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PMID: 26439684 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

British journal of cancer ·Vol. 113 ·No. 8 ·2015-10-20 ·Pages 1178-85

Micucci C, Matacchione G, Valli D, Orciari S, Catalano A

Abstract

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. A sphere formation assay, cell proliferation, RT-PCR, western blot, FACS, immunohistochemistry and tumour xenograft were used to study the role of HIF2α. 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. 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.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/genetics Carcinoma, Renal Cell/genetics Cell Line, Tumor Cell Proliferation/genetics Humans Kidney Neoplasms/genetics Mice Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells/metabolism Receptors, CXCR4/genetics Signal Transduction/genetics Up-Regulation/genetics
Chemicals
Basic Helix-Loop-Helix Transcription Factors CXCR4 protein, human Receptors, CXCR4 endothelial PAS domain-containing protein 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Micucci Carla
Department of Clinical and Molecular Sciences, Polytechnic University of Marche, School of Medicine, Via Tronto 10/A, 60100 Ancona, Italy.
Matacchione Giulia
Department of Clinical and Molecular Sciences, Polytechnic University of Marche, School of Medicine, Via Tronto 10/A, 60100 Ancona, Italy.
Valli Debora
Department of Clinical and Molecular Sciences, Polytechnic University of Marche, School of Medicine, Via Tronto 10/A, 60100 Ancona, Italy.
Orciari Silvia
Department of Clinical and Molecular Sciences, Polytechnic University of Marche, School of Medicine, Via Tronto 10/A, 60100 Ancona, Italy.
Catalano Alfonso
Department of Clinical and Molecular Sciences, Polytechnic University of Marche, School of Medicine, Via Tronto 10/A, 60100 Ancona, Italy.
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Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
1532-1827
DOI
10.1038/bjc.2015.338
Published
2015-10-20
Epub
2015-00-06
Pages
1178-85
Language
English
Region
England
NLM ID
0370635
PMCID
PMC4647880
Subset
IM
External Links
PubMed source DOI: 10.1038/bjc.2015.338 PMC Full Text View journal details
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