Intermittent induction of HIF-1? produces lasting effects on malignant progression independent of its continued expression.

ABSTRACT: Dysregulation of hypoxia-inducible transcription factors HIF-1? and HIF-2? 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-1? 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-1? variant, HIF1?(PP), in various cancer cell lines and examined the effects on malignant progression in xenografts of immunocompromised mice in comparison to those of HIF2?(PP). Although 8-week treatment led to eventual loss of HIF1?(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-1? on malignant progression are specific because neither HIF2?(PP) nor ?-galactosidase yielded similar effects. By contrast, transient expression of HIF1?(PP) in U-87 MG cells or constitutive expression of HIF1?(PP) but not HIF2?(PP) in a patient-derived glioma sphere culture inhibited tumor growth and spread. Our results indicate that intermittent induction of HIF-1? produces lasting effects on malignant progression even at its own expense.

SUBMITTER: Choi H 

PROVIDER: S-EPMC4404255 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature