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The risk variant rs884225 within EGFR impairs miR-103a-3p’s anti-tumourigenic function in non-small cell lung cancer

Oncogene volume 38, pages 2291–2304 (2019)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) status is the major determinant of non-small cell lung cancer (NSCLC) therapy selection. Studies have hinted that EGFR antibodies or tyrosine kinase inhibitors were beneficial in patients with EGFR mutation-negative but EGFR-overexpressing of NSCLC. However, the mechanisms underlying EGFR amplification and overexpression in NSCLC remain largely unknown. Here, we report that rs884225, a single nucleotide polymorphism in the EGFR 3′-terminal untranslated region, was significantly associated with EGFR expression level and contributed to NSCLC susceptibility. Mechanistically, the rs884225 C allele enhanced EGFR expression by altering the miR-103a-3p binding site, thus impairing miR-103a-3p’s anti-tumourigenic function. As a tumour suppressor gene, miR-103a-3p expression correlated with overall and recurrence-free survival in NSCLC patients. Furthermore, miR-103a-3p inhibited growth and metastasis via effects on the KRAS pathway and epithelial-to-mesenchymal transition in EGFR wild-type NSCLC cell lines, respectively, which substantially reduced EGFR expression and activity. Thus, rs884225 may be a biomarker for NSCLC susceptibility, and miR-103a-3p may be a potential therapeutic target in NSCLC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81702936, 81672602, 81822037, 81472589 and 81630067), Scientific Research Project of Health Care (15BJZ43), the Natural Science Foundation of Beijing (7172199), Logistics Scientific Research Project (BWS16J010) and General Financial Grant from the Postdoctoral Science Foundation of China (2017M613389, 2018T111142 and 2017T100809). The PLA General Hospital and Beijing Institute of Biotechnology made equal contributions to this work.

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  1. These authors contributed equally: Zhongyi Fan, Jing Yang, Dong Zhang

Authors and Affiliations

  1. Department of Oncology, PLA General Hospital, Beijing, China

    Zhongyi Fan, Xiang Yan, Quanbo Ji, Jinliang Wang, Ying Li, Sujie Zhang, Yi Hu & Shunchang Jiao

  2. Department of Nanlou Oncology, PLA General Hospital, Beijing, China

    Jing Yang & Dong Zhang

  3. Department of Nanlou Respiration, PLA General Hospital, Beijing, China

    Xuelin Zhang

  4. Department of Cardiovascular Disease, School of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China

    Xiaoyan Ma

  5. Department of Nuclear Medicine, Peking University First Hospital, Beijing, China

    Lei Kang

  6. Department of Ophthalmology, PLA General Hospital, Beijing, China

    Ying Liu

  7. Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China

    Xiang Zhu, Xiaojie Xu & Qinong Ye

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Fan, Z., Yang, J., Zhang, D. et al. The risk variant rs884225 within EGFR impairs miR-103a-3p’s anti-tumourigenic function in non-small cell lung cancer. Oncogene 38, 2291–2304 (2019). https://doi.org/10.1038/s41388-018-0576-6

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