title: CD24 is an effector of HIF-1-driven primary tumor growth and metastasis.
abstract: Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor hypoxia inducible factor-1α (HIF-1α) in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here, we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. Short hairpin RNA-mediated attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease, whereas HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their coexpression to decreased patient survival. Our results establish a mechanistic linkage between 2 critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biologic effector, strengthening the rationale to target CD24 for cancer therapy.
authors.affiliation: Departments of Urology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Shibu
authors.initials: S
authors.lastname: Thomas
authors.forename: Michael A
authors.initials: MA
authors.lastname: Harding
authors.forename: Steven C
authors.initials: SC
authors.lastname: Smith
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Overdevest
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Nitz
authors.forename: Henry F
authors.initials: HF
authors.lastname: Frierson
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D051927:CD24 Antigen / Q000096:biosynthesis / Q000235:genetics*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger