Cited by 128Cancer, Hypoxia, and MetabolismCancer Cells and MetastasisMechanisms of cancer metastasis

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CD24 Is an Effector of HIF-1–Driven Primary Tumor Growth and Metastasis

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Thomas, Shibu, Harding, Michael A., Smith, Steven C., Overdevest, Jonathan B., Nitz, Matthew D., Frierson, Henry F., Tomlins, Scott A., Kristiansen, Glen, Theodorescu, Dan·2012·Cancer Research

DOI 10.1158/0008-5472.can-11-3666PMC PMC3488144

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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. Cancer Res; 72(21); 5600–12. ©2012 AACR.

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Authors: Thomas, S., Harding, M. A., Smith, S. C., Overdevest, J. B., Nitz, M. D., Frierson, H. F., Tomlins, S. A., Kristiansen, G., & Theodorescu, D.
Affiliations: University of Bonn (DE)
ORCID: Thomas, Shibu
Harding, Michael A.
Smith, Steven C.
Overdevest, Jonathan B.
Tomlins, Scott A.
Kristiansen, Glen
Theodorescu, Dan
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2012-10-31
Volume: 72
Issue: 21
Pages: 5600-5612
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-11-3666
PMC: PMC3488144
OpenAlex: W2114076439
Cited by: 128
References: 56
Citations by year: 2026: 3 · 2025: 3 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 19 · 2019: 7 · 2018: 7 · 2017: 11 · 2016: 11 · 2015: 12 · 2014: 9 · 2013: 6 · 2012: 4
FWCI: 3.28
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: University of Virginia
National Institutes of Health
National Cancer Institute (CA 075115, P01CA104106, R01CA075115, CA 104106, R29CA075115, P30CA044579)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords: CD24, HIF-1α, hypoxia, tumor growth, metastasis, hypoxia response element, transcriptional regulation, cancer stem cells, tumor cell survival, patient survival
MeSH terms: Animals, Humans, Immunohistochemistry, Mice, Nude, Neoplasm Invasiveness, Neoplasms, Promoter Regions, Genetic, RNA, Messenger, Transplantation, Heterologous, Blotting, Western, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Disease Progression, Cell Line, Tumor, Chromatin Immunoprecipitation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, CD24 Antigen, Real-Time Polymerase Chain Reaction

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CD24 Is an Effector of HIF-1–Driven Primary Tumor Growth and Metastasis

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