Effect of chronic intermittent hypoxia on biological behavior and hypoxia‐associated gene expression in lung cancer cells

Abstract

Hypoxia plays an important role in the development of solid tumors and is associated with their therapeutic resistance. There exist three major forms of hypoxia: acute, chronic, and intermittent hypoxia. Previous studies have shown that cancer cells could behave in the form of adaptation to hypoxia in tumor growth, which could result in their biological changes and determine their responses to the therapies. To investigate the tumor cells' adaptation to hypoxia, we recreated two models using two lung cancer cell lines in the presence of intermittent hypoxia, which is characterized by changes in oxygen pressure within the disorganized vascular network. We investigated biological behaviors such as cell cycle, proliferation, radiation sensitivity, apoptosis and migration, hypoxia signal pathway in the lung cancer cells treated with chronic intermittent hypoxia, as well as the role of hypoxia inducible factor 1 there, hypoxia-inducible genes analyzed by real-time RT-PCR chip in H446 cells treated with the model. The results indicated the changes of some hypoxia target gene expressions of those induced by hypoxia, some of which were confirmed by real-time RT-PCR. The cells mediated by irradiation induced resistance to radiation and apoptosis and increased metastasis in lung cancer cells. It was found that such changes were related to hypoxia inducible factor 1, alpha subunit (HIF-1α).

Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia

“…While previous findings have shown that IH promotes cancer cell proliferation, as demonstrated by cell growth assays and cell cycle analysis [26], we did not observe any significant difference in biological behavior such as cell cycle progression or proliferation of melanoma cells that were maintained under normoxia or pre-IH-conditioned. These discrepancies might be due to , and GLUT1 mRNA-expression levels in tumors from mice in the N, IH-1, and IH-2 groups.…”

The Interaction Between Redox and Hypoxic Signalling Pathways in the Dynamic Oxygen Environment of Cancer Cells

“…Liu and colleagues demonstrated that intermittent hypoxia treated H446 lung cancer cells had a greater metastatic ability and radio-resistance. They found HIF-1α was involved in both processes [84]. Intermittent hypoxia exposed endothelial cells also showed enhanced migration and exhibited an increased resistance against irradiation as compared to their counterparts grown in normoxia or acute hypoxia.…”

“…In a separate study, intermittent hypoxia treated A549 and H446 lung cancer cells exhibited increased invasion in comparison to normoxic cells. Down-regulation of the HIF-1α gene decreased the cellular migration in these cells, thereby linking HIF-1 to cancer cell invasion under intermittent hypoxia [84]. Moreover, both thioredoxin and HIF-1 have been linked to the development of resistance against anticancer therapeutics [82,96,97].…”

Obstructive sleep apnea and the prevalence and incidence of cancer

“…32 In our subgroup analyses, similar to the study by Campos-Rodriguez and colleagues, 3 we found that oxygen desaturation, but not the apneahypopnea index, was significantly associated with smoking-related cancers. Hypoxia has been shown to cause upregulation and over expression of a number of genes related to biological behaviours of cancer cells, including apoptosis, metastasis and angiogenesis, 33 which renders the cancer cells more aggressive and resistant to therapy. 34 Indeed, chronic intermittent hypoxia has been shown to accelerate cancer progression in a mouse model of sleep apnea.…”