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  • b Department of Medical Oncology Second Clinical Medicine

    2022-05-23

    b Department of Medical Oncology, Second Clinical Medicine College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China c Department of Gastroenterology, South Building, Chinese PLA General Hospital, Beijing 100853, China
    Keywords:
    Aspirin
    Lung cancer
    Hypoxia
    Stemness
    Exosomes 
    Background: Epidemiological studies have illustrated that regular aspirin consumption may decrease the risk of non-small cell lung cancer (NSCLC). The present study aims to investigate the mechanism of aspirin-induced inhibition of NSCLC development during hypoxia. Methods: A549 cells were pre-treated with the vehicle control or aspirin and then subjected to hypoxic culture. Cell viability was monitored by CCK-8 assay, and flow cytometry was performed to detect Testosterone distribu-tions, apoptosis, and proportion of cancer stem cells (CSCs). Flow cytometric cell sorting was used to separate CSCs. Quantitative reverse transcription–polymerase chain reaction and Western blot were used to detect the mRNA and protein levels of stem cell markers and the related signaling molecules. The abundance of pros-taglandin E2 was detected by enzyme-linked immunosorbent assay. Exosomes in the cell culture medium were isolated using ExoQuick, and the number of exosomes was quantified by the EXOCET exosome quantification assay kit. Cell migration and angiogenesis were monitored by transwell migration assay and in vitro angiogenesis experiments.
    Results: Aspirin inhibited cell proliferation and induced G2/M cell cycle arrest in hypoxic A549 cells; it also inhibited hypoxia-enhanced stemness in both A549 and ALDH+ cells. The drug reduced hypoxia-enhanced numbers of exosomes in A549 cells and exerted negative effects on the hypoxia-mediated up-regulation of exosomal HIF-1α/COX-2 and expression of exosomal miR-135b and miR-210. While hypoxic-induced exosomes can promote the proliferation, migration, and angiogenesis of other A549 cells, aspirin can weaken this pro-motion by reducing the amount of exosome secreted and changing exosome contents. Conclusions: Aspirin inhibits the hypoxia-induced stemness, hypoxic-mediated exosome release, and malignant paracrine effects of A549 cells.
    1. Introduction
    Lung cancer is a very common cancer and the leading cause of cancer-related deaths worldwide [1,2]. Despite recent advances in clinical practice, including target therapies, however, the 5-year sur-vival rate of lung cancer remains at approximately 16%. One of the main reasons behind the poor prognosis of this cancer type is its re-sistance to various treatments [2]. A subpopulation of cancer cells with treatment-resistant potential is characterized by the abilities of self-renewal, differentiation, and metastasis, and cells of this subpopulation are called cancer stem cells (CSCs) [3]. Developing specific therapies targeting CSCs is important to improve the clinical outcomes of lung cancer.
    The tumor microenvironment (TME) of a solid tumor is composed of
    Corresponding author.
    cancer cells, stromal cells, blood vessels, and immune cells [4]; it has been implicated in the regulation of cell proliferation, invasion, and metastasis and contributes to the outcome of cancer therapy. Solid tu-mors feature hypoxic microenvironments due to their rapid expansion and irregular blood flow. Accumulating evidence suggests that hypoxia is associated with the invasive and metastatic potential of cancer cells, as well as their resistance to radio- and chemotherapies, all of which lead to poor clinical outcomes [4,5]. Hypoxia up-regulates the expres-sion of hypoxia-inducible factor-1α (HIF-1α), which, in turn, regulates various biological signals, including stem cell markers (e.g., SOX2 and OCT4) [6]. Hypoxia has consistently been reported to promote cancer cell stemness and drug resistance in lung cancer [7]. HIF-1α also up-regulates cyclooxygenase-2 (COX-2) during hypoxia, thereby leading to the increased abundance of its enzymatic product prostaglandin E2