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

Oncogene (2024)Cite this article

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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.

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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.

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Data availability

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

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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).

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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

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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.

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Correspondence to Yiqian Liang.

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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).

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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 (2024). https://doi.org/10.1038/s41388-024-03129-7

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