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[Cancer Research 61, 2154-2161, March 1, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

HuR, a RNA Stability Factor, Is Expressed in Malignant Brain Tumors and Binds to Adenine- and Uridine-rich Elements within the 3' Untranslated Regions of Cytokine and Angiogenic Factor mRNAs1

L. Burt Nabors, G. Yancey Gillespie, Lualhati Harkins and Peter H. King2

Departments of Neurology [L. B. N., P. H. K.], Neurosurgery [G. Y. G.], and Physiology and Biophysics [P. H. K.], University of Alabama at Birmingham, Birmingham, Alabama 35233-7340, and Birmingham Veterans Affairs Medical Center [L. B. N., L. H., P. H. K.], Birmingham, Alabama

Tumors of the central nervous system (CNS) often have sustained expression of labile genes, including angiogenic growth factors and immunosuppressive cytokines, which promote tumor progression. Stabilization of the RNA transcripts for these genes, such as vascular endothelial growth factor (VEGF), is an important molecular pathway for this up-regulation. HuR, a member of the Elav family of RNA-binding proteins, has been implicated in this pathway through its binding to adenine and uridine (AU)-rich stability elements (ARE) located in the 3' untranslated regions (3'-UTRs) of the mRNA. Whereas three of the Elav family members (Hel-N1, HuC, and HuD) are restricted to young and mature neurons, HuR is more broadly expressed, including proliferating cells of the developing CNS. Because RNA stabilization of labile genes may promote tumor growth, we analyzed and compared the expression pattern of HuR in 35 freshly resected and cultured CNS tumors to determine whether there was any correlation with tumor grade or histological type. We found that HuR mRNA was consistently expressed in all of the tumors, regardless of cell origin or degree of malignancy. Using a novel HuR-specific polyclonal antibody, we found that strong HuR protein expression was limited to high-grade malignancies (glioblastoma multiforme and medulloblastoma). Within the glioblastoma multiforme, prominent HuR expression was also detected in perinecrotic areas in which angiogenic growth factors are up-regulated. To further define its role as a potential RNA stabilizer, we analyzed whether HuR could bind to the stability motifs within the 3'-UTRs of cytokines and growth factors linked to brain tumor progression. We used a novel ELISA-based RNA binding assay and focused on the 3'-UTRs of angiogenic factors VEGF, COX-2, and (interleukin) IL-8 as well as the immunomodulating factors IL-6, transforming growth factor (TGF)-ß and tumor necrosis factor (TNF)-{alpha} as potential RNA ligands. Our results indicated overall a very high binding affinity to these RNA targets. A comparison of these ligands revealed a hierarchy of binding affinities with the angiogenic factors, and TGF-ß showing the highest (Kd of 1.8–3.4 nM), and TNF-{alpha} the lowest (Kd of 18.3 nM). The expression pattern of HuR, coupled with the RNA binding data, strongly suggests a role for this protein in the posttranscriptional regulation of these genes in CNS tumors.




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