Role of the RNA-binding protein HuR in human renal cell carcinoma.
Human conventional renal cell carcinoma (CRCC) remains resistant to therapy. The RNA-binding protein HuR regulates the stability and/or translation of multiple messenger RNAs involved in malignant transformation. In this study, we aimed to evaluate the potential role of HuR in this pathology. Using seven human CRCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as well as 15 normal/renal cell carcinoma tumor pairs, we showed that HuR is overexpressed in all tumors independently of the VHL status. Futhermore, HuR cytoplasmic presence appears to be more common in early tumor stages, suggesting a role in tumor promotion. We then assessed the effect of HuR knockdown using small interfering RNA in cultured cell and in tumor-bearing mice. Both in vitro and in vivo, we observed that cell growth was inhibited by 60% and that this effect was obtained through an inhibition of cell proliferation and an induction of cell apoptosis. Finally, we found that expression of vascular endothelium growth factor, tumor growth factor-beta and of the hypoxia-induced transcription factor-2alpha as well as the constitutive activation of the oncogenic phosphoinositide 3-kinase/Akt, nuclear factor-kappaB and mitogen-activated protein kinase pathways were decreased in HuR-depleted cells and tumors. All these results suggest a pivotal role for HuR in human CRCC.
Danilin
Sabrina
S
Institut National de la Sante et de la Recherche Medicale U682, Section of Renal Cancer and Physiopathology, University de Strasbourg, School of Medicine, Strasbourg, 67085 France.
Sourbier
Carole
C
Thomas
Lionel
L
Lindner
Véronique
V
Rothhut
Sylvie
S
Dormoy
Valérian
V
Helwig
Jean-Jacques
JJ
Jacqmin
Didier
D
Lang
Hervé
H
Massfelder
Thierry
T
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins