Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment
Abstract
:1. Introduction
2. Role of Non-Coding RNAs in TME
2.1. Cytokines and Non-Coding RNA Intertwined in TME
2.2. Exosomes as External and Internal Carriers of Non-Coding RNAs in TME
2.3. Role of Non-Coding RNA in Cancer-Associated Fibroblasts (CAFs) in TME
2.4. Non-Coding RNA in the Regulation of Response of Macrophages in TME
2.5. Non-Coding RNAs in the Regulation of T-Cell Activity in the TME
2.6. Non-Coding RNAs in the Regulation of B Cells in TME
2.7. Non-Coding RNA in the Regulation of EMT in TME
3. RNA Sequencing to Characterize ncRNAs in the TME
3.1. RNA Sequencing for Breast Cancer
3.2. RNA Sequencing for Lung Cancer
3.3. RNA Sequencing of Colorectal Cancer
3.4. RNA Sequencing of Ovarian Cancer
3.5. RNA Sequencing of Prostate Cancer
3.6. RNA Sequencing of Gastric Cancer
3.7. RNA Sequencing of Pediatric Cancers
3.7.1. RNA Sequencing of Pediatric Leukemias
3.7.2. RNA Sequencing of Pediatric Brain Tumors
4. ncRNA Promising Drugs and Drug Targets in Cancer Treatment
4.1. ncRNA-Based Therapeutics in Cancer Treatment
4.1.1. MiRNA-Based Therapeutics for Cancer Treatment
4.1.2. eRNA-Based Therapeutics for Cancer Treatment
4.1.3. CircRNA-Based Therapeutics for Cancer Treatment
4.1.4. lncRNA-Based Therapeutics for Cancer Treatment
4.1.5. siRNA-Based Therapeutics for Cancer Treatment
4.1.6. piRNA-Based Therapeutics for Cancer Treatment
4.1.7. saRNA Small Activating RNA-Based Therapeutics for Cancer Treatment
4.2. Therapeutics Targeting ncRNAs in Cancer Treatment
5. Achievements and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AI | Artificial Intelligence |
ALL | Acute Lymphoblastic Leukemia |
AML | Acute Myeloid Leukemia |
Bru | 5′-Bromouridine |
Bulk RNA-seq | Bulk RNA Sequencing |
CAF | Cancer-Associated Fibroblasts |
Cas9n | Cas9 nickase |
CHIP | Chromatin Immunoprecipitation |
circRNA | Circular RNA |
CML | Chronic Myeloid Leukemia |
CTR9 | Component of PAF complex |
DC | Dendritic Cells |
DLBC | Diffuse Large B Cell Lymphoma |
EMT | Epithelial-Mesenchymal Transition |
ERG-TMPRSS2 | Ets-Related Gene—Transmembrane Protease Serine 2 |
eRNA | Enhancer RNA |
ESCA | Esophageal Carcinoma |
EU | Ethynyluridine |
GD-PEG-ECO | arginine/glycine/aspartate peptide—polyethylene glycol-1-aminoethyliminobis[N-oleicylcysteinyl-1-aminoethylpropionamide |
HBOC | Hereditary Breast And Ovarian Cancer Predisposition Syndrome |
hnRNP | Heterogeneous Nuclear Ribonucleoprotein |
HNSCC | Head And Neck Squamous Cell Carcinoma |
IL-1Ra | Interleukin-1 Receptor Antagonist |
KICH | Kidney Chromophobe |
LGG | Brain Lower Grade Glioma |
lncRNA | Long Non-Coding RNA |
LUAD | Lung Adenocarcinoma |
LUSC | Lung Squamous Cell Carcinoma |
LUSC | Lung Squamous Cell Carcinoma |
miRNA | Micro-RNA |
ncRNA | Non-Coding RNA |
NK | Natural Killers |
NSCLC | Non-Small Cell Lung Cancer |
PAMAM | Poly(Amidoamine) |
paRNA | Promoter-Associated RNA |
pBs | Peripheral Blood Cells |
pDCs | Plasmacytoid Dendritic Cells |
piRNA | PIWI-Interacting RNA |
RHA | RNA helicase A |
RNAP II | RNA polymerase II |
rRNA | Ribosomal RNA |
RT-qPCR | Reverse Transcription–Quantitative Polymerase Chain Reaction |
s4U | 4-Thiouridine |
saRNA | Small activating RNA |
SCLC | Small Lung Cell Cancer |
sc-RNA-seq | Single-Cell RNA Sequencing |
siRNA | Small Interfering RNA |
SKCM | Skin Cutaneous Melanoma |
snoRNA | Small Nucleolar RNA |
snRNA | Small Nuclear RNA |
sp-RNA-seq | Spatial RNA Sequencing |
TERC | Telomerase RNA |
THCA | Thyroid Carcinoma |
TIMER | Tumor Immune Estimation Resource |
TME | Tumor Microenvironment |
TNBC | Triple-Negative Breast Cancer |
TNF | Tumor Necrosis Factors |
tRF | TRNA Derived Fragments |
tRNA | Transfer RNA |
UVM | Uveal Melanoma |
XAI | Explainable Artificial Intelligence |
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Method | Brief Description | Advantages | Disadvantages | References |
---|---|---|---|---|
RT-qPCR | Technique based on PCR | High sensitivity | Time-consuming; requires primers; Allows for the evaluation of the expression of known transcripts | [9] |
Microarray | Technique based on the ability of complementary nucleic acid molecules to form double-stranded structures | Well-defined protocols for hybridization | Stringent criteria for sample collection requires a high quantity of RNA; expensive | [10] |
Bulk RNA-seq | Technique to evaluate mean gene expression of thousands of cells | Costs less than single-cell and spatial RNA-seq; requires less time compared to single-cell RNA-seq and spatial RNA-seq | Less detailed information on individual cells provide averaged gene expression in whole cells | [11] |
Single-cell RNA-seq | Sequencing technique to evaluate mRNA in a single cell | Enables analysis of the whole transcriptome including non-coding sequences; low background noise | Requires adequate preparation of tissue/cells; expensive; time-consuming; does not provide spatial information on transcriptome | [12] |
Spatial RNA-seq | Sequencing technique for evaluation of mRNA in the tissue area | Analyzes the whole transcriptome evaluates the interactions between cancer cells and tumor microenvironment | Requires adequate preparation of tissue/cells; cannot analyze a single cell; expensive; time-consuming | [13] |
Metabolic labeling | Technique in which RNA is labeled with uracil analogs (s4U, EU, Bru) in cell culture | Efficient; well-validated; high resolution | Uracil analogs are cytotoxic | [14] |
Nuclear run-on | Technique in which RNA in the isolated nucleus is labeled | Measurement of transcription in the primary state; allows distinct transcription and post-transcription changes in gene expression | Requires the ice-cold temperature to isolate nuclei; requires a large number of cells; results are dependent on the efficient induction of transcription outside the cell | [15] |
Chromatin immunoprecipitation (ChIP) | Technology based on antibodies to selectively isolate DNA-binding proteins and their DNA targets | Allows monitoring of changes in a single promoter in a time-dependent manner; may be used to follow transcription factors in the whole human genome | Low resolution; expensive; risk of protein rearrangement during analysis | [16] |
Type of ncRNA | Clinical Trial | Objectives of Study | Cancer | Reference |
---|---|---|---|---|
EphA-2 siRNA (siRNA) | Phase 1 (recruiting) | Silencing EphA-2 | Solid tumors | [188,189] |
CpG-STAT3 siRNA CAS3/SS3 (CpG oligonucleotide and siRNA) | Phase 1 (recruiting) | Downregulation of STAT3 | Relapsed B-cell non-Hodgkin lymphomas | [190] |
KRAS G12- LODER (siRNA) | Phase 1 (recruiting) | Silencing KRAS G12D | Pancreatic cancer | [191,192] |
Phase 2 (recruiting) | Silencing KRAS G12D to increase the anticancer activity of gemcitabine in combination with nab-paclitaxel or FOLFIRINOX chemotherapy | Pancreatic cancer | [193] | |
GSTP siRNA/NBF-006(siRNA) | Phase 1 (recruiting) | Silencing GSTP to decrease KRAS signaling pathway | NSCLC Pancreatic cancer Colorectal cancer | [194,195] |
Two siRNAs: TGF-β1 COX-2 /STP705 (siRNA) | Phase 2 (not recruiting) | Silencing expression of TGF-β1 and COX-2 to inhibit cell survival and induce tumor cell apoptosis | Cutaneous squamous cell carcinoma skin cancer | [196,197] |
DCR-MYC (siRNA) | Phase 1/2 (terminated) | Inhibition of MYC expression | Hepatocellular carcinoma | [198] |
Phase 1 (terminated) | Inhibition of MYC expression | Solid tumors Multiple Myeloma Non-Hodgkins Lymphoma Pancreatic Neuroendocrine Tumors Primary Central Nervous system tumors (PNET) N | [199] | |
TBI-1301 (siRNA) | Phase 1 (active) | Silencing endogenous TCR on T cells in combination with cyclophosphamide and fludarabine | Synovial Sarcoma Melanoma Esophageal Cancer Ovarian Cancer Lung Cancer Bladder Cancer Liver Cancer | [200] |
Phase 1/2 (active) | Combination of TBI-1301 and cyclophosphamide | Synovial Sarcoma | [201] | |
Phase 1 (unknown) | Combination of TBI-1301, cyclophosphamide and fludarabine | Solid tumors | [202] | |
TKM-080301 (siRNA) | Phase 1/2 (completed) | Inhibition of PLK1 expression | Hepatocellular carcinoma Hepatoma Liver cancer | [203] |
Phase 1/2 (completed) | Neuroendocrine Tumors Adrenocortical Carcinoma | [204] | ||
Phase 1 (completed) | Solid cancers with hepatic metastases | [205] | ||
INT1-B3 (mimic miRNA) | Phase 1 (recruiting) | Mimic miRNA-193a-3p | Solid tumors | [206] |
MRX34 (mimic miRNA) | Phase 1/2 (withdrawn) | Combination of MRX34 and dexamethasone | Melanoma | [207] |
Phase 1 (terminated) | Mimic miRNA-34 | Primary Liver Cancer SCLC Lymphoma Melanoma Multiple Myeloma Renal Cell Carcinoma NSCLC | [208] | |
Mesomir-1 (mimic miRNA) | Phase 1 (completed) | Mimic miRNA-16 | Malignant Pleural Mesothelioma NSCLC | [209] |
MTL-CEBPA (saRNA) | Phase 2 (recruiting) | Increase C/EBP-α expression | Hepatocellular carcinoma | [210,211] |
Phase 1 (active) | Combination therapy of MTL-CEBPA and pembrolizumab | Breast cancer Lung Cancer Ovarian Cancer Pancreatic cancer Gall bladder cancer Hepatocellular cancer Neuroendocrine cancer Cholangiocarcinoma | [212] | |
Phase 1 (active) | Combination therapy MTL-CEBPA and sorafenib | Hepatocellular carcinoma | [213] | |
Phase 1 (recruiting) | Combination therapy MTL-CEBPA and atezolizumab and bevacizumab | Hepatocellular carcinoma | [214] |
Gapmer | Cancer | Function | Type of Research | Reference |
---|---|---|---|---|
CT102 gapmer for IGF1R mRNA | HCC | Inhibition of PI3K/AKT pathway, Induction of apoptosis in tumor cells by interaction with GAS2, POLA2, LGALS2 | In vitro, in vivo | [220] |
Gapmers for ALKBH5 or FTO | Clear Renal Cell Carcinoma | Inhibition of migration, proliferation of tumor cells, downregulation of Vimentin and PCNA | In vitro | [221] |
Gapmer for HIF1A-As2 | NSCLC | Increase sensitivity of NSCLC tumors to MYC inhibitor (10058-F4) and cisplatin treatment Inhibition of colony formation, spheroid formation in vitro Inhibition of tumor growth in PDX (patient-derived xenograft) model | In vitro, in vivo | [222] |
Gapmer for SRRM4 | NSCLC, Prostate cancer | Reduction in cell growth | In vitro | [223] |
Gapmer for SOX12 | Human Acute Myeloid Leukemia Cells | Inhibition of expression of SOX12 Activation of apoptosis by increased activity of caspase 3 and 9 | In vitro | [224] |
Gapmer for Smyca | Breast cancer | Inhibition of TGF-β/Smad and c-Myc pathways Inhibition of tumor growth | In vitro In vivo | [225] |
Gapmer for GGCT | Lung cancer | Inhibition of expression of GGCT to decrease the viability of tumor cells Activation of apoptosis via caspase 3 and 8 Activation of AMPK Inhibition of tumor growth | In vitro, in vivo | [226] |
Gapmer for p53 mutant protein | Breast and pancreas cancers | Inhibition of cell viability and proliferation Decrease expression of proapoptotic protein Bcl-2 | In vitro | [227] |
Gapmer for lncRNA MIR100HG | Acute Megakaryocyte Leukemia | Inhibition of lncRNA MIR100HG Induction of apoptosis Increased level of TGF-B expression | In vitro | [228] |
G3139 for Bcl-2 mRNA | Breast cancer | Reduction in cell viability of breast cancer cells Induction of apoptosis Inhibition of tumor growth Decreasing expression of Bcl-2 | In vitro, in vivo | [229] |
Gapmer for SRRM4 | SCLC | Inhibition of miRNA-4516 expression Inhibition of cell growth | In vitro, in vivo | [230] |
Gapmer for NEAT1 | Multiple Myeloma | Inhibition of cell Activation of caspase 3 Inhibition of cell proliferation Inhibition of tumor growth | In vitro, in vivo | [231] |
Gapmer ISTH0047 and ISTH2047 | Glioblastoma | Decrease expression of TGFB1/2 Inhibition of migration and invasion Increased survival of rodent glioma models in vivo | In vitro, in vivo | [232] |
Gapmer for b2a2 and b3a2 BCR/ABL | Leukemia | Inhibit viability of cells Activation of executive caspases 3/7 | In vitro | [233] |
SPC3042 | Prostate cancer | Increase expression of caspase 3/7 activity Decrease expression of antiapoptotic Bcl-2 mRNA Decrease tumor weight in combination with taxol | In vitro, in vivo | [234] |
Gapmer for DNp73 | Lung cancer, Melanoma | Induction of apoptosis Inhibition of tumor growth | In vitro, in vivo | [235] |
Gapmer for let-7 miRNA | Multiple myeloma | Decrease expression of MYC, KRAAS, CCND1, E2F6, DICER1, HMGA1 Inhibition of tumor growth | In vitro, in vivo | [236] |
Gapmer for Bcl-2 | Lung cancer | Induction of apoptosis Decrease expression of Bcl-2 mRNA Inhibition of tumor growth | In vitro, in vivo | [237] |
Gapmer targeting TGF-B3 | Glioblastoma | Decrease expression of pSMAD2, Inhibition of invasion, Inhibition of tumor growth | In vitro, in vivo | [238] |
Gapmer for BC200 | Breast cancer, Hepatocellular cancer, Lung cancer, Ovarian Cancer | Induction of apoptosis | In vitro | [239] |
GapmeR for XLOC_109948 | Acute Myeloid Leukemia | Induction of apoptosis | In vitro | [240] |
Gapmer for lncRNA MALAT1 | Multiple Myeloma | Decrease expression of MALAT1, inhibition of colony formation, inhibition of tumor growth | In vitro, in vivo | [241] |
Gapmer for MALAT1 | Multiple Myeloma | Increased activation of PAR signaling Induction of caspase-3 activity Activation of apoptosis | In vitro, in vivo | [242] |
Gapmer for MALAT1 | Lung cancer | Decreased cell migration, reduced number of nodules | In vitro, in vivo | [243] |
Gapmer for MALAT1 | Multiple Myeloma | Induction of apoptosis Inhibition of tumor growth | In vivo | [252] |
Gapmer for miR-17–92s | Multiple Myeloma | Reduced viability of cells, induction of apoptosis | In vitro, in vivo | [244] |
Gapmer for lncRNA PVT1 | Acute Erythroleukemia | Induction of apoptosis Inhibition of c-MYC expression | In vitro | [245,246] |
Gapmers for Bcl-XL | Lung cancer | Inhibition of Bcl-2 expression Induction of apoptosis by activation of caspase 3 | In vitro | [247] |
Gapmer for p21 | Breast cancer | Inhibition of ERα expression | In vitro | [248] |
Gapmer for Bcl-2 | Breast cancer | Inhibition of cell viability Activation of caspase 3 | In vitro | [249] |
Gapmer for Clusterin | Breast cancer | Induction of apoptosis in combination with trastuzumab | In vitro | [250] |
Gapmer for SAMMSON | Melanoma | Inhibition of lncRNA SAMMSON | In vitro, in vivo | [251] |
Name of Drug (Type of Drug) | Clinical Trial Phase | Objectives of Study | Cancer | Reference |
---|---|---|---|---|
Anti-mir-10b (antagomir) | Diagnostic (Recruiting) | Testing in vitro sensitivity of individual primary tumors | Glioblastomas | [255] |
Cobomarsen/MRG-106 (antagomir) | Phase 2 (Terminated) | Inhibition of miRNA-155 | Cutaneous T-Cell Lymphoma | [256] |
Phase 2 (Terminated) | Combination of cobomarsen with vorinostat | Cutaneous T-Cell Lymphoma | [257] | |
Phase 1 (Completed) | Inhibition of miRNA-155 | Cutaneous T-cell Lymphoma Chronic Lymphocytic Leukemia Diffuse Large B-Cell Lymphoma Adult T-cell Leukemia | [258] | |
OGX-011 | Phase 1 (Completed) | Increase anticancer activity of flutamide and buserelin | Prostate cancer | [259] |
Phase 1 (Completed) | Combination therapy with docetaxel | Solid tumors | [260] | |
Phase 2 (Completed) | Combination therapy with docetaxel | Breast cancer | [261] | |
OGX427 (Apatorsen) | Phase 1 (Unknown) | Inhibition of Hsp27 to treat patients with advanced cancers | Advanced cancer | [262] |
Phase 1 (Completed) | Safety of OGX427 in the treatment of prostate cancer, ovarian cancer, NSCLC, breast cancer, bladder cancer | Cancers | [263] | |
Phase 2 (Completed) | Inhibition of Hsp27 to slow the progression of prostate cancer | Prostate cancer | [264] | |
Phase 2 (Completed) | Combination therapy of OGX-427 and docetaxel | Bladder carcinoma | [265] | |
Danvatirsen (AZD9150) | Phase 2 (Recruiting) | Effectiveness of combination therapy of danvatirsen and pembrolizumab | HNSCC | [266] |
Phase 2 (Active, not recruiting) | Effectiveness of combination therapy davatirsen and durvalumab | Advanced and refractory pancreatic, non-small cell lung cancer, colorectal cancer | [267] | |
Phase 2 (Completed) | Effectiveness of combination therapy of duralumab with oleclumab or monalizumab or danvatirsen | Lung cancer | [268] | |
Phase 1 (Active, not recruiting) | Effectiveness of durvalumab with davatirsen/oleclumab/carboplatin/gemcitabine/cisplatin/Nab-paclitaxel | NSCLC | [269] |
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Szymanowska, A.; Rodriguez-Aguayo, C.; Lopez-Berestein, G.; Amero, P. Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment. Non-Coding RNA 2023, 9, 52. https://doi.org/10.3390/ncrna9050052
Szymanowska A, Rodriguez-Aguayo C, Lopez-Berestein G, Amero P. Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment. Non-Coding RNA. 2023; 9(5):52. https://doi.org/10.3390/ncrna9050052
Chicago/Turabian StyleSzymanowska, Anna, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, and Paola Amero. 2023. "Non-Coding RNAs: Foes or Friends for Targeting Tumor Microenvironment" Non-Coding RNA 9, no. 5: 52. https://doi.org/10.3390/ncrna9050052