NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward
Abstract
:Simple Summary
Abstract
1. Introduction
2. Brief Overview of the NRF2 Signaling Pathway: Negative and Positive Regulators and ARE Genes’ Targets
3. NRF2 Deregulation in Cancer: Focus on the Epigenetic Modifications
4. LncRNAs Intercepting the NRF2 Axis
4.1. LncRNAs Modulated by NRF2 Signaling
4.1.1. SCAL1 (LUCAT1)
4.1.2. NLUCAT1
4.1.3. NMRAL2P
4.1.4. TUG1
4.1.5. LINC00942
4.2. Positive and Negative LncRNA Regulators of the NRF2 Activity
4.2.1. HOTAIR
4.2.2. MALAT1
4.2.3. UCA1
4.2.4. BLNC1
4.2.5. MIAT and AK094457
4.2.6. SLC7A11-AS1
4.2.7. KRAL and NRAL
4.2.8. MT1DP
5. miRNAs Intercepting the NRF2 Axis
5.1. Positive miRNA Regulators of NRF2 Activity
5.2. Negative miRNA Regulators of NRF2 Activity
6. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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(A) | ||||||
LncRNA ID | Chr Location * | Role | NRF2 Levels | NRF2-Related Effects | Cell Cultures/Validation Models | Refs. |
SCAL1 (LUCAT1) | chr5: 91,285,160–91,314,516 | Transcriptional activity | Upregulated | Downstream mediator of NRF2 against ROS-induced oxidative stress, having a pro-tumorigenic role | HBE cells; Lung ADC and SqCC | [54,55] |
NLUCAT1 | 5q14.3 | Transcriptional activity | Upregulated | It induces a positive loop on the NRF2 network, correlates with hypoxic stress and contributes to tumor invasion and proliferation | A549 ADC cells | [56] |
NMRAL2P | chr3: 185,959,943–185,980,872 | Transcriptional activity | Upregulated | Downstream regulator of NRF2-dependent NQO1 activation. It exerts an oncogenic action by promoting EMT | Colon cancer cells | [57] |
TUG1 | chr22: 30,970,182–30,978,847 | Transcriptional activity | Upregulated | Oncogenic roles in apoptosis, proliferation and chemoresistance by modulating the NRF2 signaling | UCB cells; prostate cancer cells | [58,59] |
LINC00942 | chr12: 1,500,525–1,504,424 | Transcriptional activity | Upregulated | It concurs on NRF2 antioxidant pathway activation | 19 cancer types from TCGA | [60] |
(B) | ||||||
LncRNA ID | Chr Locations * | Role | NRF2-Related Effects | Cell Cultures/Validation Models | Refs. | |
HOTAIR | chr12: 53,962,308–53,974,956 | Negative regulator | Mediates histone H4 acetylation at the NFE2L2 gene promoter and is also involved in the epigenetic suppression via NRF2-MRP2/4 pathway | GC-1 spg; human hepatocytes L02 cells | [61,62] | |
MALAT1 | chr11: 65,497,688–65,506,431 | Positive regulator | Participates in MALAT1-mediated HUVEC protection from hydrogen peroxide and it is negatively regulated by KEAP1 | HUVEC cells; mouse primary hepatocytes | [63,64] | |
UCA1 | chr19: 15,828,206–15,836,136 | Positive regulator | It has an oncogenic role promotes proliferation through p21 repression, it enhances chemoresistance to cisplatin via UCA1/NRF2 crosstalk signaling by sponging miR-495 and promoting the inhibition of apoptosis | Human RCC cells; A549 lung ADC cells; HEK-293 cells | [65,66,67] | |
BLNC1 | chr9: 95,559,657–95,568,023 | Positive regulator | Participates in the hyperactivation of HO-1/NRF2 and crosstalks with NF-κB pathway by attenuating renal fibrosis, inflammation and oxidative stress | Renal HK-2 cells | [62] | |
MIAT | chr22: 26,657,520–26,676,475 | Positive regulator | Targets NRF2 by mediating high glucose- induced tubular injury | renal HK-2 epithelial cells | [68] | |
AK094457 | chr10: 124,745,200–124,748,551 | Positive regulator | Inversely correlates with the upregulation of NRF2 and HO-1 | VSMC cells | [69] | |
SLC7A11-AS1 | chr4: 138,089,014–138,178,177 | Negative regulator | Promotes resistance to gemcitabine by repressing SCFβ-TRCP-mediated degradation of NRF2 | PDAC cells | [70] | |
KRAL | 19q10.14 | Positive regulator | Increases sensitivity to fluorouracil by targeting miR-141/KEAP1 axis as ceRNA | HCC SMMC-7721 and HepG2 cells | [71] | |
NRAL | 19q10.14 | Negative regulator | Enhances resistance to cisplatin for NRF2 by binding to miR-340–5p | HCC SMMC-7721 and HepG2 cells | [72] | |
TUG1 | chr22: 30,970,182–30,978,847 | Positive regulator | Promotes cisplatin resistance by regulating and stabilizing the NRF2 protein | human EC TE-1 cells | [73] | |
MT1DP | chr16: 56,643,705–56,644,786 | Negative regulator | Enhances the sensitivity of NRF2 overexpression to erastin-induced ferroptosis by stabilizing miR-365a-3p | HCC HepG2 cells; NSCLC A549 and H1299 cells | [74,75] |
miRNA ID | Direct or Indirect Interaction/ Targets | NRF2-Related Effects | Cell Cultures/Validation Models | Refs. |
---|---|---|---|---|
Let 7b/c | Indirect; BACH1, HO-1 | Participates in negative regulation by suppressing BACH1 and thus stimulating the overexpression of HO-1 via NRF2 | HaCaT human keratinocytes cells; HCC (Huh-7 and HepG2) cells | [86,87] |
MiR-19b | Indirect; SIRT-1 | Stimulates the activation of SIRT1 by activating NRF2 cascade and its downstream target genes; enhancing drug hepatotoxicity | Human liver LO2 cells | [88] |
MiR-32 | Indirect; PI3K | Exerts an oncogenic role by inducing the upregulation of NRF2and promoting cells survival | Human RPE cells | [89] |
MiR-125b | Indirect; PRXL2A | Promotes PRXL2A activation by positive feedback loops involving NRF2 signaling pathway | OSCC (SAS, OECM1, HSC3, FaDu, OC3) cells, HEK-293 and primary NOK cells | [90] |
MiR-144 | Direct | Regulates the ROS scavenging via NRF2 and stimulates the GSH synthesis | Neuroblastoma SH-SY5Y cells | [91] |
MiR-153 | Direct | Acts as an oncogene by promoting cell migration and invasion via NRF2 signaling | CRC cells; OSCC (CAL 27) cells and tissues | [92] |
MiR-155 | Direct | Upregulates NRF2 and its downstream targets (HO-1 and NQO1) by inhibiting apoptosis and mediating ATO resistance | Human lung ADC A549 cells | [93] |
MiR-181c | Direct | Enhances the activation of NRF2 and other multiple pro-survival pathways | Human CRC (HT29) cells | [108] |
MiR-200a | Indirect; KEAP1 | Stimulates NRF2 signaling pathway by suppressing KEAP1 and decreasing ROS concentration | OB-6 human osteoblastic cells | [94] |
MiR-200c | Indirect; PI3K/AKT | Its downregulation provides a feedback mechanism by which NRF2 indirectly regulates E-cadherin and metastasis via PI3K/AKT activation | RPE (ARPE-19) cells | [89] |
MiR-365/193b/29b | Direct | Enforces NRF2 and its downstream targets activation | Lymphoblast cells | [96] |
MiR-432 | Indirect; KEAP1 | Targets KEAP1 and decreases the sensitivity to cisplatin (CDDP) drug via activation and stabilization of NRF2 | ESCC (KYSE170, KYSE770, and KYSE2270) cells | [100] |
MiR-455 | Indirect; HDAC2 | Promotes NRF2 expression via its upstream mediator, HDAC2, by ensuring more protection against oxidative injury and activating ARE-related genes (NQO1, HO-1 and GCLC) | MC3T3-E1 and hFOB1.19 osteoblastic cells | [101,102] |
MiR-601 | Indirect; CUL3/KEAP1 | Targets CUL3 and concurs into a dependent mechanism of CUL3-KEAP1-NRF2 activation against oxidative damage | RPE (ARPE-19) cells | [103] |
MiR-617/592/1207/550 | Direct | Exert a pro-oncogenic actions on the NRF2 upregulation; promote cell growth and proliferation by activating antioxidant defense system | ESCC cells; colorectal and liver carcinoma cells; prostate cancer cells | [41,104,105,106,107] |
miRNA ID | Direct or Indirect Interaction/Targets | NRF2-Related Effects | Cell Cultures/Validation Models | Refs. |
---|---|---|---|---|
MiR-28 | Indirect; KEAP1 | Exerts a negative effect by repressing NRF2 and inhibiting tumor cell growth independently from KEAP1, without any changes at protein level | Human breast MCF-7 and HEK-293 cells | [109] |
MiR-92a | Indirect; KEAP1/ARE | Its inhibition leads to cell proliferation by decreasing apoptosis-inducing factors and KEAP1 expression with a consequent upregulation of NRF2 and its target genes | HUVECs | [110] |
MiR-93 | Direct | Acts as a oncogenic regulator by downregulating NRF2 gene and by targeting specific 3′UTR sites with a strong impact on decreasing apoptosis, increasing colony formation and cell migration | Human breast epithelial MCF-10A and neoplastic T47D cells | [111] |
MiR-101 | Direct | Affects the binding to 3′UTR of NRF2, thus promoting NRF2 overexpression and inhibiting cell proliferation | Human breast MCF-7 cells | [112] |
MiR-140 | Direct | Targets NRF2 gene by ensuring more radioprotection against TGF-β1-mediated inflammation and fibroblasts differentiation | Human normal lung fibroblast (CCD-19Lu) and mammary epithelial MCF10A cells | [113,114] |
MiR-144 | Direct | Exerts an oncogenic role by inhibiting NRF2 signaling pathway as well as promotes cell viability, suppresses apoptosis and finally reverses chemoresistance NRF2-related | HL-60 AML and Bel-7402 HCC cells | [115,116] |
MiR-148b | Direct | Suppresses cell proliferation and regulates the oxidative stress response by downregulating HIF-1 and NRF2 and inhibiting ERMP1 | RL95-2 human endometrial cancer cells | [117] |
MiR-153/27a/142/144 | Direct | Act as oncogenic miRNAs which decrease apoptosis and successively reinforce cells proliferation via repressing NRF2 and its downstream target genes (GCLC, GSR) | Breast cancer and CRC cell lines; SH-SY5Y neuroblastoma cells | [92,118] |
MiR-155 | Direct | Accelerates cell malignant transformation by targeting NRF2-mediated oxidative damage and repressing NRF2 and its related gene expressions (GSH, NO and SOD) | 16-HBE cells | [119] |
MiR-181 | Indirect; SIRT1/PGC-1α | Suppresses SIRT1/PGC-1α/NRF2 signaling pathway by activating cell apoptosis and oxidative stress | SH-SY5Y neuroblastoma cells | [121] |
MiR-340 | Direct | Inhibits NRF2-dependent antioxidant pathway and enhancing cells sensitivity to cisplatin | HCC SMMC-7721 and HepG2 cells | [122] |
MiR-365 | Indirect; MT1DP | Represses NRF2 activity via direct binding to its 3′UTR and induce an aggravation of oxidative stress by activating MT1DP | HCC HepG2 cells | [74] |
MiR-507/634/450a/129 | Direct | Negatively affect NRF2 oncogenic regulation by directly targeting NRF2, thus increasing cisplatin sensitivity and suppressing cell growth | A549 ADC cells | [123,124] |
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Fabrizio, F.P.; Sparaneo, A.; Muscarella, L.A. NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward. Cancers 2020, 12, 3621. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123621
Fabrizio FP, Sparaneo A, Muscarella LA. NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward. Cancers. 2020; 12(12):3621. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123621
Chicago/Turabian StyleFabrizio, Federico Pio, Angelo Sparaneo, and Lucia Anna Muscarella. 2020. "NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward" Cancers 12, no. 12: 3621. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123621