Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

M2 macrophage exosomal LINC01001 promotes non-small cell lung cancer development by affecting METTL3 and glycolysis pathway

Cancer Gene Therapy volume 30, pages 1569–1580 (2023)Cite this article

Subjects

Abstract

There have been data showing that LINC01001 is highly expressed in lung cancer, but the effect of M2 macrophage exosomal LINC01001 to METTL3, glycolysis and immunity in non-small cell lung cancer (NSCLC) has not been reported. In this study, we aimed to explore the regulatory effect and mechanism of M2 macrophage exosomal LINC01001 in NSCLC. The results of our study show that the verification of macrophage exosomes, it was confirmed that exosomes regulated proliferation, glucose intake, lactate production and ATP levels of NSCLC cells. Exosomes also promoted the expression of METTL3. Bioinformatics screening showed that LINC01001 regulated METTL3. Subsequent experiments revealed exosomal LINC01001 influenced the glycolysis processes of NSCLC cells. Through RIP, it was proved that LINC01001 functioned in combination with METTL3. Bioinformatics predicted that NASP was a METTL3-targeted gene. LINC01001 could also regulate NASP methylation. Tumorigenesis in mice also indicated that LINC01001 mediated METTL3 to stimulate the development of tumors. In this study, LINC01001 was successfully verified in the exosomes-derived from M2 macrophages. It was confirmed that LINC01001 could interact with METTL3 and regulate glycolysis process in NSCLC cells. LINC01001 also inhibited T cell proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Extraction and identification of exosomes.
Fig. 2: Study on the function of macrophage exosomes.
Fig. 3: Screening for lncRNAs regulating METTL3.
Fig. 4: Clinical samples and cell samples were used to verify bioinformatics results.
Fig. 5: Functional exploration of LINC01001.
Fig. 6: Bioinformatics methods were performed to screen for the glycolytic pathways targeted by METTL3.
Fig. 7: Validation of LINC01001 in immunity.
Fig. 8: The function of LIN01001 was verified in vivo.

Similar content being viewed by others

Data availability

The expression data of NSCLC was downloaded from TCGA database (https://portal.gdc.cancer.gov). The genes related to glycolysis were obtained from GSEA website (http://wiki.c2b2.columbia.edu/workbench/index.php/GSEA).

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Lee SS, Cheah YK. The Interplay between MicroRNAs and Cellular Components of Tumour Microenvironment (TME) on Non-Small-Cell Lung Cancer (NSCLC) Progression. J Immunol Res. 2019;2019:3046379.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ettinger DS, Akerley W, Borghaei H, Chang AC, Cheney RT, Chirieac LR, et al. Non-small cell lung cancer, version 2.2013. J Natl Compr Canc Netw. 2013;11:645–53.

    Article  PubMed  Google Scholar 

  4. Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong K-K. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14:535–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ruiz-Cordero R, Devine WP. Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer. Surg Pathol Clin. 2020;13:17–33.

    Article  PubMed  Google Scholar 

  6. Arbour KC, Riely GJ. Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. JAMA. 2019;322:764–74.

    Article  CAS  PubMed  Google Scholar 

  7. Imyanitov EN, Iyevleva AG, Levchenko EV. Molecular testing and targeted therapy for non-small cell lung cancer: Current status and perspectives. Crit Rev Oncol Hematol. 2021;157:103194.

    Article  PubMed  Google Scholar 

  8. Liu Z, Wang T, She Y, Wu K, Gu S, Li L, et al. N(6)-methyladenosine-modified circIGF2BP3 inhibits CD8(+) T-cell responses to facilitate tumor immune evasion by promoting the deubiquitination of PD-L1 in non-small cell lung cancer. Mol Cancer. 2021;20:105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fu X-L, Duan W, Su C-Y, Mao F-Y, Lv Y-P, Teng Y-S, et al. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Cancer Immunol Immunother. 2017;66:1597–608.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Z-Y, Gao X-H, Ma M-Y, Zhao C-L, Zhang Y-L, Guo S-S. CircRNA_101237 promotes NSCLC progression via the miRNA-490-3p/MAPK1 axis. Sci Rep. 2020;10:9024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang J, Li H, Wu Q, Chen Y, Deng Y, Yang Z, et al. Tumoral NOX4 recruits M2 tumor-associated macrophages via ROS/PI3K signaling-dependent various cytokine production to promote NSCLC growth. Redox Biol. 2019;22:101116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhu Z, Zhang H, Chen B, Liu X, Zhang S, Zong Z, et al. PD-L1-Mediated Immunosuppression in Glioblastoma Is Associated With the Infiltration and M2-Polarization of Tumor-Associated Macrophages. Front Immunol. 2020;11:588552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Binenbaum Y, Fridman E, Yaari Z, Milman N, Schroeder A, Ben David G, et al. Transfer of miRNA in Macrophage-Derived Exosomes Induces Drug Resistance in Pancreatic Adenocarcinoma. Cancer Res. 2018;78:5287–99.

    Article  CAS  PubMed  Google Scholar 

  15. Li W, Xie P, Ruan W-H. Overexpression of lncRNA UCA1 promotes osteosarcoma progression and correlates with poor prognosis. J Bone Oncol. 2016;5:80–85.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yin Z, Zhou Y, Ma T, Chen S, Shi N, Zou Y, et al. Down-regulated lncRNA SBF2-AS1 in M2 macrophage-derived exosomes elevates miR-122-5p to restrict XIAP, thereby limiting pancreatic cancer development. J Cell Mol Med. 2020;24:5028–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Luo H-L, Huang M-D, Guo J-N, Fan R-H, Xia X-T, He J-D, et al. AFAP1-AS1 is upregulated and promotes esophageal squamous cell carcinoma cell proliferation and inhibits cell apoptosis. Cancer Med. 2016;5:2879–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mi X, Xu R, Hong S, Xu T, Zhang W, Liu M. M2 Macrophage-Derived Exosomal lncRNA AFAP1-AS1 and MicroRNA-26a Affect Cell Migration and Metastasis in Esophageal Cancer. Mol Ther Nucl Acids. 2020;22:779–90.

    Article  CAS  Google Scholar 

  19. Xin L, Zhou L-Q, Liu C, Zeng F, Yuan Y-W, Zhou Q, et al. Transfer of LncRNA CRNDE in TAM-derived exosomes is linked with cisplatin resistance in gastric cancer. EMBO Rep. 2021;22:e52124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zeng C, Huang W, Li Y, Weng H. Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol. 2020;13:117.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lee H, Bao S, Qian Y, Geula S, Leslie J, Zhang C, et al. Stage-specific requirement for Mettl3-dependent mA mRNA methylation during haematopoietic stem cell differentiation. Nat Cell Biol. 2019;21:700–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hua W, Zhao Y, Jin X, Yu D, He J, Xie D, et al. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol Oncol. 2018;151:356–65.

    Article  CAS  PubMed  Google Scholar 

  23. Wang Q, Chen C, Ding Q, Zhao Y, Wang Z, Chen J, et al. METTL3-mediated mA modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut. 2020;69:1193–205.

    Article  CAS  PubMed  Google Scholar 

  24. Wang L, Hui H, Agrawal K, Kang Y, Li N, Tang R, et al. m A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy. EMBO J. 2020;39:e104514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jin D, Guo J, Wu Y, Du J, Yang L, Wang X, et al. mA 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. 2019;12:135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu S, Zhuo L, Wang J, Zhang Q, Li Q, Li G, et al. METTL3 plays multiple functions in biological processes. Am J Cancer Res. 2020;10:1631–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Li DS, Ainiwaer JL, Sheyhiding I, Zhang Z, Zhang LW. Identification of key long non-coding RNAs as competing endogenous RNAs for miRNA-mRNA in lung adenocarcinoma. Eur Rev Med Pharm Sci. 2016;20:2285–95.

    Google Scholar 

  28. Zhou Y, Yamamoto Y, Takeshita F, Yamamoto T, Xiao Z, Ochiya T. Delivery of miR-424-5p via Extracellular Vesicles Promotes the Apoptosis of MDA-MB-231 TNBC Cells in the Tumor Microenvironment. Int J Mol Sci. 2021;22:844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li X, Chen Z, Ni Y, Bian C, Huang J, Chen L, et al. Tumor-associated macrophages secret exosomal miR-155 and miR-196a-5p to promote metastasis of non-small-cell lung cancer. Transl Lung Cancer Res. 2021;10:1338–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wan X, Xie B, Sun H, Gu W, Wang C, Deng Q, et al. Exosomes derived from M2 type tumor-associated macrophages promote osimertinib resistance in non-small cell lung cancer through MSTRG.292666.16-miR-6836-5p-MAPK8IP3 axis. Cancer Cell Int. 2022;22:83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhang T, Zhang P, Li H-X. CAFs-Derived Exosomal miRNA-130a Confers Cisplatin Resistance of NSCLC Cells Through PUM2-Dependent Packaging. Int J Nanomed. 2021;16:561–77.

    Article  Google Scholar 

  32. Wang H-M, Zhang X-H, Ye L-Q, Zhang K, Yang N-N, Geng S, et al. Insufficient CD100 shedding contributes to suppression of CD8 T-cell activity in non-small cell lung cancer. Immunology. 2020;160:209–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lu L, Huang J, Mo J, Da X, Li Q, Fan M, et al. Exosomal lncRNA TUG1 from cancer-associated fibroblasts promotes liver cancer cell migration, invasion, and glycolysis by regulating the miR-524-5p/SIX1 axis. Cell Mol Biol Lett. 2022;27:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ma L, Xue X, Zhang X, Yu K, Xu X, Tian X, et al. The essential roles of mA RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma. J Exp Clin Cancer Res. 2022;41:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bose S, Le A. Glucose Metabolism in Cancer. Adv Exp Med Biol. 2018;1063:3–12.

    Article  CAS  PubMed  Google Scholar 

  36. Cai W, Ji Y, Han L, Zhang J, Ni Y, Cheng Y, et al. METTL3-Dependent Glycolysis Regulates Dental Pulp Stem Cell Differentiation. J Dent Res. 2022;101:580–9.

    Article  CAS  PubMed  Google Scholar 

  37. Ni Z, Sun P, Zheng J, Wu M, Yang C, Cheng M, et al. JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA. Cancer Res. 2022;82:1789–802.

    Article  CAS  PubMed  Google Scholar 

  38. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.

    Article  CAS  PubMed  Google Scholar 

  39. Théry C. Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep. 2011;3:15.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Iero M, Valenti R, Huber V, Filipazzi P, Parmiani G, Fais S, et al. Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ. 2008;15:80–88.

    Article  CAS  PubMed  Google Scholar 

  41. Zhu J, Liu B, Wang Z, Wang D, Ni H, Zhang L, et al. Exosomes from nicotine-stimulated macrophages accelerate atherosclerosis through miR-21-3p/PTEN-mediated VSMC migration and proliferation. Theranostics. 2019;9:6901–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang X, Zhang H, Yang H, Bai M, Ning T, Deng T, et al. Exosome-delivered circRNA promotes glycolysis to induce chemoresistance through the miR-122-PKM2 axis in colorectal cancer. Mol Oncol. 2020;14:539–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 (Georget, Tex). 2021;20:1279–94.

    Article  CAS  Google Scholar 

  44. Xue L, Li J, Lin Y, Liu D, Yang Q, Jian J, et al. m A transferase METTL3-induced lncRNA ABHD11-AS1 promotes the Warburg effect of non-small-cell lung cancer. J Cell Physiol. 2021;236:2649–58.

    Article  CAS  PubMed  Google Scholar 

  45. Liu H-T, Zou Y-X, Zhu W-J, Sen L, Zhang G-H, Ma R-R, et al. lncRNA THAP7-AS1, transcriptionally activated by SP1 and post-transcriptionally stabilized by METTL3-mediated m6A modification, exerts oncogenic properties by improving CUL4B entry into the nucleus. Cell Death Differ. 2022;29:627–41.

    Article  CAS  PubMed  Google Scholar 

  46. Sheng X, Fan T, Jin X. Identification of Key Genes Involved in Acute Myocardial Infarction by Comparative Transcriptome Analysis. Biomed Res Int. 2020;2020:1470867.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhang M, Wang Q, Ke Z, Liu Y, Guo H, Fang S, et al. LINC01001 Promotes Progression of Crizotinib-Resistant NSCLC by Modulating IGF2BP2/MYC Axis. Front Pharm. 2021;12:759267.

    Article  CAS  Google Scholar 

  48. Lin Y, Wei X, Jian Z, Zhang X. METTL3 expression is associated with glycolysis metabolism and sensitivity to glycolytic stress in hepatocellular carcinoma. Cancer Med. 2020;9:2859–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang Z, Quan Y, Chen Y, Huang Y, Huang R, Yu W, et al. Knockdown of RNA N6-methyladenosine methyltransferase METTL3 represses Warburg effect in colorectal cancer via regulating HIF-1α. Signal Transduct Target Ther. 2021;6:89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    Article  CAS  PubMed  Google Scholar 

  51. Kaufmann SHE. Immunology’s Coming of Age. Front Immunol. 2019;10:684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen YG, Satpathy AT, Chang HY. Gene regulation in the immune system by long noncoding RNAs. Nat Immunol. 2017;18:962–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hur K, Kim S-H, Kim J-M. Potential Implications of Long Noncoding RNAs in Autoimmune Diseases. Immune Netw. 2019;19:e4.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sharma S, Findlay GM, Bandukwala HS, Oberdoerffer S, Baust B, Li Z, et al. Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex. Proc Natl Acad Sci USA. 2011;108:11381–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hu Q, Ye Y, Chan L-C, Li Y, Liang K, Lin A, et al. Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression. Nat Immunol. 2019;20:835–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Terry S, Savagner P, Ortiz-Cuaran S, Mahjoubi L, Saintigny P, Thiery J-P, et al. New insights into the role of EMT in tumor immune escape. Mol Oncol. 2017;11:824–46.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the FiGDRAW software. The Graphical Abstract of this study was drawn by Figdraw (www.figdraw.com).

Funding

This work was supported by the Natural Science Foundation of Hunan Province (No. 2023JJ30369), the Key Guidance Subject of Scientific Research Program of Hunan Health Commission (No. C202303027597), and the High-level Talents Project of Hunan Health Commission (No. [2023]32-131).

Author information

Author notes

  1. These authors contributed equally: Li Xu, Kang Li.

Authors and Affiliations

  1. The Second Department of Thoracic Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, P. R. China

    Li Xu, Kang Li, Jia Li, Fang Xu, Shuzhi Liang, Yi Kong & Bolin Chen

Authors
  1. Li Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shuzhi Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bolin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BC: guarantor of integrity of the entire study, literature research, study design and manuscript review; LX and KL: study design, experimental studies and manuscript editing; JL: statistical analysis; FX: data analysis; SL: data acquisition; YK: clinical studies and manuscript review; All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yi Kong or Bolin Chen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

This study was conducted according to the principles of the Declaration of Helsinki, and was approved by the Medical Ethics Committee of Hunan Cancer Hospital (Number: SBQLL-2022-113). All the information about the study will be fully explained to the subjects by the researchers. All the participants provided informed consent before sampling. This study was approved by the Animals Ethics Committee of the Hunan Cancer Hospital (Number: 2022-084). All experimental procedures were conducted in accordance with the ARRIVE Guidelines.

Additional information

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

Supplementary information

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

Xu, L., Li, K., Li, J. et al. M2 macrophage exosomal LINC01001 promotes non-small cell lung cancer development by affecting METTL3 and glycolysis pathway. Cancer Gene Ther 30, 1569–1580 (2023). https://doi.org/10.1038/s41417-023-00661-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-023-00661-8

Search

Advanced search

Quick links