Abstract
Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play vital roles in human diseases. We aimed to identify the effect of the lncRNA AGAP2 antisense RNA 1 (AGAP2-AS1)/miR-296/notch homolog protein 2 (NOTCH2) axis on the progression and radioresistance of lung cancer. Expression of AGAP2-AS1, miR-296, and NOTCH2 in lung cancer cells and tissues from radiosensitive and radioresistant patients was determined, and the predictive role of AGAP2-AS1 in the prognosis of patients was identified. THP-1 cells were induced and exosomes were extracted, and the lung cancer cells were respectively treated with silenced AGAP2-AS1, exosomes, and exosomes upregulating AGAP2-AS1 or downregulating miR-296. The cells were radiated under different doses, and the biological processes of cells were assessed. Moreover, the natural killing cell-mediated cytotoxicity on lung cancer cells was determined. The relationships between AGAP2-AS1 and miR-296, and between miR-296 and NOTCH2 were verified. AGAP2-AS1 and NOTCH2 increased while miR-296 decreased in radioresistant patients and lung cancer cells. The malignant behaviors of radioresistant cells were promoted compared with the parent cells. Inhibited AGAP2-AS1, macrophage-derived exosomes, and exosomes overexpressing AGAP2-AS1 or inhibiting miR-296 facilitated the malignant phenotypes of radioresistant lung cancer cells. Furthermore, AGAP2-AS1 negatively regulated miR-296, and NOTCH2 was targeted by miR-296. M2 macrophage-derived exosomal AGAP2-AS1 enhances radiotherapy immunity in lung cancer by reducing miR-296 and elevating NOTCH2. This study may be helpful for the investigation of radiotherapy of lung cancer.
Highlights
Lung cancer is a major cause of cancer death throughout the world[1]
Due to the side effects of radiotherapy in lung cancer patients, it is urgent to explore factors related to tumor radiation resistance, thereby developing radiosensitizers that increase the efficacy of radiotherapy and suppress the required radiation dose through targeting these factors[21]
We conducted this research to identify the roles of M2 macrophage-derived exosomal AGAP2-AS1 in the development of lung cancer, and we found that exosomal AGAP2-AS1 promoted radiotherapy immunity of lung cancer patients after radiotherapy by downregulating miR-296 and overexpressing notch homolog protein 2 (NOTCH2)
Summary
Lung cancer is a major cause of cancer death throughout the world[1]. There are over 1.8 million newly diagnosed lung cancer cases each year and the mortality rate is more than 90%2. Lung cancer is traditionally classified into two major histological types, small cell lung cancer (SCLC) (15–25%) and non-SCLC (NSCLC) (75–85%)[3]. As to 70% of lung cancer patients diagnosed at advanced stages, the 5-year survival rate is roughly 16%. Only 15% of lung cancers were diagnosed at early stages[5]. Radiotherapy exerts a critical effect on SCLC and NSCLC, together with surgery and chemotherapy[6]. It is important to investigate the molecular mechanism of radiotherapy in lung cancer
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