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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

The Mediating Role of miR-451/ETV4/MMP13 Signaling Axis on Epithelialmesenchymal Transition in Promoting Non-small Cell Lung Cancer Progression

Author(s): Xue-Jiao Qian, Jing-Wen Wang, Jiang-Bo Liu and Xi Yu*

Volume 17, 2024

Published on: 06 October, 2023

Article ID: e210723218988 Pages: 9

DOI: 10.2174/1874467217666230721123554

open_access

Abstract

Background: Lung cancer is a leading cause of cancer mortality. It is one of the most abundant cancer types clinically, with 2 million new cases diagnosed yearly.

Aims: Using clinically collected non-small cell lung cancer (NSCLC) samples, we sought to hypothesize an innovative intact signaling cascade for the disorder.

Methods: We dissected snap-frozen NSCLC tissues along with sibling-paired nearby non-tumorous tissues from 108 NSCLC patients. We measured the expression levels of miR-451/ETV4/MMP13 using qRT-PCR and did a thorough investigation of the molecular mechanism for the signaling axis in NSCLC cell line A549. We also studied the epithelial-mesenchymal transition (EMT) process.

Results: The activity of miR-451 was significantly decreased in NSCLC tissues, while the expression levels of ETV4 and MMP13 were remarkably increased. At the same time, miR-451 levels maintained a declining trend across TNM stage I–III. Inversely, ETV4 and MMP13 increased as the TNM stage increased. The miR-451/ETV4/MMP13 signaling axis was closely associated with prognosis in NSCLC patients. Based on in vitro experiments, ETV4 was a direct targeting factor for miRNA-451. Meanwhile, ETV4 promoted the tumor properties of NSCLC cells by directly activating MMP13. Silencing MMP13 blocked the EMT progress of NSCLC cells.

Conclusion: Overall, we hypothesized an impeccable signaling pathway for NSCLC from a new aspect, and this can offer alternative insights for a better understanding of the disorder.

Keywords: ETV4, Lung cancer, miR-451, MMP13, Non-small cell lung cancer, TNM stage I–III.

[1]
Thai, A.A.; Solomon, B.J.; Sequist, L.V.; Gainor, J.F.; Heist, R.S. Lung cancer. Lancet, 2021, 398(10299), 535-554.
[http://dx.doi.org/10.1016/S0140-6736(21)00312-3] [PMID: 34273294]
[2]
Schabath, M.B.; Cote, M.L. Cancer progress and priorities: Lung cancer. Cancer Epidemiol. Biomarkers Prev., 2019, 28(10), 1563-1579.
[http://dx.doi.org/10.1158/1055-9965.EPI-19-0221] [PMID: 31575553]
[3]
Ruiz-Cordero, R.; Devine, W.P. Targeted therapy and checkpoint immunotherapy in lung cancer. Surg. Pathol. Clin., 2020, 13(1), 17-33.
[http://dx.doi.org/10.1016/j.path.2019.11.002] [PMID: 32005431]
[4]
Mao, Y.; Yang, D.; He, J.; Krasna, M.J. Epidemiology of lung cancer. Surg. Oncol. Clin. N. Am., 2016, 25(3), 439-445.
[http://dx.doi.org/10.1016/j.soc.2016.02.001] [PMID: 27261907]
[5]
Alexander, M.; Kim, S.Y.; Cheng, H. Update 2020: Management of non-small cell lung cancer. Lung, 2020, 198(6), 897-907.
[http://dx.doi.org/10.1007/s00408-020-00407-5] [PMID: 33175991]
[6]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin., 2016, 66(1), 7-30.
[http://dx.doi.org/10.3322/caac.21332] [PMID: 26742998]
[7]
Nasim, F.; Sabath, B.F.; Eapen, G.A. Lung cancer. Med. Clin. North Am., 2019, 103(3), 463-473.
[http://dx.doi.org/10.1016/j.mcna.2018.12.006] [PMID: 30955514]
[8]
Wadowska, K.; Bil-Lula, I.; Trembecki, Ł.; Śliwińska-Mossoń, M. Genetic markers in lung cancer diagnosis: A review. Int. J. Mol. Sci., 2020, 21(13), 4569.
[http://dx.doi.org/10.3390/ijms21134569] [PMID: 32604993]
[9]
Correia de Sousa, M.; Gjorgjieva, M.; Dolicka, D.; Sobolewski, C.; Foti, M. Deciphering miRNAs’ Action through miRNA editing. Int. J. Mol. Sci., 2019, 20(24), 6249.
[http://dx.doi.org/10.3390/ijms20246249] [PMID: 31835747]
[10]
Zhang, Z.; Gao, X.; Ma, M.; Zhao, C.; Zhang, Y.; Guo, S. CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Sci. Rep., 2020, 10(1), 9024.
[http://dx.doi.org/10.1038/s41598-020-65920-2] [PMID: 32494004]
[11]
Chen, Y.; Min, L.; Ren, C.; Xu, X.; Yang, J.; Sun, X.; Wang, T.; Wang, F.; Sun, C.; Zhang, X. miRNA-148a serves as a prognostic factor and suppresses migration and invasion through Wnt1 in non-small cell lung cancer. PLoS One, 2017, 12(2), e0171751.
[http://dx.doi.org/10.1371/journal.pone.0171751] [PMID: 28199399]
[12]
Xin, J.H.; Cowie, A.; Lachance, P.; Hassell, J.A. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. Genes Dev., 1992, 6(3), 481-496.
[http://dx.doi.org/10.1101/gad.6.3.481] [PMID: 1547944]
[13]
Oh, S.; Shin, S.; Janknecht, R. ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors. Biochim. Biophys. Acta, 2012, 1826(1), 1-12.
[PMID: 22425584]
[14]
Fontanet, P.A.; Ríos, A.S.; Alsina, F.C.; Paratcha, G.; Ledda, F. Pea3 transcription factors, Etv4 and Etv5, Are required for proper hippocampal dendrite development and plasticity. Cereb. Cortex, 2018, 28(1), 236-249.
[http://dx.doi.org/10.1093/cercor/bhw372] [PMID: 27909004]
[15]
Lu, B.C.; Cebrian, C.; Chi, X.; Kuure, S.; Kuo, R.; Bates, C.M.; Arber, S.; Hassell, J.; MacNeil, L.; Hoshi, M.; Jain, S.; Asai, N.; Takahashi, M.; Schmidt-Ott, K.M.; Barasch, J.; D’Agati, V.; Costantini, F. Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat. Genet., 2009, 41(12), 1295-1302.
[http://dx.doi.org/10.1038/ng.476] [PMID: 19898483]
[16]
Ross-Innes, C.S.; Stark, R.; Teschendorff, A.E.; Holmes, K.A.; Ali, H.R.; Dunning, M.J.; Brown, G.D.; Gojis, O.; Ellis, I.O.; Green, A.R.; Ali, S.; Chin, S.F.; Palmieri, C.; Caldas, C.; Carroll, J.S. Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature, 2012, 481(7381), 389-393.
[http://dx.doi.org/10.1038/nature10730] [PMID: 22217937]
[17]
Yuen, H.F.; Chan, Y.K.; Grills, C.; McCrudden, C.M.; Gunasekharan, V.; Shi, Z.; Wong, A.S.Y.; Lappin, T.R.; Chan, K.W.; Fennell, D.A.; Khoo, U.S.; Johnston, P.G.; El-Tanani, M. Polyomavirus enhancer activator 3 protein promotes breast cancer metastatic progression through Snail-induced epithelial-mesenchymal transition. J. Pathol., 2011, 224(1), 78-89.
[http://dx.doi.org/10.1002/path.2859] [PMID: 21404275]
[18]
Freije, J.M.; Díez-Itza, I.; Balbín, M.; Sánchez, L.M.; Blasco, R.; Tolivia, J.; López-Otín, C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem., 1994, 269(24), 16766-16773.
[http://dx.doi.org/10.1016/S0021-9258(19)89457-7] [PMID: 8207000]
[19]
Firlej, V.; Ladam, F.; Brysbaert, G.; Dumont, P.; Fuks, F.; de Launoit, Y.; Benecke, A.; Chotteau-Lelievre, A. Reduced tumorigenesis in mouse mammary cancer cells following inhibition of Pea3- or Erm-dependent transcription. J. Cell Sci., 2008, 121(20), 3393-3402.
[http://dx.doi.org/10.1242/jcs.027201] [PMID: 18827017]
[20]
Obenauf, A.C.; Massagué, J. Surviving at a distance: Organ-specific metastasis. Trends Cancer, 2015, 1(1), 76-91.
[http://dx.doi.org/10.1016/j.trecan.2015.07.009] [PMID: 28741564]
[21]
Dumortier, M.; Ladam, F.; Damour, I.; Vacher, S.; Bièche, I.; Marchand, N.; de Launoit, Y.; Tulasne, D.; Chotteau-Lelièvre, A. ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis. Breast Cancer Res., 2018, 20(1), 73.
[http://dx.doi.org/10.1186/s13058-018-0992-0] [PMID: 29996935]
[22]
Duma, N.; Santana-Davila, R.; Molina, J.R. Non–small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin. Proc., 2019, 94(8), 1623-1640.
[http://dx.doi.org/10.1016/j.mayocp.2019.01.013] [PMID: 31378236]
[23]
Ladam, F.; Damour, I.; Dumont, P.; Kherrouche, Z.; de Launoit, Y.; Tulasne, D.; Chotteau-Lelievre, A. Loss of a negative feedback loop involving pea3 and cyclin d2 is required for pea3-induced migration in transformed mammary epithelial cells. Mol. Cancer Res., 2013, 11(11), 1412-1424.
[http://dx.doi.org/10.1158/1541-7786.MCR-13-0229] [PMID: 23989931]
[24]
Firlej, V.; Bocquet, B.; Desbiens, X.; de Launoit, Y.; Chotteau-Lelièvre, A. Pea3 transcription factor cooperates with USF-1 in regulation of the murine bax transcription without binding to an Ets-binding site. J. Biol. Chem., 2005, 280(2), 887-898.
[http://dx.doi.org/10.1074/jbc.M408017200] [PMID: 15466854]
[25]
Kaczorowska, A.; Miękus, N.; Stefanowicz, J.; Adamkiewicz-Drożyńska, E. Selected matrix metalloproteinases (MMP-2, MMP-7) and their inhibitor (TIMP-2) in adult and pediatric cancer. Diagnostics, 2020, 10(8), 547.
[http://dx.doi.org/10.3390/diagnostics10080547] [PMID: 32751899]
[26]
Knäuper, V.; López-Otin, C.; Smith, B.; Knight, G.; Murphy, G. Biochemical characterization of human collagenase-3. J. Biol. Chem., 1996, 271(3), 1544-1550.
[http://dx.doi.org/10.1074/jbc.271.3.1544] [PMID: 8576151]
[27]
Li, W.; Jia, M.; Wang, J.; Lu, J.; Deng, J.; Tang, J.; Liu, C. association of MMP9-1562C/T and MMP13-77A/G polymorphisms with non-small cell lung cancer in southern chinese population. Biomolecules, 2019, 9(3), 107.
[http://dx.doi.org/10.3390/biom9030107] [PMID: 30889876]
[28]
Babaei, G.; Aziz, S.G.G.; Jaghi, N.Z.Z. EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomed. Pharmacother., 2021, 133, 110909.
[http://dx.doi.org/10.1016/j.biopha.2020.110909] [PMID: 33227701]
[29]
Aruna, L.; Li, L.M. Overexpression of golgi membrane protein 1 promotes non-small-cell carcinoma aggressiveness by regulating the matrix metallopeptidase 13. Am. J. Cancer Res., 2018, 8(3), 551-565.
[PMID: 29637008]
[30]
Bai, H.; Wu, S. miR-451: A novel biomarker and potential therapeutic target for cancer. OncoTargets Ther., 2019, 12, 11069-11082.
[http://dx.doi.org/10.2147/OTT.S230963] [PMID: 31908476]
[31]
Liu, Y.; Li, H.; Li, L.H.; Tang, J.B.; Sheng, Y.L. Mir-451 inhibits proliferation and migration of non-small cell lung cancer cells via targeting LKB1/AMPK. Eur. Rev. Med. Pharmacol. Sci., 2019, 23(3), 274-280.
[PMID: 31389598]
[32]
Shen, Y.Y.; Cui, J.Y.; Yuan, J.; Wang, X. MiR-451a suppressed cell migration and invasion in non-small cell lung cancer through targeting ATF2. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(17), 5554-5561.
[PMID: 30229828]

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