Beyond Conventional: The New Horizon of Anti-Angiogenic microRNAs in Non-Small Cell Lung Cancer Therapy
Abstract
:1. Introduction
2. Major Angiogenic Factors Are Regulated by microRNAs
2.1. VEGF as a Central Player and Its miRNA Regulation
2.2. FGF2—A Multifaceted Proangiogenic Factor and Its miRNA Modulation
2.3. The Extracellular Matrix: Support for Angiogenesis
2.4. Hypoxia Modulates the Angiogenic Process in Lung Cancer
2.5. miRNAs with Regulatory Potential in Lung Cancer
3. Current and Future Anti-Angiogenic Therapeutic Options in NSCLC
3.1. Conventional Anti-Angiogenics
3.2. MiRNAs as Therapeutic Agents: Prospects
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene | Gene Mutation Frequency 1 | miRNAs Regulating the Gene 2 | References 5 |
---|---|---|---|
Proangiogenic | |||
VEGFA | <0.1% | miR-125a, miR-185, miR-29a, miR-101, miR-15a, miR-195, miR-140, miR-145, miR-126, miR-133 | [18,19,20,21,22,23] |
FGF2 | No mutations identified | No strong evidence miRNAs identified in the database searchmiR-101-1 3, miR-101-2 3 | NR |
PDGFB | 0.3% | miR-29b 4 | NR |
EGF | No mutations identified | No strong evidence miRNAs identified in the database searchmiR-3188 3 | NR |
TGFB1 | miR-144, miR-29b 4 | NR | |
IL8 | miR-520b | NR | |
MMP2 | miR-451, miR-29a, miR-29b 4, miR-29c, miR-338, miR-451 | [24,25,26] | |
Anti-angiogenic | |||
THBS1 | No mutations identified | miR-182 | NR |
TIMP1 | miR-1293 | [27] | |
IL1A | No strong evidence miRNAs identified in the database searchmiR-181b-2 3 | [28] | |
COL18A1 | No strong evidence miRNAs identified in the database searchmiR-450a-1 3, miR-450a-2 3, miR-1292 3, miR-877 3 | NR |
miRNA | Expression | Study Type | Target | Overall Action | References |
---|---|---|---|---|---|
miR-106a | ▲ | [44]—ex vivo (tissue) [67]—ex vivo (tissue) [91]—in vitro [92]—clinical/ex vivo | Predicted: VEGF, FGFR2, STAT3 | Upregulated during hypoxia in breast and colon cancer. Augmented expression in NSCLC. | [44,67,91,92] |
miR-141 | ▲ in [93] | [93]—in vitro, ex vivo (tissue) [94]—in vitro, in vivo, ex vivo (tissue) | KLF6, NRP1, GAB1, CXCL12β, TGFβ2, GATA6 | In a lung adenocarcinoma model, overexpression of miR-141 inhibited KLF6 and consecutively increased VEGF-A levels, thus promoting angiogenesis. Opposite results were obtained by Dong et al. who found that miR-141 overexpression exhibits anti-angiogenic properties by suppressing endothelial cell proliferation, migration and tube formation. These effects are the result of miR-141 acting on NRP1, GAB1, CXCL12β, TGFβ2 and GATA6. However, Dong et al. proposed that the effects may vary in different tumor environments. | [93,94] |
miR-155 | ▲ | [44]—ex vivo (tissue) [67]—ex vivo (tissue) | Predicted: FGF2 | MiR-155 has been significantly correlated with FGF2 and with a poor OS in lung AC and SCC. | [44,67,71] |
miR-182 | ▲ | [44]—ex vivo (tissue) [64]—in vitro, ex vivo (tissue) [65]—ex vivo (tissue) | FRS2, Tsp1 | The action of miR-182 is intricated, acting on at least 2 targets with antagonizing effect. However, miR-182 is mostly viewed as an oncogene by suppressing the antiangiogenic Tsp1 and thus promoting angiogenesis. | [44,64,65] |
miR-21 | ▲ | [51]—in vitro, ex vivo (serum) [53]—in vitro, ex vivo (blood) | HIF-1α, PTEN, PDCD4, hMSH2 | MiR-21 is a well-known oncomiR with various implications in lung cancer. A study by Liu et al. showed that exosome-derived miR-21 induces STAT3 activation, increasing VEGF levels and thus activating angiogenesis. Furthermore, the X study showed that A549 cells within the miR-21 inhibition group showed almost no tube formation when compared to the control group and the mock group. | [51,53,95] |
miR-210 | ▲ | [74]—in vitro, in vivo [96]—in vitro | Succinate dehydrogenase complex subunit D (SDHD), E2F3 | MiR-210 exhibits its proangiogenic effects through a CAF-associated mechanism. A study by Fan et al. showed that miR-210 was able to increase the expression of FGF2, VEGFA and MMP9 by activating JAK2/STAT3 and TET2 pathways. | [74,96] |
miR-221/222 cluster | ▲ | [97]—in vitro, in vivo [98]—in vitro, in vivo, ex vivo (tissue) | TIMP-3 PTEN | MiR-221/222 are over-expressed in NSCLC cells. The cluster suppresses PTEN and TIMP-3 expression, inducing migration and invasiveness. Janssen et al. proved that TIMP-3 knockdown tumors had a higher level of vascularization versus control. | [97,98] |
miR-23a | ▲ | [90]—in vitro, in vivo, ex vivo (tissue) | PHD2, ZO-1 | The Hsu study found that miR-23a increases tumor angiogenesis in both hypoxic and normoxic environment. MiR-23a is able to directly target the 3′-UTR of PHD2 in HUVECs, leading to enhanced HIF-1α activity with proangiogenic features. Furthermore, Hsu et al. showed that miR-23a can target ZO-1, disrupting the endothelial barrier and promoting angiogenesis. | [90] |
miR-378 | ▲ | [99]—in vitro, in vivo, ex vivo (tissue) [100]—in vitro, in vivo, ex vivo (tissue) [62]—in vitro, in vivo | RBX1, CRKL | MiR-378 is upregulated in highly invasive lung cancer sub-cell lines. MiR-378 promotes invasion, metastasis through EMT (RBX1, CRKL) and angiogenesis in vivo. A study by Ho et al. showed that RBX1 intervenes in HIF-1α pathway to produce VEGF with a subsequent inductive effect on angiogenesis. Accumulating evidence suggests that miR-378 could act as both oncogene and tumor suppressor. | [62,99,100] |
miR-494 | ▲ | [89]—in vitro, in vivo | PTEN | MiR-494 promotes angiogenesis in HUVECs/A549 cells and effectively targets PTEN with the consequent inhibition of the Akt/eNOS pathway. | [89] |
miR-15-16 cluster | ▼ | [101]—in vitro, in vivo, ex vivo (tissue) | FGF2 | In a study conducted by Xue et al., hypoxia repressed the miR-15-16 cluster, with a loss of restriction of its target gene, FGF2. This action promoted tumor angiogenesis and metastasis. | [101] |
miR-106b | ▼ | [102]—in vitro, in vivo [103]—in vitro | STAT3 | MiR-106b exhibits anti-angiogenic effects by inhibiting STAT3 in ECs. Niu et al. found that VEGF expression correlated positively with STAT3 activity in different human cancer cell lines. | [102,103] |
miR-128 | ▼ | [104]—in vitro, in vivo, ex vivo (tissue) | VEGF-A, VEGF-C, VEGFR-2, VEGFR-3 | MiR-128 was significantly downregulated in NSCLC tissues and cancer cells and was correlated with NSCLC differentiation, stage and metastasis to lymph nodes. Overexpression of miR-128 in NSCLC cells decreased expression of VEGF-A, VEGFR-2, VEGFR-3, in in vitro and in vivo experiments. | [104] |
miR-200b | ▼ | [105]—in vitro | VEGFA, FLT/VEGFR1, KDR/VEGFR2, Ets1 | MiR-200b binds to the 3′-UTR of Ets-1 mRNA to induce translational repression. Ets-1 is a key transcription factor known for its role in promoting angiogenesis. Physiological levels of miR-200b have an inhibitory effect on angiogenesis. In hypoxic conditions, miR-200b downregulation cancels Ets-1 repression, thus promoting angiogenesis. MiR-200b also targets VEGF and its receptors. | [105] |
miR-206 | ▼ | [42]—in vitro, in vivo, ex vivo (tissue) [106]—in vitro, ex vivo (tissue) | SOX9, 14-3-3 ζ | A study by Zhang et al. found downregulated levels of miR-206 and concluded that miR-206 may act as a tumor suppressor partly by targeting SOX9. In another study by Xue et al., miR-206 decreased the angiogenic ability in NSCLC by inhibiting the 14-3-3 ζ/STAT3/HIF-1α/VEGF pathway. | [42,106] |
miR-497 | ▼ | [107]—in vitro, in vivo, ex vivo (tissue) | HDGF, FGF2 | MiR-497 is downregulated in NSCLC tumors and cell lines. Ectopic expression inhibited cell proliferation and angiogenesis in a SCID mouse xenograft model. | [107,108] |
miR-126 | ▼ | [23]—in vitro, in vivo [43]—in vitro, in vivo [46]—in vitro, ex vivo (tissue) [47]—in vitro, in vivo, ex vivo (tissue) [48]—in vitro, ex vivo (tissue) | VEGFA, EGFL7, PI3KR2 | MiR-126 is one of the most differentially expressed miRNA in lung cancer, with an overall reduced expression. A number of studies found that miR-126 targets the VEGFA with a silencing effect. Enhanced miR-126 expression increases the sensitivity of NSCLC cells to chemotherapy through the VEGFA/PI3K/Akt/MRP1 pathway. Furthermore, two studies showed that miR-126 may target PI3KR2 and that by targeting VEGFA it inactivates the VEGFA/VEGFR2/ERK signaling pathway. | [23,43,46,47,48] |
miR-135a | ▼ | [60]—in vitro, ex vivo (tissue) | IGF-1 | The Zhou study identified IGF-1 as a direct target of miR-135a. Zhou et al. showed that miR-135a decreased the angiogenic factors VEGF, FGF2 and IL-8 in the A549 cell line by IGF-1 inhibition. | [60] |
miR-29b | ▼/▲ (TCGA analysis) | [24]—in vitro, ex vivo (tissue) | MMP-2, PTEN, PDGFB, TGF-β1 | MMP-2 is a known promoter of angiogenesis. In a paper by Wang et al., bioinformatics analysis combined with a polymerase chain reaction study suggested that MMP-2 and PTEN may represent important targets of miR-29b. The same authors concluded that miR-29b behaves as a tumor metastasis suppressor through MMP-2 inhibition. Our analysis found that PDGFB and TGF-β1 may also be targets of miR-29b, marking it as a therapeutic candidate. | [24] |
miR-204 | ▼ (TCGA analysis) | [109]—in vitro, in vivo | Predicted: JAK2/STAT3 | MiR-204 functions as a tumor suppressor in LUAD; in the Liu study, miR-204 promoted cancer cell apoptosis and inhibited cell migration and proliferation in vitro, and tumor growth in the in vivo model. Conditioned media from A549 cancer cell line with overexpression of miR-204 hampered tube formation and migration of HUVECs. The same authors found decreased levels of HIF-1α, VEGF, PDGF in the A549 cells transfected with miR-204 mimics. Liu et al. concluded that miR-204 inhibits angiogenesis in LUAD, probably via the JAK2/STAT3 pathway. | [109] |
Therapeutic Agent | Type | Target | Mechanism of Action | Status by the FDA | References |
---|---|---|---|---|---|
Bevacizumab | Monoclonal antibody | VEGF-A | Recombinant humanized monoclonal antibody directed against VEGF-A. | Approved in combination with carboplatin and paclitaxel chemotherapy for first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. | [110] |
Ramucirumab | Monoclonal antibody | VEGFR2 | Fully humanized monoclonal antibody that specifically binds to VEGFR2, inhibiting angiogenesis. | Approved in combination with docetaxel for metastatic NSCLC with progression after platinum-based chemotherapy. Approved by FDA in May 2020 in combination with erlotinib for first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations in accordance to the RELAY trial (ClinicalTrials.gov identifier: NCT02411448). | [111] |
Nintedanib | Small-molecule, multi-targeted TKI | VEGFR1-3; FGFR1-3; PDGFR-α, β; Src family | Nintedanib inhibits downstream signaling by binding to the adenosine triphosphate (ATP) sites of proangiogenic receptors. | Approved in combination with docetaxel for the treatment of locally advanced, recurrent or metastatic lung adenocarcinoma 1. | [112,113] |
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Tirpe, A.; Gulei, D.; Tirpe, G.R.; Nutu, A.; Irimie, A.; Campomenosi, P.; Pop, L.A.; Berindan-Neagoe, I. Beyond Conventional: The New Horizon of Anti-Angiogenic microRNAs in Non-Small Cell Lung Cancer Therapy. Int. J. Mol. Sci. 2020, 21, 8002. https://doi.org/10.3390/ijms21218002
Tirpe A, Gulei D, Tirpe GR, Nutu A, Irimie A, Campomenosi P, Pop LA, Berindan-Neagoe I. Beyond Conventional: The New Horizon of Anti-Angiogenic microRNAs in Non-Small Cell Lung Cancer Therapy. International Journal of Molecular Sciences. 2020; 21(21):8002. https://doi.org/10.3390/ijms21218002
Chicago/Turabian StyleTirpe, Alexandru, Diana Gulei, George Razvan Tirpe, Andreea Nutu, Alexandru Irimie, Paola Campomenosi, Laura Ancuta Pop, and Ioana Berindan-Neagoe. 2020. "Beyond Conventional: The New Horizon of Anti-Angiogenic microRNAs in Non-Small Cell Lung Cancer Therapy" International Journal of Molecular Sciences 21, no. 21: 8002. https://doi.org/10.3390/ijms21218002