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.

M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway

Cell Death & Differentiation volume 30, pages 605–617 (2023)Cite this article

Subjects

A Correction to this article was published on 10 October 2022

This article has been updated

Abstract

Non-small cell lung cancer (NSCLC) has the highest mortality rate among all malignancies worldwide. The role of long noncoding RNAs (lncRNAs) in the progression of cancers is a contemporary research hotspot. Based on an integrative analysis of The Cancer Genome Atlas database, we identified lncRNA-RNA Component of Mitochondrial RNA Processing Endoribonuclease (RMRP) as one of the most highly upregulated lncRNAs that are associated with poor survival in NSCLC. Furthermore, N(6)-methyladenosine (m6A) was highly enriched within RMRP and enhanced its RNA stability. In vitro and in vivo experiments showed that RMRP promoted NSCLC cell proliferation, invasion, and migration. In terms of mechanism, RMRP recruited YBX1 to the TGFBR1 promotor region, leading to upregulation of the transcription of TGFBR1. The TGFBR1/SMAD2/SMAD3 pathway was also regulated by RMRP. In addition, RMRP promoted the cancer stem cells properties and epithelial mesenchymal transition, which promote the resistance to radiation therapy and cisplatin. Clinical data further confirmed a positive correlation between RMRP and TGFBR1. In short, our work reveals that m6A RNA methylation-mediated RMRP stability renders proliferation and progression of NSCLC through regulating TGFBR1/SMAD2/SMAD3 pathway.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1: Integrated analysis of NSCLC reveals that lncRNA-RMRP is a potential biomarker for NSCLC patients.
Fig. 2: The m6A level of RMRP was upregulated in NSCLC cells than lung epithelial cells.
Fig. 3: RMRP promotes NSCLC cell proliferation.
Fig. 4: TGFBR1 is a critical target by which RMRP promotes proliferation, invasion, and migration.
Fig. 5: RMRP is associated with the transcription factor YBX1.
Fig. 6: RMRP promotes TGFBR1 transcription by recruiting YBX1 to the TGFBR1 promoter.
Fig. 7: RMRP regulated the TGFBR1/SMAD2/ SMAD3 pathway in NSCLC.
Fig. 8: Knockdown of RMRP limited tumor growth in vivo.

Data availability

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

Change history

References

  1. DeSantis CE, Miller KD, Goding Sauer A, Jemal A, Siegel RL Cancer statistics for African Americans, 2019 CA Cancer J Clin. 2019;69:211–33.

    Article  PubMed  Google Scholar 

  2. Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376:2109–21.

    Article  CAS  PubMed  Google Scholar 

  3. Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019;394:1145–58.

  4. Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96:1297–325.

    Article  CAS  PubMed  Google Scholar 

  5. Yin H, Wang X, Zhang X, Wang Y, Zeng Y, Xiong Y, et al. Integrated analysis of long noncoding RNA associated-competing endogenous RNA as prognostic biomarkers in clear cell renal carcinoma. Cancer Sci. 2018;109:3336–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang Y, Liu Y, Guan Y, Li H, Liu Y, Zhang M, et al. Integrated analysis of immune-related genes in endometrial carcinoma. Cancer Cell Int. 2020;20:477.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Wang X, Yin H, Zhang L, Zheng D, Yang Y, Zhang J, et al. The construction and analysis of the aberrant lncRNA-miRNA-mRNA network in non-small cell lung cancer. J Thorac Dis. 2019;11:1772–8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Xu Q, Yin H, Ao H, Leng X, Liu M, Liu Y, et al. An 11-lncRNA expression could be potential prognostic biomarkers in head and neck squamous cell carcinoma. J Cell Biochem. 2019;120:18094–103.

    Article  CAS  PubMed  Google Scholar 

  9. Feng S, Liu W, Bai X, Pan W, Jia Z, Zhang S, et al. LncRNA-CTS promotes metastasis and epithelial-to-mesenchymal transition through regulating miR-505/ZEB2 axis in cervical cancer. Cancer Lett. 2019;465:105–17.

    Article  CAS  PubMed  Google Scholar 

  10. Xu M, Xu X, Pan B, Chen X, Lin K, Zeng K, et al. LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2. Mol Cancer. 2019;18:135.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ridanpaa M, van Eenennaam H, Pelin K, Chadwick R, Johnson C, Yuan B, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104:195–203.

    Article  CAS  PubMed  Google Scholar 

  12. Maida Y, Yasukawa M, Furuuchi M, Lassmann T, Possemato R, Okamoto N, et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature. 2009;461:230–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cao HL, Liu ZJ, Huang PL, Yue YL, Xi JN. lncRNA-RMRP promotes proliferation, migration and invasion of bladder cancer via miR-206. Eur Rev Med Pharm Sci. 2019;23:1012–21.

    Google Scholar 

  14. Wang Y, Luo X, Liu Y, Han G, Sun D. Long noncoding RNA RMRP promotes proliferation and invasion via targeting miR-1-3p in non-small-cell lung cancer. J Cell Biochem. 2019;120:15170–81.

    Article  CAS  PubMed  Google Scholar 

  15. Meng Q, Ren M, Li Y, Song X. LncRNA-RMRP acts as an oncogene in lung cancer. PLoS One. 2016;11:e0164845.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Moore-Smith L, Pasche B. TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia. 2011;16:89–95.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang X, Chen X, Meng Q, Jing H, Lu H, Yang Y, et al. MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFbetaR1/Smad signaling pathway in NSCLC. Sci Rep. 2015;5:17618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhao Y, Qiao W, Wang X, Yin H, Cui J, Cui Y, et al. 14-3-3zeta/TGFbetaR1 promotes tumor metastasis in lung squamous cell carcinoma. Oncotarget. 2016;7:82972–84.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kabbout M, Garcia MM, Fujimoto J, Liu DD, Woods D, Chow CW, et al. ETS2 mediated tumor-suppressive function and MET oncogene inhibition in human non-small cell lung cancer. Clin Cancer Res. 2013;19:3383–95.

    Article  CAS  PubMed  Google Scholar 

  20. Cai L, Lin S, Girard L, Zhou Y, Yang L, Ci B, et al. LCE: an open web portal to explore gene expression and clinical associations in lung cancer. Oncogene. 2019;38:2551–64.

    Article  CAS  PubMed  Google Scholar 

  21. Mendell JT. Targeting a long noncoding RNA in breast cancer. N Engl J Med. 2016;374:2287–9.

    Article  PubMed  Google Scholar 

  22. Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, et al. lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/beta-catenin signaling. Nat Med. 2017;23:1331–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yin D, Lu X, Su J, He X, De W, Yang J, et al. Long noncoding RNA AFAP1-AS1 predicts a poor prognosis and regulates non-small cell lung cancer cell proliferation by epigenetically repressing p21 expression. Mol Cancer. 2018;17:92.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rheinbay E, Parasuraman P, Grimsby J, Tiao G, Engreitz JM, Kim J, et al. Recurrent and functional regulatory mutations in breast cancer. Nature. 2017;547:55–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shao Y, Ye M, Li Q, Sun W, Ye G, Zhang X, et al. LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer. Oncotarget. 2016;7:37812–24.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Fournier PG, Juarez P, Jiang G, Clines GA, Niewolna M, Kim HS, et al. The TGF-beta signaling regulator PMEPA1 suppresses prostate cancer metastases to bone. Cancer Cell. 2015;27:809–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tang YH, He GL, Huang SZ, Zhong KB, Liao H, Cai L, et al. The long noncoding RNA AK002107 negatively modulates miR-140-5p and targets TGFBR1 to induce epithelial-mesenchymal transition in hepatocellular carcinoma. Mol Oncol. 2019;13:1296–310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhou B, Guo W, Sun C, Zhang B, Zheng F. Linc00462 promotes pancreatic cancer invasiveness through the miR-665/TGFBR1-TGFBR2/SMAD2/3 pathway. Cell Death Dis. 2018;9:706.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schmitt ME, Clayton DA. Nuclear RNase MRP is required for correct processing of pre-5.8S rRNA in Saccharomyces cerevisiae. Mol Cell Biol. 1993;13:7935–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gill T, Cai T, Aulds J, Wierzbicki S, Schmitt ME. RNase MRP cleaves the CLB2 mRNA to promote cell cycle progression: novel method of mRNA degradation. Mol Cell Biol. 2004;24:945–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang M, Ke H, Zhou W. LncRNA RMRP promotes cell proliferation and invasion through miR-613/NFAT5 axis in non-small cell lung cancer. OncoTargets Ther. 2020;13:8941–50.

    Article  CAS  Google Scholar 

  32. Noh JH, Kim KM, Abdelmohsen K, Yoon JH, Panda AC, Munk R, et al. HuR and GRSF1 modulate the nuclear export and mitochondrial localization of the lncRNA RMRP. Genes Dev. 2016;30:1224–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. El-Naggar AM, Veinotte CJ, Cheng H, Grunewald TG, Negri GL, Somasekharan SP, et al. Translational activation of HIF1alpha by YB-1 promotes sarcoma metastasis. Cancer Cell. 2015;27:682–97.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang E, He X, Zhang C, Su J, Lu X, Si X, et al. A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1. Genome Biol 2018;19:154.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Moharamoghli M, Hassan-Zadeh V, Dolatshahi E, Alizadeh Z, Farazmand A. The expression of GAS5, THRIL, and RMRP lncRNAs is increased in T cells of patients with rheumatoid arthritis. Clin Rheumatol. 2019;38:3073–80.

    Article  PubMed  Google Scholar 

  36. Atianand MK, Fitzgerald KA. IMMUNOLOGY. An RNA twist to T(H)17 cells. Science. 2016;351:1032.

    Article  CAS  PubMed  Google Scholar 

  37. de la Fuente MA, Recher M, Rider NL, Strauss KA, Morton DH, Adair M, et al. Reduced thymic output, cell cycle abnormalities, and increased apoptosis of T lymphocytes in patients with cartilage-hair hypoplasia. J Allergy Clin Immunol. 2011;128:139–46.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Huang X, Zhang G, Liang T. Cancer environmental immunotherapy: starving tumor cell to death by targeting TGFB on immune cell. J Immunother Cancer. 2021;9:e002823.

  39. Li J, Lee Y, Li Y, Jiang Y, Lu H, Zang W, et al. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8(+) T Cells. Immunity 2018;48:773–86 e5.

    Article  CAS  PubMed  Google Scholar 

  40. Amelio I, Mancini M, Petrova V, Cairns RA, Vikhreva P, Nicolai S, et al. p53 mutants cooperate with HIF-1 in transcriptional regulation of extracellular matrix components to promote tumor progression. Proc Natl Acad Sci USA. 2018;115:E10869–E78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sang LJ, Ju HQ, Liu GP, Tian T, Ma GL, Lu YX, et al. LncRNA CamK-A regulates Ca(2+)-signaling-mediated tumor microenvironment remodeling. Mol Cell. 2018;72:71–83 e7.

    Article  CAS  PubMed  Google Scholar 

  42. Ghafouri-Fard S, Esmaeili M, Taheri M. H19 lncRNA: roles in tumorigenesis. Biomed Pharmacother. 2020;123:109774.

    Article  CAS  PubMed  Google Scholar 

  43. Wan P, Su W, Zhang Y, Li Z, Deng C, Li J, et al. LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury. Cell Death Differ. 2020;27:176–91.

    Article  CAS  PubMed  Google Scholar 

  44. Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552:126–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N(6) -methyladenosine-dependent primary MicroRNA processing. Hepatology. 2017;65:529–43.

    Article  CAS  PubMed  Google Scholar 

  46. Zheng ZQ, Li ZX, Zhou GQ, Lin L, Zhang LL, Lv JW, et al. Long noncoding RNA FAM225A promotes nasopharyngeal carcinoma tumorigenesis and metastasis by acting as ceRNA to sponge miR-590-3p/miR-1275 and upregulate ITGB3. Cancer Res. 2019;79:4612–26.

    Article  CAS  PubMed  Google Scholar 

  47. Yin H, Wang X, Zhang X, Zeng Y, Xu Q, Wang W, et al. UBE2T promotes radiation resistance in non-small cell lung cancer via inducing epithelial-mesenchymal transition and the ubiquitination-mediated FOXO1 degradation. Cancer Lett. 2020;494:121–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank TCGA database. This study was supported by the National Natural Science Foundation of China (81903120 to HY; 81902317 to XW), Young Innovative Talents Training Program of Higher Education Institutions in Heilongjiang Province (UNPYSCT-2020161 to HY), Haiyan Foundation of Harbin Medical University Cancer Hospital (No. JJQN2019-01 to XW; JJZD2021-13 to HY), Postdoctoral Foundation of Heilongjiang Province (LBH-Z18224 to XW; LBH-Z20076 to HY), the Natural science funding of Heilongjiang (LH2019H041 to XW; YQ2021H024 to HY), China Postdoctoral Science Foundation (2018M641861to XW; 2020M681117 and 2021T140170 to HY), Young Talents Foundation of Harbin Medical University Cancer Hospital (No. BJQN2019-06 to XW; No. BJQN2020-01 to HY).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, PR China

    Hang Yin, Lin Chen & Shiqi Piao

  2. Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, PR China

    Hang Yin, Zhange Li, Yuan Lin & Xueqing Tang

  3. Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, PR China

    Yiru Wang & Xiaoyuan Wang

  4. Department of Pharmacology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, PR China

    Zhange Li

  5. Department of Oncology, Yuhuangding Hospital, Yantai, Shangdong Province, PR China

    Huijuan Zhang

  6. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China

    Haiyang Zhang

Authors
  1. Hang Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiqi Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yiru Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhange Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuan Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xueqing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huijuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Haiyang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HY supervised the project. HY and XYW designed the overall study, interpreted the experiments, and wrote the paper. LC, SQP, YRW, ZGL, HYZ and YL performed in vitro experiments and analyzed data. XQT, HJZ and HYZ performed in vivo experiments and analyzed data.

Corresponding author

Correspondence to Xiaoyuan Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics statement

All procedures followed were in accordance with the ethical standards approved by Institutional Ethics Committee on human experimentation and with the Helsinki Declaration. All institutional and national guidelines for the care and use of laboratory animals were followed.

Additional information

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

The original online version of this article was revised: Due to a figure error.

Edited by R De Maria

Supplementary information

Rights and permissions

Springer Nature or its licensor 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

Yin, H., Chen, L., Piao, S. et al. M6A RNA methylation-mediated RMRP stability renders proliferation and progression of non-small cell lung cancer through regulating TGFBR1/SMAD2/SMAD3 pathway. Cell Death Differ 30, 605–617 (2023). https://doi.org/10.1038/s41418-021-00888-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41418-021-00888-8

This article is cited by

Search

Advanced search

Quick links