Research Article

METTL3 promotes non-small-cell lung cancer growth and metastasis by inhibiting FDX1 through copper death-associated pri-miR-21-5p maturation

Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, People's Republic of China

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Jun Liu

https://orcid.org/0009-0009-1017-6708

Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, People's Republic of China

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Wenliang Liao

https://orcid.org/0009-0008-0298-4046

Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, People's Republic of China

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Fengping Wang

*Author for correspondence: Tel.: +86 156 5705 0100;

E-mail Address: xiniluohe@wmu.edu.cn

https://orcid.org/0009-0005-4483-890X

Department of Clinical Laboratory, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, People's Republic of China

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Published Online:21 Dec 2023https://doi.org/10.2217/epi-2023-0230

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Abstract

Objective: We probed into the significance of METTL3 in the maturation process of pri-miR-21-5p. We specifically investigated its impact on the regulation of FDX1 and its involvement in the progression of non-small-cell lung cancer (NSCLC). Methods: The Cancer Genome Atlas (TCGA) identified NSCLC factors. Methylation-specific PCR (MSP), clonogenic tests and flow cytometry analyzed cells. Methylated RNA immunoprecipitation (Me-RIP) and dual-luciferase studied miR-21-5p/FDX1. Mice xenografts showed METTL3's tumorigenic effect. Results: METTL3, with high expression but low methylation in NSCLC, influenced cell behaviors. Its suppression reduced oncogenic properties. METTL3 enhanced miR-21-5p maturation, targeting FDX1 and boosting NSCLC tumorigenicity in mice. Conclusion: METTL3 may promote NSCLC development by facilitating pri-miR-21-5p maturation, upregulating miR-21-5p and targeting inhibition of FDX1.

Plain language summary

We investigated a protein called METTL3, which is overly active in lung cancer cells, and how it affects the function of other small molecules. We discovered that as the activity of METTL3 increases, the growth and mobility of lung cancer cells also enhance, potentially accelerating the progression of lung cancer. Through a series of experiments, we observed how METTL3 interacts with other small molecules and further influences the behavior of lung cancer cells. This study helps us understand the role of METTL3 in the development of lung cancer and may offer new strategies for future treatments.

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METTL3 aids NSCLC progression by boosting miR-21-5p maturation, targeting FDX1. Understanding this can open new NSCLC treatment avenues.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Bade BC, Dela Cruz CS. Lung cancer 2020: epidemiology, etiology, and prevention. Clin. Chest Med. 41(1), 1–24 (2020).
MedlineGoogle Scholar
2. Suster DI, Mino-Kenudson M. Molecular pathology of primary non-small cell lung cancer. Arch. Med. Res. 51(8), 784–798 (2020). • Provides comprehensive insights into the molecular pathology of non-small-cell lung cancer (NSCLC), offering a foundational understanding that complements the specific molecular mechanisms highlighted by METTL3's influence on pri-miR-21-5p maturation and FDX1 regulation.
Medline CASGoogle Scholar
3. Flores R, Patel P, Alpert N, Pyenson B, Taioli E. Association of stage shift and population mortality among patients with non-small cell lung cancer. JAMA Netw. Open 4(12), e2137508 (2021). • The study on the association between stage shift and population mortality in NSCLC patients offers valuable context on clinical outcomes, aiding in understanding the real-world implications of molecular findings.
MedlineGoogle Scholar
4. Wadowska K, Bil-Lula I, Trembecki L, Sliwinska-Mosson M. Genetic markers in lung cancer diagnosis: a review. Int. J. Mol. Sci. 21(13), 4569 (2020). • Provides an essential overview of genetic markers in lung cancer, offering deeper insights into the broader genetic landscape of the disease and complementing the specific findings related to METTL3 and miR-21-5p.
Medline CASGoogle Scholar
5. Zhong S, Golpon H, Zardo P, Borlak J. miRNAs in lung cancer. A systematic review identifies predictive and prognostic miRNA candidates for precision medicine in lung cancer. Transl. Res. 230, 164–196 (2021).
Medline CASGoogle Scholar
6. Cao X, Zhong W, Guo S, Zhang Z, Xie C. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR. Open Med. (Wars.) 17(1), 816–825 (2022).
Medline CASGoogle Scholar
7. Friedlaender A, Addeo A, Russo A, Gregorc V, Cortinovis D, Rolfo CD. Targeted therapies in early stage NSCLC: hype or hope? Int. J. Mol. Sci. 21(17), 6329 (2020).
Medline CASGoogle Scholar
8. Jonna S, Subramaniam DS. Molecular diagnostics and targeted therapies in non-small cell lung cancer (NSCLC): an update. Discov. Med. 27(148), 167–170 (2019). • Provides an updated synthesis on molecular diagnostics and targeted therapies in NSCLC, enriching the reader's understanding of the broader therapeutic landscape while contextualizing the specific role of METTL3 and miR-21-5p.
MedlineGoogle Scholar
9. Reck M, Remon J, Hellmann MD. First-line immunotherapy for non-small-cell lung cancer. J. Clin. Oncol. 40(6), 586–597 (2022).
Medline CASGoogle Scholar
10. Chen T, Ning J, Campisi A et al. Neoadjuvant PD-1 inhibitors and chemotherapy for locally advanced NSCLC: a retrospective study. Ann. Thorac. Surg. 113(3), 993–999 (2022). • Provides a clinically relevant perspective on therapeutic interventions, specifically the combination of neoadjuvant PD-1 inhibitors and chemotherapy, offering insights into contemporary treatment modalities for locally advanced NSCLC.
MedlineGoogle Scholar
11. Rodriguez-Abreu D, Powell SF, Hochmair MJ et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann. Oncol. 32(7), 881–895 (2021).
Medline CASGoogle Scholar
12. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol. Cell 62(3), 335–345 (2016).
Medline CASGoogle Scholar
13. Maldonado Lopez A, Capell BC. The METTL3-m(6)A epitranscriptome: dynamic regulator of epithelial development, differentiation, and cancer. Genes (Basel) 12(7), 1019 (2021).
MedlineGoogle Scholar
14. Jin D, Guo J, Wu Y et al. m(6)A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J. Hematol. Oncol. 12(1), 135 (2019). • Dives deep into the molecular intricacies of m6A mRNA methylation initiated by METTL3, presenting a complementary understanding of METTL3's influence on NSCLC drug resistance and metastasis, especially in relation to miRNA regulatory axes.
Medline CASGoogle Scholar
15. Wanna-Udom S, Terashima M, Lyu H et al. The m6A methyltransferase METTL3 contributes to transforming growth factor-beta-induced epithelial–mesenchymal transition of lung cancer cells through the regulation of JUNB. Biochem. Biophys. Res. Commun. 524(1), 150–155 (2020).
Medline CASGoogle Scholar
16. Cai K, Tonelli M, Frederick RO, Markley JL. Human mitochondrial ferredoxin 1 (FDX1) and ferredoxin 2 (FDX2) both bind cysteine desulfurase and donate electrons for iron-sulfur cluster biosynthesis. Biochemistry 56(3), 487–499 (2017).
Medline CASGoogle Scholar
17. Tsvetkov P, Coy S, Petrova B et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375(6586), 1254–1261 (2022).
Medline CASGoogle Scholar
18. Xu Q, Liu T, Wang J. Radiosensitization-related cuproptosis lncRNA signature in non-small cell lung cancer. Genes (Basel) 13(11), 2080 (2022).
Medline CASGoogle Scholar
19. Li X, Dai Z, Liu J et al. Characterization of the functional effects of ferredoxin 1 as a cuproptosis biomarker in cancer. Front. Genet. 13, 969856 (2022).
Medline CASGoogle Scholar
20. Chen G, Zhang J, Teng W, Luo Y, Ji X. FDX1 inhibits thyroid cancer malignant progression by inducing cuprotosis. Heliyon 9(8), e18655 (2023).
Medline CASGoogle Scholar
21. Lu H, Liang J, He X et al. A novel oncogenic role of FDX1 in human melanoma related to PD-L1 immune checkpoint. Int. J. Mol. Sci. 24(11), 9182 (2023).
Medline CASGoogle Scholar
22. Dreishpoon MB, Bick NR, Petrova B et al. FDX1 regulates cellular protein lipoylation through direct binding to LIAS. J. Biol. Chem. 299(9), 105046 (2023).
Medline CASGoogle Scholar
23. Olivieri F, Prattichizzo F, Giuliani A et al. miR-21 and miR-146a: the microRNAs of inflammaging and age-related diseases. Ageing Res. Rev. 70, 101374 (2021). • Provides a broader context on the role and significance of miR-21 in the realm of inflammaging and age-related diseases, offering a comprehensive perspective on this microRNA's multifaceted implications in human health.
Medline CASGoogle Scholar
24. Bautista-Sanchez D, Arriaga-Canon C, Pedroza-Torres A et al. The promising role of miR-21 as a cancer biomarker and its importance in RNA-based therapeutics. Mol. Ther. Nucleic Acids 20, 409–420 (2020).
Medline CASGoogle Scholar
25. Bica-Pop C, Cojocneanu-Petric R, Magdo L, Raduly L, Gulei D, Berindan-Neagoe I. Overview upon miR-21 in lung cancer: focus on NSCLC. Cell. Mol. Life Sci. 75(19), 3539–3551 (2018).
Medline CASGoogle Scholar
26. Zhan Y, Chen Z, Li Y et al. Long non-coding RNA DANCR promotes malignant phenotypes of bladder cancer cells by modulating the miR-149/MSI2 axis as a ceRNA. J. Exp. Clin. Cancer Res. 37(1), 273 (2018).
Medline CASGoogle Scholar
27. Wang P, Chen D, Ma H, Li Y. LncRNA MEG3 enhances cisplatin sensitivity in non-small cell lung cancer by regulating miR-21-5p/SOX7 axis. Onco Targets Ther. 10, 5137–5149 (2017).
MedlineGoogle Scholar
28. Kong B, Lv ZD, Wang Y, Jin LY, Ding L, Yang ZC. Down-regulation of BRMS1 by DNA hypermethylation and its association with metastatic progression in triple-negative breast cancer. Int. J. Clin. Exp. Pathol. 8(9), 11076–11083 (2015).
Medline CASGoogle Scholar
29. Cao Y, Li Y, Zhang N et al. Quantitative DNA hypomethylation of ligand Jagged1 and receptor Notch1 signifies occurrence and progression of breast carcinoma. Am. J. Cancer Res. 5(6), 1897–1910 (2015).
MedlineGoogle Scholar
30. Xu S, Yue Y, Zhang S et al. STON2 negatively modulates stem-like properties in ovarian cancer cells via DNMT1/MUC1 pathway. J. Exp. Clin. Cancer Res. 37(1), 305 (2018).
Medline CASGoogle Scholar
31. Han J, Wang JZ, Yang X et al. METTL3 promotes tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in an m6A-dependent manner. Mol. Cancer 18(1), 110 (2019).
MedlineGoogle Scholar
32. Peng W, Li J, Chen R et al. Upregulated METTL3 promotes metastasis of colorectal cancer via miR-1246/SPRED2/MAPK signaling pathway. J. Exp. Clin. Cancer Res. 38(1), 393 (2019).
MedlineGoogle Scholar
33. Kim JH, Ahn JH, Lee M. Upregulation of microRNA-1246 is associated with BRAF inhibitor resistance in melanoma cells with mutant BRAF. Cancer Res. Treat. 49(4), 947–959 (2017).
Medline CASGoogle Scholar
34. Chang L, Guo R, Yuan Z, Shi H, Zhang D. LncRNA HOTAIR regulates CCND1 and CCND2 expression by sponging miR-206 in ovarian cancer. Cell Physiol. Biochem. 49(4), 1289–1303 (2018).
Medline CASGoogle Scholar
35. Salem M, Shan Y, Bernaudo S, Peng C. miR-590-3p targets cyclin G2 and FOXO3 to promote ovarian cancer cell proliferation, invasion, and spheroid formation. Int. J. Mol. Sci. 20(8), 1810 (2019).
Medline CASGoogle Scholar
36. Lin S, Liu J, Jiang W et al. METTL3 promotes the proliferation and mobility of gastric cancer cells. Open Med. (Wars.) 14, 25–31 (2019).
Medline CASGoogle Scholar
37. Wei W, Huo B, Shi X. miR-600 inhibits lung cancer via downregulating the expression of METTL3. Cancer Manag. Res. 11, 1177–1187 (2019). •• Offers pivotal insights into how miR-600 acts as a tumor suppressor by targeting and downregulating METTL3, enhancing our understanding of molecular regulatory mechanisms in lung cancer progression.
MedlineGoogle Scholar
38. Yan H, Li H, Li P et al. Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis. J. Exp. Clin. Cancer Res. 37(1), 237 (2018).
MedlineGoogle Scholar
39. Chen Q, Zhang J, He Y, Wang Y. hsa_circ_0061140 knockdown reverses FOXM1-mediated cell growth and metastasis in ovarian cancer through miR-370 sponge activity. Mol. Ther. Nucleic Acids 13, 55–63 (2018).
Medline CASGoogle Scholar
40. Sheng N, Xu YZ, Xi QH et al. Overexpression of KIF2A is suppressed by miR-206 and associated with poor prognosis in ovarian cancer. Cell Physiol. Biochem. 50(3), 810–822 (2018).
Medline CASGoogle Scholar
41. Tang X, Zeng X, Huang Y et al. miR-423-5p serves as a diagnostic indicator and inhibits the proliferation and invasion of ovarian cancer. Exp. Ther. Med. 15(6), 4723–4730 (2018).
MedlineGoogle Scholar
42. Yuan L, Li S, Zhou Q et al. MiR-124 inhibits invasion and induces apoptosis of ovarian cancer cells by targeting programmed cell death 6. Oncol. Lett. 14(6), 7311–7317 (2017).
MedlineGoogle Scholar
43. Lai XJ, Cheng HF. LncRNA colon cancer-associated transcript 1 (CCAT1) promotes proliferation and metastasis of ovarian cancer via miR-1290. Eur. Rev. Med. Pharmacol. Sci. 22(2), 322–328 (2018).
MedlineGoogle Scholar
44. Yang Z, Li J, Feng G et al. MicroRNA-145 modulates N(6)-methyladenosine levels by targeting the 3′-untranslated mRNA region of the N(6)-methyladenosine binding YTH domain family 2 protein. J. Biol. Chem. 292(9), 3614–3623 (2017).
Medline CASGoogle Scholar
45. Yue B, Song C, Yang L et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial–mesenchymal transition and metastasis of gastric cancer. Mol. Cancer 18(1), 142 (2019).
MedlineGoogle Scholar
46. Li T, Hu PS, Zuo Z et al. METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol. Cancer 18(1), 112 (2019).
MedlineGoogle Scholar
47. Yang F, Jin H, Que B et al. Dynamic m(6)A mRNA methylation reveals the role of METTL3-m(6)A-CDCP1 signaling axis in chemical carcinogenesis. Oncogene 38(24), 4755–4772 (2019).
Medline CASGoogle Scholar
48. Wang H, Deng Q, Lv Z et al. N6-methyladenosine induced miR-143-3p promotes the brain metastasis of lung cancer via regulation of VASH1. Mol. Cancer 18(1), 181 (2019).
Medline CASGoogle Scholar
49. Zhou Z, Wang P, Sun R et al. Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3. J. Immunother. Cancer 9(3), e001946 (2021).
MedlineGoogle Scholar
50. Diggs LP, Ruf B, Ma C et al. CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma. J. Hepatol. 74(5), 1145–1154 (2021).
Medline CASGoogle Scholar
51. Li Y, Gu J, Xu F et al. Molecular characterization, biological function, tumor microenvironment association and clinical significance of m6A regulators in lung adenocarcinoma. Brief. Bioinform. 22(4), (2021).
Google Scholar
52. Chen M, Wei L, Law CT et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2. Hepatology 67(6), 2254–2270 (2018).
Medline CASGoogle Scholar
53. Hua W, Zhao Y, Jin X et al. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol. Oncol. 151(2), 356–365 (2018).
Medline CASGoogle Scholar
54. Ye K, Li L, Wu B, Wang D. METTL3 m6A-dependently promotes miR-21-5p maturation to accelerate choriocarcinoma progression via the HIF1AN-induced inactivation of the HIF1A/VEGF pathway. Genes Genomics 44(11), 1311–1322 (2022).
Medline CASGoogle Scholar
55. Bernaudo S, Salem M, Qi X et al. Cyclin G2 inhibits epithelial-to-mesenchymal transition by disrupting Wnt/beta-catenin signaling. Oncogene 35(36), 4816–4827 (2016).
Medline CASGoogle Scholar
56. Xue L, Li J, Lin Y et al. m(6) A transferase METTL3-induced lncRNA ABHD11-AS1 promotes the Warburg effect of non-small-cell lung cancer. J. Cell. Physiol. 236(4), 2649–2658 (2021).
Medline CASGoogle Scholar
57. Li M, Wang Q, Zhang X, Yan N, Li X. CircPUM1 promotes cell growth and glycolysis in NSCLC via up-regulating METTL3 expression through miR-590-5p. Cell Cycle 20(13), 1279–1294 (2021).
Medline CASGoogle Scholar
58. Zhang Y, Liu S, Zhao T, Dang C. METTL3-mediated m6A modification of Bcl-2 mRNA promotes non-small cell lung cancer progression. Oncol. Rep. 46(2), 163 (2021).
Medline CASGoogle Scholar
59. Dou X, Wang Z, Lu W, Miao L, Zhao Y. Correction: METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way. BMC Pulm. Med. 22(1), 450 (2022).
MedlineGoogle Scholar
60. Shi L, Gong Y, Zhuo L, Wang S, Chen S, Ke B. Methyltransferase-like 3 upregulation is involved in the chemoresistance of non-small cell lung cancer. Ann. Transl. Med. 10(3), 139 (2022).
Medline CASGoogle Scholar
61. Huang S, Luo S, Gong C et al. MTTL3 upregulates microRNA-1246 to promote occurrence and progression of NSCLC via targeting paternally expressed gene 3. Mol. Ther. Nucleic Acids 24, 542–553 (2021).
Medline CASGoogle Scholar
62. Xie M, Cheng B, Yu S et al. Cuproptosis-related MiR-21-5p/FDX1 axis in clear cell renal cell carcinoma and its potential impact on tumor microenvironment. Cells 12(1), 173 (2022).
MedlineGoogle Scholar
63. Cao Y, Di X, Cong S et al. RBM10 recruits METTL3 to induce N6-methyladenosine-MALAT1-dependent modification, inhibiting the invasion and migration of NSCLC. Life Sci. 315, 121359 (2023).
Medline CASGoogle Scholar
64. Zhong J, Ren X, Chen Z et al. miR-21-5p promotes lung adenocarcinoma progression partially through targeting SET/TAF-Iα. Life Sci. 231, 116539 (2019).
Medline CASGoogle Scholar

Vol. 15, No. 23

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Received 26 June 2023

Accepted 23 November 2023

Published online 21 December 2023

Published in print December 2023

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Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0230

Author contributions

S Qian and J Liu wrote the paper and conceived and designed the experiments, W Liao analyzed the data, and F Wang collected and provided the sample for this study. All authors have read and approved the final submitted manuscript.

Financial disclosure

This study was supported by Quzhou Science and Technology Bureau 2023 Guiding Science and Technology Research Project (2023ZD031).

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval (Animal committee of The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital (QZRMYY-20231209-001).

Data sharing statement

The data that supports the findings of this study are available on request from the corresponding author.

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