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

• Published in: Oncogene 2019-03, Vol.38 (13), p.2291-2304
• Main Authors: Fan, Zhongyi, Yang, Jing, Zhang, Dong, Zhang, Xuelin, Ma, Xiaoyan, Kang, Lei, Liu, Ying, Yan, Xiang, Ji, Quanbo, Wang, Jinliang, Li, Ying, Zhang, Sujie, Zhu, Xiang, Hu, Yi, Xu, Xiaojie, Ye, Qinong, Jiao, Shunchang
• Format: Article
• Language: English
• Subjects: 13/109; 3' Untranslated Regions; 38/1; 38/35; 38/77; 631/67/1612/1350; 631/67/395; Animals; Antibodies; Apoptosis; Binding sites; Binding Sites - genetics; Cancer metastasis; Cancer research; Cancer treatment; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Case-Control Studies; Cell Biology; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Chromosome 3; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; Epithelial-Mesenchymal Transition - genetics; ErbB Receptors - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic; Gene mutation; Genes; Genetic aspects; Genetic polymorphisms; Genetic Predisposition to Disease; Genetic variation; Human Genetics; Humans; Internal Medicine; Kinases; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Mice; MicroRNAs - metabolism; MicroRNAs - physiology; Non-small cell lung cancer; Non-small cell lung carcinoma; Oncology; Phenols (Class of compounds); Polymorphism, Single Nucleotide; Prognosis; Protein-tyrosine kinase; Risk Factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Small cell lung cancer; Stem cells; Therapeutic applications; Tumors; Tyrosine
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0576-6

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.