Skip to main content
SpringerLink
Log in

m6A-mediated lncRNA NEAT1 plays an oncogenic role in non-small cell lung cancer by upregulating the HMGA1 expression through binding miR-361-3p

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

Abstract

Background

Lung cancer is the most common primary malignant tumor of the lung, and 85% of lung cancer is non-small cell lung cancer (NSCLC). The N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) have been widely reported to participate in the development of non-small cell lung cancer.

Objective

However, the potential molecular mechanisms of m6A-regulated lncRNAs in NSCLC still need further investigation.

Methods

The expression levels and the role of lncRNA NEAT1 in NSCLC tissues or cells were measured by RT-qPCR, Western blot, cell counting kit 8 (CCK-8), flow cytometry assay. RNA immunoprecipitation (RIP) was used to measure the levels of m6A modification of NEAT1. Bioinformatics analysis and dual-luciferase reporter gene assay were detected the relationship between miR-361-3p and NEAT1/HMGA1. Mouse xenograft tumor models were established to confirm the effects of lncRNA NEAT1 in vivo.

Results

In this study, we verified whether m6A-modified lncRNA nuclear enriched abundant transcript 1 (NEAT1) is involved in NSCLC progression via miR-361-3p/HMGA1 axis. Firstly, we found that lncRNA NEAT1 was upregulated in NSCLC, and was associated with a poor survival in NSCLC patients. Methyltransferase like 3 (METTL3)-mediated m6A modification stabilized and upregulated NEAT1 expression. Next, function experiment indicated that depletion of METTL3 and NEAT1 induced cell apoptosis and inhibited cell proliferation, epithelial-mesenchymal transition (EMT). Likewise, in vivo experiments further supported the oncogenic role of NEAT1 in NSCLC. In addition, the molecular mechanism was uncovered in our study, and we found that lncRNA NEAT1 promoted the expression of high-mobility group AT-hook 1 (HMGA1) by sponging miR-361-3p and then promoted tumorigenesis of NSCLC.

Conclusion

In conclusion, our findings demonstrated that METTL3-mediated m6A modification accelerated NSCLC progression by regulating the NEAT1/miR-361-3p/HMGA1 axis, which provides important targets for the treatment of NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data in our study are available from the corresponding author upon reasonable request.

References

  • Boehm EM, Gildenberg MS, Washington MT (2016) The many roles of PCNA in eukaryotic DNA replication. Enzymes 39:231–254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bridges MC, Daulagala AC, Kourtidis A (2021) LNCcation: lncRNA localization and function. J Cell Biol 220

  • Brown S, Banfill K, Aznar MC, Whitehurst P, Faivre Finn C (2019) The evolving role of radiotherapy in non-small cell lung cancer. Br J Radiol 92:20190524

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Lin Y, Shu Y, He J, Gao W (2020) Interaction between N(6)-methyladenosine (m(6)A) modification and noncoding RNAs in cancer. Mol Cancer 19:94

    Article  PubMed  PubMed Central  Google Scholar 

  • Dong B, Zhang F, Zhang W, Gao Y (2023) IncRNA EPB41L4A-AS1 mitigates the proliferation of Non-Small-Cell Lung Cancer cells through the miR-105-5p/GIMAP6 Axis. Crit Rev Eukaryot Gene Expr 33:27–40

    Article  PubMed  Google Scholar 

  • Dou X, Wang Z, Lu W, Miao L, Zhao Y (2022) METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way. BMC Pulm Med 22:324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eloranta S, Smedby KE, Dickman PW, Andersson TM (2021) Cancer survival statistics for patients and healthcare professionals - a tutorial of real-world data analysis. J Intern Med 289:12–28

    Article  CAS  PubMed  Google Scholar 

  • Fan Z, Wu Z, Yang B (2021) The effect of mir-361-3p targeting TRAF6 on apoptosis of multiple myeloma cells. J Microbiol Biotechnol 31:197–206

    Article  PubMed  Google Scholar 

  • Feng ZH, Liang YP, Cen JJ, Yao HH, Lin HS, Li JY, Liang H, Wang Z, Deng Q, Cao JZ et al (2022) m6A-immune-related lncRNA prognostic signature for predicting immune landscape and prognosis of bladder cancer. J Transl Med 20:492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong Z, Zhang Y, Jiang Y, Chen P, Ji J (2022) LncRNA NEAT1 Targets miR-342-3p/CUL4B to Inhibit the Proliferation of Cutaneous Squamous Cell Carcinoma Cells. J Oncol 2022:8145129

  • Hao J, Zhang W, Lyu Y, Zou J, Zhang Y, Lyu J, Zhang J, Xie S, Zhang C, Zhang J et al (2021) Combined use of cyclinD1 and Ki67 for prognosis of Luminal-Like breast Cancer patients. Front Oncol 11:737794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haruehanroengra P, Zheng YY, Zhou Y, Huang Y, Sheng J (2020) RNA modifications and cancer. RNA Biol 17:1560–1575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He L, Li H, Wu A, Peng Y, Shu G, Yin G (2019) Functions of N6-methyladenosine and its role in cancer. Mol Cancer 18:176

    Article  PubMed  PubMed Central  Google Scholar 

  • Hu Y, Gong C, Li Z, Liu J, Chen Y, Huang Y, Luo Q, Wang S, Hou Y, Yang S et al (2022) Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification. Mol Cancer 21:34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang C, Zhang N, Hu X, Wang H (2021a) Tumor-associated exosomes promote lung cancer metastasis through multiple mechanisms. Mol Cancer 20:117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, Yang C, Chen Y (2021b) The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther 6:74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong X, Duan Y, Sang Y, Li Y, Zhang H, Liang Y, Liu Y, Zhang N, Yang Q (2019) LncRNA-CDC6 promotes breast cancer progression and function as ceRNA to target CDC6 by sponging microRNA-215. J Cell Physiol 234:9105–9117

    Article  CAS  PubMed  Google Scholar 

  • Lang C, Yin C, Lin K, Li Y, Yang Q, Wu Z, Du H, Ren D, Dai Y, Peng X (2021) M(6) a modification of lncRNA PCAT6 promotes bone metastasis in prostate cancer through IGF2BP2-mediated IGF1R mRNA stabilization. Clin Transl Med 11:e426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li T, Song T, Ni L, Yang G, Song X, Wu L, Liu B, Liu C (2014) The p-ERK-p-c-Jun-cyclinD1 pathway is involved in proliferation of smooth muscle cells after exposure to cigarette smoke extract. Biochem Biophys Res Commun 453:316–320

    Article  CAS  PubMed  Google Scholar 

  • Li B, Jiang HY, Wang ZH, Ma YC, Bao YN, Jin Y (2021) Effect of fenofibrate on proliferation of SMMC-7721 cells via regulating cell cycle. Hum Exp Toxicol 40:1208–1221

    Article  PubMed  Google Scholar 

  • Li L, Kim JH, Lu W, Williams DM, Kim J, Cope L, Rampal RK, Koche RP, Xian L, Luo LZ et al (2022) HMGA1 chromatin regulators induce transcriptional networks involved in GATA2 and proliferation during MPN progression. Blood 139:2797–2815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim JU, Yeo CD (2022) Update on adjuvant therapy in completely resected NSCLC patients. Thorac Cancer 13:277–283

    Article  PubMed  Google Scholar 

  • Liu J, Yao L, Zhang M, Jiang J, Yang M, Wang Y (2019) Downregulation of LncRNA-XIST inhibited development of non-small cell lung cancer by activating miR-335/SOD2/ROS signal pathway mediated pyroptotic cell death. Aging 11:7830–7846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu T, Wang H, Fu Z, Wang Z, Wang J, Gan X, Wang A, Wang L (2022a) Methyltransferase-like 14 suppresses growth and metastasis of renal cell carcinoma by decreasing long noncoding RNA NEAT1. Cancer Sci 113:446–458

    Article  CAS  PubMed  Google Scholar 

  • Liu X, He H, Zhang F, Hu X, Bi F, Li K, Yu H, Zhao Y, Teng X, Li J et al (2022b) m6A methylated EphA2 and VEGFA through IGF2BP2/3 regulation promotes vasculogenic mimicry in colorectal cancer via PI3K/AKT and ERK1/2 signaling. Cell Death Dis 13:483

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu S, Wei W, Wang J, Chen T (2023) Theranostic applications of selenium nanomedicines against lung cancer. J Nanobiotechnol 21:96

    Article  CAS  Google Scholar 

  • Ma S, Chen C, Ji X, Liu J, Zhou Q, Wang G, Yuan W, Kan Q, Sun Z (2019) The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol 12:121

    Article  PubMed  PubMed Central  Google Scholar 

  • Méndez O, Pérez J, Soberino J, Racca F, Cortés J, Villanueva J (2019) Clinical implications of Extracellular HMGA1 in breast Cancer. Int J Mol Sci 20

  • Peng K, Xia RP, Zhao F, Xiao Y, Ma TD, Li M, Feng Y, Zhou CG (2022) ALKBH5 promotes the progression of infantile hemangioma through regulating the NEAT1/miR-378b/FOSL1 axis. Mol Cell Biochem 477:1527–1540

    Article  CAS  PubMed  Google Scholar 

  • Saed L, Jeleń A, Mirowski M, Sałagacka-Kubiak A (2022) Prognostic significance of HMGA1 expression in Lung Cancer based on Bioinformatics Analysis. Int J Mol Sci 23

  • She K, He S, Lu X, Yu S, Li M, Xiong W, Zhou M (2023) LncRNA SNHG7 promotes non-small cell lung cancer progression and cisplatin resistance by inducing autophagic activity. J Thorac Dis 15:155–167

    Article  PubMed  PubMed Central  Google Scholar 

  • Sun T, Wu R, Ming L (2019) The role of m6A RNA methylation in cancer. Biomed Pharmacother 112:108613

    Article  CAS  PubMed  Google Scholar 

  • Teng PC, Liang Y, Yarmishyn AA, Hsiao YJ, Lin TY, Lin TW, Teng YC, Yang YP, Wang ML, Chien CS et al (2021) RNA modifications and epigenetics in modulation of Lung Cancer and Pulmonary Diseases. Int J Mol Sci 22

  • Tripathi SK, Pal A, Ghosh S, Goel A, Aggarwal R, Banerjee S, Das S (2022) LncRNA NEAT1 regulates HCV-induced hepatocellular carcinoma by modulating the mir-9-BGH3 axis. J Gen Virol 103

  • Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B (2019) Long noncoding RNA (lncRNA)-Mediated competing endogenous RNA networks provide Novel potential biomarkers and therapeutic targets for Colorectal Cancer. Int J Mol Sci 20

  • Wen S, Wei Y, Zen C, Xiong W, Niu Y, Zhao Y (2020) Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine. Mol Cancer 19:171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie Y, Zheng ZW, He HT, Chang ZB (2022) LncRNA NEAT1 induces autophagy through the miR-128-3p/ADAM28 axis to suppress apoptosis of nonsmall-cell lung cancer. Kaohsiung J Med Sci 38:933–949

    Article  CAS  PubMed  Google Scholar 

  • Xu D, Dong P, Xiong Y, Yue J, Konno Y, Ihira K, Kobayashi N, Todo Y, Watari H (2020) MicroRNA-361-Mediated inhibition of HSP90 expression and EMT in Cervical Cancer is counteracted by oncogenic lncRNA NEAT1. Cells 9

  • Xue L, Li J, Lin Y, Liu D, Yang Q, Jian J, Peng J (2021) M(6) a transferase METTL3-induced lncRNA ABHD11-AS1 promotes the Warburg effect of non-small-cell lung cancer. J Cell Physiol 236:2649–2658

    Article  CAS  PubMed  Google Scholar 

  • Yang Q, Wang Y, Li M, Wang Z, Zhang J, Dai W, Pei M, Hong L, Xiao Y, Hu H et al (2021) HMGA1 promotes gastric cancer growth and metastasis by transactivating SUZ12 and CCDC43 expression. Aging 13:16043–16061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao FY, Zhao C, Zhong FM, Qin TY, Wen F, Li MY, Liu J, Huang B, Wang XZ (2021) M(6)a modification of lncRNA NEAT1 regulates chronic myelocytic leukemia progression via miR-766-5p/CDKN1A Axis. Front Oncol 11:679634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Weng W, Zhang Q, Wu Y, Ni S, Tan C, Xu M, Sun H, Liu C, Wei P et al (2018) The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5. J Hematol Oncol 11:113

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Guo S, Piao HY, Wang Y, Wu Y, Meng XY, Yang D, Zheng ZC, Zhao Y (2019) ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1. J Physiol Biochem 75:379–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W, Xiao P, Tang J, Wang R, Wang X, Wang F, Ruan J, Yu S, Tang J, Huang R et al (2022) m6A Regulator-Mediated tumour infiltration and methylation modification in Cervical Cancer Microenvironment. Front Immunol 13:888650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao MM, Ge LY, Yang LF, Zheng HX, Chen G, Wu LZ, Shi SM, Wang N, Hang YP (2020) LncRNA NEAT1/miR-204/NUAK1 Axis is a potential therapeutic target for Non-Small Cell Lung Cancer. Cancer Manag Res 12:13357–13368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou D, Ji G, Wei G, Li Z, Yu N, Wang Y, Lin B, Zhang L, Yin Y (2022) MiR-361-3p promotes tumorigenesis of osteosarcoma cells via targeting ARID3A. Tissue Cell 76:101759

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by the research grant from the Beijing Health Promotion Association (BJHPA) and China Guanghua Technology Foundation.

Author information

Authors and Affiliations

  1. Department of Oncology and Radiotherapy, The Second Affiliated Hospital of Harbin Medical University, No.246 Xuefu Road, Nangang District, Harbin, 150001, China

    Li Qi & Yue Yin

  2. Department of Oncology and Radiotherapy, Shenzhen People’s Hospital, Shenzhen, 518020, China

    Mengqi Sun

Authors
  1. Li Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengqi Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Li Qi conceived the designed and wrote the manuscript, Yue Yin and Mengqi Sun contributed the data collection and performed the experiments. Yue Yin conducted data analysis. All authors reviewed and accepted the manuscript.

Corresponding author

Correspondence to Li Qi.

Ethics declarations

Ethics approval and consent to participate

All tissues samples were collected using protocols approved by the Ethics Committee of the Affiliated Second Hospital of Harbin Medical University. Written informed consent was signed by each patient or legal guardianship. All animal experiments were approved by the Animal Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (SYDW2022-115), and complies with the NIH Guide for the Care and Use of Laboratory Animals.

Conflict of interest

All authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qi, L., Yin, Y. & Sun, M. m6A-mediated lncRNA NEAT1 plays an oncogenic role in non-small cell lung cancer by upregulating the HMGA1 expression through binding miR-361-3p. Genes Genom 45, 1537–1547 (2023). https://doi.org/10.1007/s13258-023-01442-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-023-01442-1

Keywords

Search

Navigation