Abstract
Human non-small cell lung cancer (NSCLC)is a very common disease with limited treatment options. Hypoxia is a characteristic feature of solid tumors associated with the resistance of cancer cells to radiotherapy and chemotherapy. Therefore, the expression changes in cancer-resistance genes may be biomarkers of hypoxia with value in targeted therapy. The aim of the present study was to examine the effect of hypoxia on gene expression and the changes that occur in relation to drug resistance in a human NSCLC cell line (A549). A549 cells were exposed to 72-h hypoxic episodes (<1% oxygen) for a total of 10 episodes (acute). The alterations in gene expression were examined using PCR array technology after 10 episodes of acute hypoxia and compared with normoxic cells. The chemoresistance of hypoxic cells toward doxorubicin was measured using a MTT cell proliferation assay. A549 cells were affected by acute hypoxia leading to induced doxorubicin chemoresistance. Evident changes in the gene expression level were identified following episodes of acute hypoxia. The most important changes occurred in the estrogen receptor 1 (ESR1) and Finkel-Biskis-Jinkins osteosarcoma (FOS) pathways and in different nucleic transcription factors such as aryl hydrocarbon receptor and cyclin-dependent kinase inhibitor. The present study showed that exposing cells to prolonged periods of hypoxia results in different gene expression changes. There was induction of chemo-resistance due to acute hypoxia. ESR1 and c-FOS are proposed as a potential hypoxia genes in lung cancer.