Carcinogenesis Advance Access originally published online on August 6, 2008
Carcinogenesis 2008 29(11):2053-2061; doi:10.1093/carcin/bgn185
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HuR and the bioenergetic signature of breast cancer: a low tumor expression of the RNA-binding protein predicts a higher risk of disease recurrence
1 Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid
2 CIBER de Enfermedades Raras
3 Servicio de Oncología Médica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, 28049 Madrid, Spain
* To whom correspondence should be addressed. Tel: +34 911 964 618; Fax: +34 911 964 420; Email: jmcuezva{at}cbm.uam.es
Downregulation of the catalytic subunit of the mitochondrial H+-ATP synthase (β-F1-ATPase) is a hallmark of many types of cancer. The expression of β-F1-ATPase is stringently controlled by posttranscriptional mechanisms. Herein, we pursue the identification of β-F1-ATPase messenger RNA-binding proteins (β-mRNABPs) that interact and could define the bioenergetic phenotype of the cancer cell in order to establish its relevance as markers of breast cancer progression. RNA immunoprecipitation and RNA affinity chromatography identify HuR as a β-mRNABP that interacts with the 3'-untranslated region of the transcript. Subcellular fractionation and high-resolution immunoelectron microscopy revealed the cofractionation and presence of HuR in subcellular structures associated to liver mitochondria. Analysis of the expression level of HuR in a cohort of breast carcinomas shows its association with the degree of alteration of the bioenergetic phenotype of the tumor. Moreover, HuR expression is shown to be an independent marker of breast cancer prognosis. A low tumor expression of HuR predicts a higher risk of disease recurrence in early stage breast cancer patients as assessed by clinical and bioenergetic markers of prognosis, strongly supporting the incorporation of HuR as an additional marker for the follow-up of these patients. Mechanistically, overexpression experiments and short hairpin RNA-mediated silencing of HuR in human embryonic kidney and HeLa cells indicate that HuR is not regulating β-F1-ATPase expression. Overall, the participation of additional RNA-binding proteins in controlling β-F1-ATPase expression and therefore in defining the bioenergetic signature of the cancer cell is expected.
Abbreviations: BEC index, bioenergetic cellular index [(beta/Hsp60)/GAPDH]; β-F1-ATPase, β-subunit of the mitochondrial H+-ATP synthase; β-mRNABPs, β-F1-ATPase messenger RNA-binding proteins; β-mRNA, β-F1-ATPase mRNA; β-RNP, β-F1-ATPase ribonucleoprotein; CP, coat protein; DFS, disease-free survival; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; HEK, human embryonic kidney; hRNA, hybrid RNA; IP, immunoprecipitate; MBP, maltose-binding protein; mRNA, messenger RNA; PBS, phosphate-buffered saline; shRNA, short hairpin RNA; 3'UTR, 3'-untranslated region
Received April 24, 2008; revised July 24, 2008; accepted August 3, 2008.
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