Abstract
BackgroundA hypoxic microenvironment leads to an increase in the invasiveness and the metastatic potential of cancer cells within tumors via the epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. However, hypoxia-induced changes in the expression and function of candidate stem cell markers and their possible molecular mechanism is still not understood.MethodsLung cell lines were analyzed in normoxic or hypoxic conditions. For screening among the stem cell markers, a transcriptome analysis using next-generation sequencing was performed. For validation, the EMT and stem cell characteristics were analyzed. To determine whether an epigenetic mechanism was involved, the cell lines were treated with a DNA methyltransferase inhibitor (AZA), and methylation-specific PCR and bisulfite sequencing were performed.ResultsNext-generation sequencing revealed that the CXCR4 expression was significantly higher after the hypoxic condition, which functionally resulted in the EMT and cancer stemness acquisition. The acquisition of the EMT and stemness properties was inhibited by treatment with CXCR4 siRNA. The CXCR4 was activated by either the hypoxic condition or treatment with AZA. The methylation-specific PCR and bisulfite sequencing displayed a decreased CXCR4 promoter methylation in the hypoxic condition.ConclusionsThese results suggest that hypoxia-induced acquisition of cancer stem cell characteristics was associated with CXCR4 activation by its aberrant promoter demethylation.
Highlights
A hypoxic microenvironment leads to an increase in the invasiveness and the metastatic potential of cancer cells within tumors via the epithelial-mesenchymal transition (EMT) and cancer stemness acquisition
Hypoxia is a major feature of solid tumors that can promote the invasion and metastatic potential of tumor cells, which results from epithelial-mesenchymal transition (EMT) and the acquisition of stemness in multiple cancers
Transcriptome analysis of EMT and stem cell markers To examine the effect of hypoxia on the mRNA expression in the BEAS-2B and A549 cells, a transcriptome analysis was performed using next-generation sequencing
Summary
A hypoxic microenvironment leads to an increase in the invasiveness and the metastatic potential of cancer cells within tumors via the epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. Hypoxia is a major feature of solid tumors that can promote the invasion and metastatic potential of tumor cells, which results from epithelial-mesenchymal transition (EMT) and the acquisition of stemness in multiple cancers. Tumor hypoxia may result in aggressive phenotypes and poor response to therapy [4]. Kang et al BMC Cancer (2019) 19:148 with high motility. During this transition, epithelial cells acquire migratory and invasive properties to become cells with stem-like characteristics [5]. Hypoxia-induced EMT may be related to the acquisition of stemness by cancer cells in solid tumors. The EMT and stemness acquisition may be related to drug resistance, which is a factor that is strongly associated with poor prognosis [6]
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