchorage-independent cell growth, contributing to the differentiated phenotype. | [115] |
| Oral squamous cell carcinoma | ||||||
| miR-32 | EZH2 | SCC-4, SCC-9, SCC-25 and Tca8113; normal oral keratinocyte cell line (hNOK) | mature miR-32 mimics; luciferase reporter assay (in Tca8113 cells) | ND | miR-32 overexpression reduces cell proliferation, migration and invasion, promotes cell apoptosis; miR-32 down-regulates the expression of EZH2. | [116] |
| Ovarian cancer | ||||||
|
miR-15a
miR-16 |
BMI1 | OVCAR-5, OV-167, OV-202, CP-70, A2780 and OSE (ovarian surface epithelial cell) | pre-miR-15a, pre-miR-16; luciferase reporter assay (in OV-202 and CP-70 cells) | ND | miR-15a or miR-16 overexpression decreases cell proliferation and clonal growth; downregulates BMI1 protein levels. | [117] |
|
miR-152
miR-185 |
DNMT1 | SKOV3, A2780, A2780/DDP (cisplatin-resistant), A549 and HepG2 | miR-152 and miR-185 mimics; luciferase reporter assay (in SKOV3/DDP cells) | CD-1/CD-1 nude mice; SKOV3/DDP cells transfected with miR-152 that were injected i.p. | miR-152 or miR-185 overexpression increases cisplatin sensitivity by inhibiting proliferation and promoting apoptosis; promotes sensitivity to cisplatin through targeting DNMT1 directly. | [118] |
| Pancreatic cancer | ||||||
|
miR-148a
miR152 |
DNMT1 | MIA PaCa-2 and AsPC-1 | pre-miR-148b, pre-miR-152; luciferase reporter assay (in MIA PaCa-2 and AsPC-1 cells) | ND | miR-148b and miR-152 overexpression inhibits cell proliferation and induces apoptosis; decreases DNMT1 expression, returns DNA methylation to normal patterns and induces re-expression of tumor suppressor genes. | [119] |
| Prostate cancer | ||||||
| miR-101 | EZH2 | DU145 | pre-miR-101; luciferase reporter assay (in SKBr3 cells) | Male nude athymic BALB/c nu/nu mice, DU145 stable cells overexpressing miR-101 were injected s.c. | miR-101 overexpression attenuates cell proliferation, migration and invasive potential; reduces colony formation; reduces tumor growth in vivo. | [83] |
| miR-145 | DNMT3B | PC3 | miR-145 mimics; luciferase reporter assay (in PC3 cells) | ND | miR-145 overexpression downregulates the expression of DNMT3B; sensitizes prostate cancer cells to X-ray radiation. | [120] |
| miR-449a | HDAC1 | PC-3, DU-145, BPH-1 and LNCaP | mature miR-449a mimics; a longer, dicer-dependent pre-miR-449a; luciferase reporter assays (in PC-3 cells) | ND | miR-449 expression arrests cell cycle, apoptosis; regulates cell growth and viability in part by repressing the expression of HDAC-1. | [121] |
| Renal cell carcinoma | ||||||
| miR-101 | UHRF1 | 786-O and Caki-1 | pre-miR-101-3p; luciferase reporter assay (in 786-O cells) | ND | Restoration of miR-101 inhibits cell proliferation, migration and decreases invasion activity; suppresses UHRF1 expression. | [122] |
| Rhabdomyosarcoma | ||||||
| miR-29 | Yin Yang 1 (YY1) | C2C12 myoblasts, RH30 and RD2 | pre-miR-29; lentivirus vector miR-29; luciferase reporter assays (in MB cells) | Athymic nu/nu female mice; RH30 cells were injected s.c.; intratumoral injection of lentivirus with miR-29. | miR-29 overexpression reduces cell growth and increases levels of the differentiation markers; intratumoral addition of miR-29 stimulates myogenic differentiation; inhibits tumor growth in vivo. | [123] |
| Testicular cancer | ||||||
| miR-199a-3p | DNMT3A (especially DNMT3A2) | Ntera 2 (NT2) | miR-199a-3p mimics; luciferase reporter assay (in NT2 cells) | ND | miR-199a-3p overexpression restores the expression of tumor-suppressor genes by affecting DNA methylation of their promoter regions. | [124] |
| Waldenström macroglobulinemia | ||||||
| miRNA-9 * |
HDAC4
HDAC5 |
BCWM.1, WM-WSU, MEC-1 and RL | pre-miRNA-9 * | ND | Restoring miRNA-9 * levels induces toxicity, apoptosis and autophagy; supports down-modulation of HDAC4 and HDAC5 and up-regulation of acetyl-histone-H3 and -H4 | [125] |
ND—no data; s.c.—subcutaneous; i.p.—intraperitoneal injection. * miR-9-3p.