MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors
Abstract
:1. Introduction
2. Methodological Approach
3. Mechanism of Action of MiR-21 in Melanoma and Melanoma Cells
3.1. MiR-21 in Melanoma Pathogenesis and Progression
3.2. MiR-21 Targets in Melanoma Cells
3.3. Endogenous Upregulation of MiR-21 in Melanoma
3.3.1. Signal Transducer and Activator of Transcription 3
3.3.2. Hippo Pathway
3.3.3. Long Non-Coding RNAs
4. Exosome-Mediated MiR-21 Transport
4.1. Exosome-Mediated Transfer of MiR-21 to Melanocytic Lesions
4.2. Melanoma-Derived MiR-21-Enriched Exosomes and Melanoma Progression
4.3. Immunological Surveillance
4.4. MiR-21 Overexpression in Melanoma-Related Tumors
5. Environmental Factors Upregulating MiR-21
5.1. Radiation
5.1.1. Ultraviolet Irradiation
5.1.2. Cosmic Ionizing Irradiation
5.1.3. Electromagnetic Radiation
5.2. Metabolic Deviations Upregulating MiR-21
5.2.1. Metabolic Syndrome and Melanoma Risk
5.2.2. Birth Weight and Height in Childhood
5.2.3. Overweight and Obesity
5.2.4. Diabetes Mellitus
5.2.5. Arterial Hypertension
5.2.6. Western Diet
5.2.7. Smoking and Pollution
5.3. Hormonal Factors
5.3.1. Androgens
5.3.2. Growth Hormone
5.3.3. Vitamin D
5.4. Aging and Chronic Inflammation
5.4.1. Aging
5.4.2. Chronic Inflammation
6. Therapeutic Suppression of MiR-21
6.1. Vemurafenib
6.2. Metformin
6.3. Beta-Blocker
6.4. Anti-MiR-21
6.5. Interferons
6.6. High-Intensity Focused Ultrasound
6.7. Iontophoretic Co-Delivery of STAT3 siRNA and Imatinib
6.8. Curcumin
6.9. Sulforaphane
6.10. Epigallocatechin-3-Gallate
6.11. Vitamin D
6.12. Exercise
7. Conclusions and Perspectives
Funding
Conflicts of Interest
Abbreviations
References
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Associations of miR-21 with Melanoma Pathology | References |
---|---|
MiR-21 expression increases from benign nevi to MM and metastatic MM | [31,33] |
MiR-21 expression correlates with mitotic activity in MM | [34] |
MiR-21 levels correlate with MM cellularity | [36] |
MiR-21 promotes proliferation, migration, and inhibits apoptosis of MM cells | [31,32] |
MiR-21 expression correlates with Breslow thickness and advanced clinical stage | [31,33] |
MiR-21 expression correlates with positive sentinel lymph node biopsy | [34] |
MiR-21 promotes MM invasion and metastasis | [37] |
MiR-21 expression correlates with shorter 5-year disease-free or overall survival | [33] |
MiR-21 inhibits PD-L1 expression of MM-associated macrophages | [38] |
Antisense-mediated miR-21 inhibition suppresses growth, increases apoptosis and enhances chemo- or radiosensitivity of human MM cells | [33] |
Target Genes | Proteins | Functions | References |
---|---|---|---|
TIPE2 | Tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 | Inhibition of RAS | [43,44,45] |
SPRY1 | Sprouty RTK signaling antagonist 1 | Inhibition of RAS and RAF | [40,42] |
SPRY2 | Sprouty RTK signaling antagonist 2 | Inhibition of RAS and RAF | [42,49] |
PTEN | Phosphatase and tensin homolog | Inhibition of PI3K and downstream AKT-mTORC1 signaling | [40,49] |
PDCD4 | Programmed cell death 4 | Inhibition of translation initiation | [40,49] |
FBXO11 | F-box only protein 11 | Tumor suppression promoting apoptosis, exhibiting decreased expression in higher Clark level MM | [50] |
SOX5 | SRY-box 5 | Suppression of MITF | [51,52] |
CDKN2C | Cyclin-dependent kinase inhibitor 2C | Inhibition of G1/S transition, proliferation | [32,49] |
MSH2 | DNA mismatch repair protein 2 | DNA repair, prevention of microsatellite instability | [49,53] |
CYP27B1 | 25-hydroxyvitamin D3-1-α-hydroxylase | Conversion of 25(OH) vitamin D to active 1,25(OH)2 vitamin D3 | [54] |
RECK | Reversion-inducing cysteine-rich protein with Kazal motifs | Extracellular matrix integrity and regulation of angiogenesis | [49,55] |
TIMP1 | Tissue inhibitor of metalloproteinase 1 | Inhibition of MMP1-mediated matrix degradation | [49,56] |
TIMP3 | Tissue inhibitor of metalloproteinase 3 | Inhibition of MMP3-mediated matrix degradation | [49,57] |
CDH1 | E-cadherin | Cell-cell adhesion | [58] |
IL12A | p35 subunit of interleukin 12 | Anti-tumor activities via NK- and cytotoxic T cell activation | [59] |
AKT1S1 | AKT1 substrate 1, proline-rich | Negative regulator of mTORC1 | [60] |
Regulatory Agent | Transcriptional Regulator | MiR-21 Expression | References |
---|---|---|---|
AP1 | Activator protein 1 (Fos, Jun) | Upregulation | [25,92] |
STAT3 | Signal transducer and activator of transcription 3 | Upregulation | [25,57,69,70,71] |
p65 | Nuclear factor kappa-B, subunit 3 | Upregulation | [25] |
AR | Androgen receptor | Upregulation | [25,93] |
PU.1 | ETS-domain transcription factor PU.1 | Upregulation | [25] |
C/EBPα | CCATT/enhancer binding protein α | Upregulation | [25] |
TGFβ1 | Transforming growth factor β1 | Upregulation | [25] |
NFIB | Nuclear factor IB | Downregulation | [25] |
VDR | Vitamin D receptor | Downregulation | [94,95] |
XIST | X inactivation-specific transcript (lncRNA) | Downregulation | [79] |
MEG3 | Maternally expressed gene 3 (lncRNA) | Downregulation | [58] |
GAS5 | Growth arrest specific transcript 5 (lncRNA) | Downregulation | [87,88,89] |
Lifestyle Factor | Biological Responses | References |
---|---|---|
Ultraviolet radiation | Keratinocyte-derived release of miR-21-enriched exosomes; increased miR-21 expression of melanocytes | [163,164,165,166,167] |
Cosmic irradiation | Increase of exosomal miR-21 | [177,178,179,180,181] |
Electromagnetic radiation | Increased expression of miR-21 | [183] |
Obese adipose tissue | Adipocyte secretome with increased release of miR-21-enriched exosomes | [232,233,234,235,236] |
High-fat diet-induced obesity | Increase of circulatory and adipocyte miR-21 | [230,231] |
High glucose intake | Increase of circulatory miR-21 | [60] |
High fructose intake | Increase of circulatory miR-21 | [256] |
Alcohol consumption | Increase of circulatory miR-21 | [276,277] |
Milk consumption | Increase of circulatory exosomal miR-21 | [210,211,212,213] |
Vitamin D deficiency | Increased expression of miR-21 | [95] |
Smoking | Increased expression of exosomal miR-21 in airway epithelial cells | [287,288,289] |
Air pollution (Diesel) | Increased expression of exosomal miR-21 in airway epithelial cells | [290] |
Sedentary lifestyle | Increase of circulatory miR-21 | [334,335] |
Aging | Increase of circulatory miR-21 | [324,325] |
Chronic inflammation | Increase of circulatory miR-21 | [331,332,333] |
Therapeutic Factors | Potential Benefits for Melanoma Prevention and Therapy | References |
---|---|---|
Anti-miR-21 | Direct suppression of miR-21 signaling in melanocytes, activation of skin-resident CD8+ memory T-cells; reduction of miR-21 in tumor-associated macrophages associated with improved cytotoxic T-cell responses | [33,366,367,368,369,370,371] |
BRAF inhibition | Attenuation of miR-21 expression | [336] |
Sunscreen | Reduction of keratinocyte-derived exosomal miR-21 | [163,164,165,166,167] |
Restriction of electro-magnetic radiation | Limitation of smart phone radiation on miR-21 expression | [189,190] |
Control of birth weight and body weight | Balanced expression of miR-21 during fetal and postnatal life | [203,204] |
Reduction of glycemic load and fat intake | Reduction of circulating and adipocyte-derived miR-21 | [60,230,231,256] |
Cessation of smoking | Reduction of airway epithelial cell-derived exosomal miR-21 | [287,288,289] |
Restriction of alcohol intake | Reduction of miR-21 expression | [276,277] |
Metformin | Reduction of STAT3 activation and miR-21 expression | [349,350,352,353] |
Beta-blocker | Suppression of STAT3 activation and miR-21 expression | [364] |
Curcumin | Suppression of STAT3 activation and inactivation of AP-1 resulting in reduced expression of miR-21 | [380,381,382,383] |
EGCG | Reduction of miR-21 expression | [397,398] |
Sulforaphane | Reduction of miR-21 expression | [388,389] |
Vitamin D | Reduction of miR-21 expression | [54,95,307] |
Exercise | Reduction of miR-21 expression | [334,335] |
HIFU | Reduction of miR-21 in metastatic melanoma tissue | [376] |
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Melnik, B.C.; John, S.M.; Carrera-Bastos, P.; Schmitz, G. MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors. Cancers 2020, 12, 2111. https://doi.org/10.3390/cancers12082111
Melnik BC, John SM, Carrera-Bastos P, Schmitz G. MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors. Cancers. 2020; 12(8):2111. https://doi.org/10.3390/cancers12082111
Chicago/Turabian StyleMelnik, Bodo C., Swen Malte John, Pedro Carrera-Bastos, and Gerd Schmitz. 2020. "MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors" Cancers 12, no. 8: 2111. https://doi.org/10.3390/cancers12082111