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:

MiR-183-5p inhibits lung squamous cell carcinoma survival through disrupting hypoxia adaptation mediated by HIF-1α/NDUFA4L2 axis

Oncogene volume 43, pages 2821–2834 (2024)Cite this article

Subjects

Abstract

Hypoxia is a common feature of lung squamous cell carcinoma (LUSC), and hypoxia-inducible factor-1 (HIF-1) overexpression is associated with poor clinical outcome in LUSC. NADH dehydrogenase 1 alpha subcomplex subunit 4-like 2 (NDUFA4L2) is a recently identified target of HIF-1, but its roles in LUSC remain unclear. Herein, the expression and regulatory mechanisms of NDUFA4L2 were investigated in LUSC, and the influences on LUSC cell oxidative metabolism and survival of NDUFA4L2 were determined. The potential microRNA targeting to NDUFA4L2 was identified and its roles on LUSC cell were detected. We found that NDUFA4L2 were overexpressed in LUSC tissues, and that NDUFA4L2 expression correlated with shorter overall survival. NDUFA4L2 was regulated by HIF-1α under hypoxia, and NDUFA4L2 decreased mitochondrial reactive oxygen species (mitoROS) production through inhibiting mitochondrial complex I activity in LUSC cells. NDUFA4L2 silencing effectively suppressed LUSC cell growth and enhanced apoptosis by inducing mitoROS accumulation. Additionally, NDUFA4L2 was a target for miR-183-5p, and LUSC patients with high miR-183-5p levels had better prognoses. MiR-183-5p significantly induced mitoROS production and suppressed LUSC survival through negatively regulating NDUFA4L2 in vitro and in vivo. Our results suggested that regulation of NDUFA4L2 by HIF-1α is an important mechanism promoting LUSC progression under hypoxia. NDUFA4L2 inhibition using enforced miR-183-5p expression might be an effective strategy for LUSC treatment.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: NDUFA4L2 is overexpressed in LUSC tissues.
Fig. 2: NDUFA4L2 is upregulated by HIF-1α during hypoxia.
Fig. 3: ChIP-PCR analysis of HIF-1α binding to the hypoxia response element (HRE) within the NDUFA4L2 promoter.
Fig. 4: NDUFA4L2 decreases oxygen consumption, mitochondrial complex I activity, and mitoROS production in LUSC cells.
Fig. 5: NDUFA4L2 inhibits mitoROS level to enhance LUSC cell survival under hypoxia.
Fig. 6: NDUFA4L2 is the direct target of miR-183-5p.
Fig. 7: MiR-183-5p overexpression induces oxidative stress and suppresses LUSC cell survival under hypoxia by targeting NDUFA4L2.
Fig. 8: MiR-183-5p impairs the growth of LUSC xenografts by downregulating NDUFA4L2 in nude mice.

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Ruiz-Ceja KA, Chirino YI. Current FDA-approved treatments for non-small cell lung cancer and potential biomarkers for its detection. Biomed Pharmacother. 2017;90:24–37.

    Article  PubMed  CAS  Google Scholar 

  2. Zhao W, Choi YL, Song JY, Zhu Y, Xu Q, Zhang F, et al. ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare. Lung Cancer. 2016;94:22–7.

    Article  PubMed  Google Scholar 

  3. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:1835–42.

    Article  PubMed  CAS  Google Scholar 

  4. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184–91.

    Article  PubMed  CAS  Google Scholar 

  5. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823–33.

    Article  PubMed  CAS  Google Scholar 

  6. Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.

    Article  PubMed  CAS  Google Scholar 

  7. Socinski MA, Obasaju C, Gandara D, Hirsch FR, Bonomi P, Bunn PA Jr, et al. Current and emergent therapy options for advanced squamous cell lung cancer. J Thorac Oncol. 2018;13:165–83.

    Article  PubMed  CAS  Google Scholar 

  8. Al Tameemi W, Dale TP, Al-Jumaily RMK, Forsyth NR. Hypoxia-modified cancer cell metabolism. Front Cell Devel Biol. 2019;7:4.

    Article  Google Scholar 

  9. Bhandari V, Hoey C, Liu LY, Lalonde E, Ray J, Livingstone J, et al. Molecular landmarks of tumor hypoxia across cancer types. Nat Genet. 2019;51:308–18.

    Article  PubMed  CAS  Google Scholar 

  10. Xiang L, Semenza GL. Hypoxia-inducible factors promote breast cancer stem cell specification and maintenance in response to hypoxia or cytotoxic chemotherapy. Adv Cancer Res. 2019;141:175–212.

    Article  PubMed  CAS  Google Scholar 

  11. Nagao A, Kobayashi M, Koyasu S, Chow CCT, Harada H. HIF-1-dependent reprogramming of glucose metabolic pathway of cancer cells and its therapeutic significance. Int J Mol Sci. 2019;20:238.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Berezowska S, Galvan JA, Langer R, Bubendorf L, Savic S, Gugger M, et al. Glycine decarboxylase and HIF-1alpha expression are negative prognostic factors in primary resected early-stage non-small cell lung cancer. Virchows Arch. 2017;470:323–30.

    Article  PubMed  CAS  Google Scholar 

  13. Takasaki C, Kobayashi M, Ishibashi H, Akashi T, Okubo K. Expression of hypoxia-inducible factor-1alpha affects tumor proliferation and antiapoptosis in surgically resected lung cancer. Mol Clin Oncol. 2016;5:295–300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Ren W, Mi D, Yang K, Cao N, Tian J, Li Z, et al. The expression of hypoxia-inducible factor-1alpha and its clinical significance in lung cancer: a systematic review and meta-analysis. Swiss Med Wkly. 2013;143:w13855.

    PubMed  Google Scholar 

  15. Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9:425–34.

    Article  PubMed  CAS  Google Scholar 

  16. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129:111–22.

    Article  PubMed  CAS  Google Scholar 

  17. Semenza Gregg L. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J. 2007;405:1–9.

    Article  PubMed  CAS  Google Scholar 

  18. Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E, Elorza A, Ordonez A, et al. Induction of the mitochondrial NDUFA4L2 protein by HIF-1alpha decreases oxygen consumption by inhibiting Complex I activity. Cell Metab. 2011;14:768–79.

    Article  PubMed  CAS  Google Scholar 

  19. Lai RK, Xu IM, Chiu DK, Tse AP, Wei LL, Law CT, et al. NDUFA4L2 fine-tunes oxidative stress in hepatocellular Carcinoma. Clin Cancer Res. 2016;22:3105–17.

    Article  PubMed  CAS  Google Scholar 

  20. Laursen KB, Chen Q, Khani F, Attarwala N, Gross SS, Dow L, et al. Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and expression of Ca9 in the TRACK model of early clear cell renal cell carcinoma. Front Oncol. 2021;11:783856.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Minton DR, Fu L, Mongan NP, Shevchuk MM, Nanus DM, Gudas LJ. Role of NADH dehydrogenase (Ubiquinone) 1 Alpha subcomplex 4-Like 2 in clear cell renal cell carcinoma. Clin Cancer Res. 2016;22:2791–801.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhou L, Mao LH, Li X, Wang QL, Chen SY, Chen ZJ, et al. Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance by decreasing reactive oxygen species in hepatocellular carcinoma. Cancer Sci. 2023;114:793.

    Article  PubMed  CAS  Google Scholar 

  23. Kubala JM, Laursen KB, Schreiner R, Williams RM, van der Mijn JC, Crowley MJ, et al. NDUFA4L2 reduces mitochondrial respiration resulting in defective lysosomal trafficking in clear cell renal cell carcinoma. Cancer Biol Therapy. 2023;24:2170669.

    Article  Google Scholar 

  24. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–W60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Salem A, Asselin MC, Reymen B, Jackson A, Lambin P, West CML, et al. Targeting hypoxia to improve non-small cell lung cancer outcome. J Natl Cancer Inst. 2018;110 https://doi.org/10.1093/jnci/djx160.

  26. Esterházy D, King MS, Yakovlev G, Hirst J. Production of reactive oxygen species by complex I (NADH: ubiquinone oxidoreductase) from Escherichia coli and comparison to the enzyme from mitochondria. Biochemistry. 2008;47:3964–71.

    Article  PubMed  Google Scholar 

  27. Nakamura H, Takada K. Reactive oxygen species in cancer: current findings and future directions. Cancer Sci. 2021;112:3945–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Checa J, Aran JM. Reactive oxygen species: drivers of physiological and pathological processes. J Inflammat Res. 2020;13:1057–73.

    Article  CAS  Google Scholar 

  29. Sgarbi G, Gorini G, Liuzzi F, Solaini G, Baracca A. Hypoxia and IF1 expression promote ROS decrease in cancer cells. Cells. 2018;7:64.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Garofalo M, Croce CM. microRNAs: master regulators as potential therapeutics in cancer. Annu Rev Pharmacol Toxicol. 2011;51:25–43.

    Article  PubMed  CAS  Google Scholar 

  32. Kudo M, Zalles N, Distefano R, Nigita G, Veneziano D, Gasparini P, et al. Synergistic apoptotic effect of miR-183-5p and Polo-Like kinase 1 inhibitor NMS-P937 in breast cancer cells. Cell Death Differ 2021;29:407–19.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Shen G, Li X, Jia Y-f, Piazza GA, Xi Y. Hypoxia-regulated microRNAs in human cancer. Acta Pharmacol Sin. 2013;34:336–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Tapeh BE-G, Alivand MR, Solalii S. Potential Interactions between miRNAs and hypoxia: a new layer in cancer hypoxia. Anti-Cancer Agents Med Chem. 2021;21:2315–26.

    Article  Google Scholar 

  35. Liang Y, Wang T, Gao R, Jia X, Ji T, Shi P, et al. Fucosyltransferase 8 is overexpressed and influences clinical outcomes in lung adenocarcinoma patients. Pathol Oncol Res. 2022;28:1610116.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhu X, Zhang Y, Wang Y, Zhang H, Wang X, Tang H, et al. Agrimoniin sensitizes pancreatic cancer to apoptosis through ROS-mediated energy metabolism dysfunction. Phytomedicine. 2022;96:153807.

    Article  PubMed  CAS  Google Scholar 

  37. He W, Zhang XY, Gong X, Luo K, Mao X, Lu E, et al. Drug‐free biomimetic oxygen supply nanovehicle promotes ischemia‐reperfusion therapy in stroke. Adv Funct Mater. 2023;33:2212919.

    Article  CAS  Google Scholar 

  38. Chen S-j, Hoffman NE, Shanmughapriya S, Bao L, Keefer K, Conrad K, et al. A splice variant of the human ion channel TRPM2 modulates neuroblastoma tumor growth through hypoxia-inducible factor (HIF)-1/2α. J Biol Chem. 2014;289:36284–302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Tahrir FG, Shanmughapriya S, Ahooyi TM, Knezevic T, Gupta MK, Kontos CD, et al. Dysregulation of mitochondrial bioenergetics and quality control by HIV‐1 Tat in cardiomyocytes. J Cell Physiol. 2018;233:748–58.

    Article  PubMed  CAS  Google Scholar 

  40. Li R, Shen Q, Wu N, He M, Liu N, Huang J, et al. MiR-145 improves macrophage-mediated inflammation through targeting Arf6. Endocrine. 2018;60:73–82.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant number 81902322), Natural Science Basic Research Program of Shaanxi Province (grant number 2020JQ-526 and 2023-JC-YB-791), Fundamental Research Funds for the Central Universities in Xi’an Jiaotong University (grant number xzy012021064).

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Peng Han, Rui Gao, Xinru Li, Aomei Zhao, Jianjun Xue, Aimin Yang & Yiqian Liang

  2. Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Peng Han

  3. Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Boxiang Zhang & Yixing Li

  4. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, China

    Hui Ren & Puyu Shi

Authors
  1. Peng Han
    View author publications

    Search author on:PubMed Google Scholar

  2. Boxiang Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yixing Li
    View author publications

    Search author on:PubMed Google Scholar

  4. Rui Gao
    View author publications

    Search author on:PubMed Google Scholar

  5. Xinru Li
    View author publications

    Search author on:PubMed Google Scholar

  6. Hui Ren
    View author publications

    Search author on:PubMed Google Scholar

  7. Puyu Shi
    View author publications

    Search author on:PubMed Google Scholar

  8. Aomei Zhao
    View author publications

    Search author on:PubMed Google Scholar

  9. Jianjun Xue
    View author publications

    Search author on:PubMed Google Scholar

  10. Aimin Yang
    View author publications

    Search author on:PubMed Google Scholar

  11. Yiqian Liang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

All authors have read the journal’s authorship agreement and that the manuscript has been reviewed by and approved by all named authors. Yiqian Liang, Aimin Yang and Boxiang Zhang conceived the study, designed the experiments, and acquired the financial support; Peng Han, Yixing Li and Aomei Zhao carried out cell culture and in vitro studies; Xinru Li, Hui Ren and Puyu Shi performed the in vivo studies and acquired data; Rui Gao and Jianjun Xue performed the database analyses; Peng Han, Yiqian Liang and Boxiang Zhan analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Yiqian Liang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All methods in this study were performed in accordance with the Declaration of Helsinki and its subsequent revisions. Tissue microarray of human LUSC and paired adjacent normal tissues (HLugS180Su02) were purchased from Shanghai Outdo Biotech Company. The study was approved by the Ethics Committee of Shanghai Outdo Biotech Company (SHYJS-CP-1910013). All samples were obtained with patient’s informed content. The tissue samples for RT-PCR were collected at the First Affiliated Hospital of Xi’an Jiaotong University. The study was approved by the Ethic Committee of the First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2020LSK-199) and informed consent was obtained from every participant. All animal studies were approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University (No. 2018-025).

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

Han, P., Zhang, B., Li, Y. et al. MiR-183-5p inhibits lung squamous cell carcinoma survival through disrupting hypoxia adaptation mediated by HIF-1α/NDUFA4L2 axis. Oncogene 43, 2821–2834 (2024). https://doi.org/10.1038/s41388-024-03129-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03129-7

This article is cited by

Search

Advanced search

Quick links