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The risk variant rs884225 within EGFR impairs miR-103a-3p's anti-tumourigenic function in non-small cell lung cancer
Zhongyi Fan1, Jing Yang2, Dong Zhang2
1Department of Oncology, PLA General Hospital, Beijing, China.
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.
Insights
A genetic variant (rs884225) in epidermal growth factor receptor (EGFR) is linked to non-small cell lung cancer (NSCLC) risk. This variant affects a microRNA, miR-103a-3p, impacting tumor growth and survival.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) status is critical for non-small cell lung cancer (NSCLC) treatment decisions.
- While EGFR-targeted therapies show promise in specific NSCLC patient groups, the mechanisms driving EGFR amplification and overexpression are not fully understood.
Purpose of the Study:
- To investigate the role of a single nucleotide polymorphism (SNP), rs884225, in the EGFR 3'-untranslated region and its association with EGFR expression and NSCLC susceptibility.
- To elucidate the molecular mechanism by which rs884225 influences EGFR expression and its impact on NSCLC progression and patient survival.
Main Methods:
- Genotyping of the rs884225 SNP in NSCLC patients and controls.
- Analysis of the association between rs884225 genotype, EGFR expression levels, and NSCLC susceptibility.
- Investigation of the regulatory role of miR-103a-3p on EGFR expression and its functional impact on NSCLC cell lines (EGFR wild-type).
- Assessment of miR-103a-3p expression correlation with patient survival outcomes.
Main Results:
- The rs884225 SNP was significantly associated with both EGFR expression levels and NSCLC susceptibility.
- The C allele of rs884225 enhances EGFR expression by disrupting the miR-103a-3p binding site, thereby reducing miR-103a-3p's tumor-suppressive activity.
- miR-103a-3p expression correlated positively with overall and recurrence-free survival in NSCLC patients.
- miR-103a-3p suppressed tumor growth and metastasis in EGFR wild-type NSCLC cells by modulating the KRAS pathway and epithelial-to-mesenchymal transition, leading to reduced EGFR expression and activity.
Conclusions:
- The rs884225 SNP may serve as a biomarker for NSCLC susceptibility.
- miR-103a-3p exhibits tumor-suppressive functions in NSCLC and represents a potential therapeutic target for NSCLC treatment, particularly in EGFR wild-type cases.