Abstract
This study aimed to investigate the expression and function of interferon regulatory factor-1 (IRF-1) in non-small cell lung cancer (NSCLC). IRF-1 expression and its prognostic value were investigated through bioinformatic analysis. The protein expression levels of IRF-1, cleaved caspase 3, and LC3-I/II were analyzed by western blotting. A lentiviral vector was used to overexpress or knockdown IRF-1 in vitro. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were analyzed by JC-1 and DCFH-DA staining, respectively. ATP, SOD, MDA, cell viability, LDH release, and caspase 3 activity were evaluated using commercial kits. Compared to the levels in normal tissues, IRF-1 expression was significantly lower in lung cancer tissues and was a prognostic factor for NSCLC. Cisplatin treatment-induced IRF-1 activation, ROS production, ATP depletion, SOD consumption, and MDA accumulation in A549 lung cancer cells. IRF-1 overexpression promoted mitochondrial depolarization, oxidative stress, and apoptotic cell death and inhibited autophagy in A549 cells, and these effects could be reversed by IRF-1 knockdown. These data suggest that IRF-1 regulates apoptosis, autophagy and oxidative stress, which might be served as a potential target for increasing chemotherapy sensitivity of lung cancer.
Highlights
Lung cancer is a malignant disease with the highest morbidity and mortality worldwide, as it accounts for 18% of cancer-associated deaths [1]
Interferon regulatory factor-1 (IRF-1) expression was downregulated in adrenocortical carcinoma (ACC), kidney chromophobe (KICH), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC) (Fig. 1A, B)
IRF-1 expression was downregulated in LUAD and LUSC samples compared to the expression in normal samples (Fig. 1C)
Summary
Lung cancer is a malignant disease with the highest morbidity and mortality worldwide, as it accounts for 18% of cancer-associated deaths [1]. 80% of lung cancers are non-small cell lung cancer (NSCLC) [2]. Re-sensitizing resistant tumors to cisplatin remains a major challenge in clinical treatment. The main mechanism of cisplatin-induced cell death is apoptosis [7, 8], and inhibitors of apoptosis proteins drive cisplatin resistance [9]. Autophagy is involved in cisplatin resistance [10], and Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that plays key roles in interferon expression, lymphocyte growth and differentiation, innate and acquired immunity, and other immune-related events [14, 15]. IRF-1 mediates apoptosis in ovarian cancer [18] and breast cancer [19] and regulates autophagy in breast cancer cells [20], splenocytes [21] and
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