Rnai Inhibition Of Hif-1¦Á Expression In Mcf-7 Cells Mtx Drug Sensitivity And In Nude Mice Into Nude Mice And Preliminary Study On The Impact Of Hadas Cells To The Endothelial Cell Differentiation

The hypoxia-inducible factor (HIF) la is a key regulator of the cellular response to oxygen deprivation. HIF-la is found to be constitutively upregulated and associated with poor prognosis in several tumor types. Specific disruption of the HIF-1 pathway is important for exploring its role in tumor biology and developing more efficient weapons to treat cancer.Previous studies regarding the effects of HIF-1α blockade in tumor growth failed to reach consistent results, possibly because of multiple functions of HIF-la depending on different genetic contexts, tumor types and experimental approaches. In this study, we stably transfected human breast tumor MCF-7 cells with short hairpin RNA expression vectors targeting HIF-la. After knockdown of HIF-la, hypoxia-induced expression of its target genes such as vascular endothelial growth factor (VEGF), Glut-1, phosphoglycerate kinase (PGK), and P-glycoprotein (P-gp) were markedly attenuated. Moreover, HIF-la knockdown was found to suppress the shift from S-phase to G1 induced by hypoxia and increase drug sensitivity to methotrexate (MTX). The growth rates of HIF la-knockdown tumors were drastically retarded in both subcutaneous and orthotopic xenograft models, which were accompanied by decreased angiogenesis and reduced expression of glucose transporter in tissue sections.Our results provide further evidence that HIF-1α might be an effective molecular target for breast cancer therapy. A combination of anti-HIF-1 strategy and traditional chemotherapy may be expected to render more favorable outcomes. These data also suggest that a vector-based RNA interference approach can serve as a useful tool for exploring potential therapeutic target for human tumors.