Abstract
Dysregulation of hypoxia-inducible transcription factors HIF-1α and HIF-2α correlates with poor prognosis in human cancers; yet, divergent and sometimes opposing activities of these factors in cancer biology have been observed. Adding to this complexity is that HIF-1α apparently possesses tumor-suppressing activities, as indicated by the loss-of-function mutations or even homozygous deletion of HIF1A in certain human cancers. As a step towards understanding this complexity, we employed 8-week intermittent induction of a stable HIF-1α variant, HIF1α(PP), in various cancer cell lines and examined the effects on malignant progression in xenografts of immunocompromised mice in comparison to those of HIF2α(PP). Although 8-week treatment led to eventual loss of HIF1α(PP) expression, treated osteosarcoma U-2 OS cells acquired tumorigenicity in the subcutaneous tissue. Furthermore, the prior treatment resulted in widespread invasion of malignant glioma U-87 MG cells in the mouse brain and sustained growth of U-118 MG glioma cells. The lasting effects of HIF-1α on malignant progression are specific because neither HIF2α(PP) nor β-galactosidase yielded similar effects. By contrast, transient expression of HIF1α(PP) in U-87 MG cells or constitutive expression of HIF1α(PP) but not HIF2α(PP) in a patient-derived glioma sphere culture inhibited tumor growth and spread. Our results indicate that intermittent induction of HIF-1α produces lasting effects on malignant progression even at its own expense.
Highlights
Malignant tumors encounter conditions of low oxygen and nutrient deprivation as they progress
Human cancer cell lines including U-2 OS of osteosarcoma and U-87 MG and U-118 MG of glioblastomas were used for HIF-α expression
Expression after continuous culture, yet retained the acquired malignant traits in the in vivo setting. These results indicate that repeated activation of HIF-1α can program cancer cells to acquire perpetual signaling possibly through feed-forward biochemical/metabolic loops or genetic/epigenetic changes, even though the underlying mechanism requires further investigation
Summary
Malignant tumors encounter conditions of low oxygen and nutrient deprivation as they progress. These adverse conditions, albeit detrimental to tumor growth, are associated with tumor progression and resistance to chemo- and radiotherapies. HIF-1 is a heterodimer consisting of HIF-1α and ARNT (aryl hydrocarbon receptor nuclear translocator) [10], and its activation depends primarily on the oxygen-sensitive HIF-1α subunit [11,12], which is degraded through the ubiquitin—proteasome pathway upon recognition by the von Hippel-Lindau (VHL) protein as part of the E3 ubiquitin ligase [13,14,15,16,17]. Stabilized HIF-1α and HIF-2α undergo nuclear translocation, dimerization with ARNT, and recruitment of the transcription coactivators p300/CBP, resulting in transcriptional activation of a series of genes for angiogenesis, metabolism, and survival
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