Abstract
The survival rate of lung cancer is low due to the high frequency of drug resistance in patients with mutations in the driver genes. Overexpression of anti-apoptotic genes is one of the most prominent features of tumor drug resistance. EGFR signaling induces the expression of anti-apoptotic genes. Also, microRNAs (miRNAs) have a critical role in regulating biological functions such as apoptosis; a process mostly eluded in cancer progression. The mutation screening was performed on one thousand non-small cell lung carcinoma patients to enroll clinical samples in this study. Bioinformatics analysis predicted that miRNAs (miR-29a, miR-143) might regulate MCL-1 and cIAP-2 expression. We investigated the expression of MCL-1, cIAP-2, miR-29a, and miR-143 encoding genes in adenocarcinoma patients with or without EGFR mutations before treatment. The potential role of miR-29a and miR-143 on gene expression was evaluated by overexpression and luciferase assays in HEK-293T cells. EGFR mutations were found in 262 patients (26.2%) with a greater incidence in females (36.23% vs. 20.37%, P = 0.001). The expression levels of MCL-1 and cIAP-2 genes in patients with mutated EGFR were higher than those of wild-type EGFR. In contrast, compared to those of patients with wild-type EGFR, the expression levels of miR-29a and miR-143 were lower in the patients carrying EGFR mutations. In cell culture, overexpression of miR-29a and miR-143 significantly downregulated the expression of MCL-1 and cIAP-2. Dual-luciferase reporter experiments confirmed that miR-29a and miR-143 target MCL-1 and cIAP-2 mRNAs, respectively. Our results suggest that upregulation of EGFR signaling in lung cancer cells may increase anti-apoptotic MCL-1 and cIAP-2 gene expression, possibly through downregulation of miR-29a-3p and miR-143-3p.
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Excellent technical support was provided by Alpha gen lab. We are very grateful for the help and assistance of Majid Pirestani, Fatemeh Saadatpour, Goli Goujani, Alireza Kourorian, Parva Karimi, Zahra Mosaferi, Parto Karimi, and Nastaran Kavossi-Nasab.
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Z.A.T. and E.A. performed all experiments, prepared the figures, and drafted the manuscript. Z.A.T., E.A., and N.R. participated in data analyses and interpretation results. Z.A.T. and S.M.A.N. designed the study. All authors have read and approved the final manuscript.
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Abrehdari-Tafreshi, Z., Arefian, E., Rakhshani, N. et al. The Role of miR-29a and miR-143 on the Anti-apoptotic MCL-1/cIAP-2 Genes Expression in EGFR Mutated Non-small Cell Lung Carcinoma Patients. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10740-6
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DOI: https://doi.org/10.1007/s10528-024-10740-6