[HTML][HTML] HIF2α is involved in the expansion of CXCR4-positive cancer stem-like cells in renal cell carcinoma

C Micucci, G Matacchione, D Valli, S Orciari… - British journal of …, 2015 - nature.com
C Micucci, G Matacchione, D Valli, S Orciari, A Catalano
British journal of cancer, 2015nature.com
Background: Hypoxia and the subsequent activation of hypoxia-inducible factor-2α (HIF2α)
contribute to the progression of a variety of cancers. However, their role in the generation of
renal cell carcinoma-derived stem cells has not been fully addressed. Methods: A sphere
formation assay, cell proliferation, RT–PCR, western blot, FACS, immunohistochemistry and
tumour xenograft were used to study the role of HIF2α. Results: Propagation of four renal cell
carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, 769-P) in anchorage-independent …
Abstract
Background:
Hypoxia and the subsequent activation of hypoxia-inducible factor-2α (HIF2α) contribute to the progression of a variety of cancers. However, their role in the generation of renal cell carcinoma-derived stem cells has not been fully addressed.
Methods:
A sphere formation assay, cell proliferation, RT–PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2α.
Results:
Propagation of four renal cell carcinoma (RCC) cell lines (Caki-1, Caki-2, 786-O, 769-P) in anchorage-independent floating spheres led to the expansion of cells bearing the CXCR4 (CD184) surface marker. Inhibition of the CXCR4 pathway reduced sphere expansion. The enhanced self-renewal activity of the CXCR4-positive spheres was preceded by the upregulation of HIF2α. Knockdown of HIF2α abrogated CXCR4 expression and sphere formation. Finally, RCC-derived spheres showed an undifferentiated phenotype in vivo and formed subcutaneous tumours that highly expressed HIF2α and CXCR4. Inhibition of HIF2α abolished tumour growth in animal models.
Conclusions:
These results suggest that the generation of RCC-derived CSCs involves the activation of HIF2α and may provide a foundation for the development of new strategies to prevent the induction of CSCs in RCC.
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