CD24 is an effector of HIF-1 driven primary tumor growth and metastasis
Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel la protéine membranaire CD24 et le facteur de transcription HIF-1α régulent le processus métastatique
Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor 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 (HRE) 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. shRNA 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 while 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 co-expression to decreased patient survival. Our results establish a mechanistic linkage between two critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biological effector, strengthening the rationale to target CD24 for cancer therapy.
Cancer Research 2012