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LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma

Oncogene volume 30, pages 1753–1763 (2011)Cite this article

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Abstract

Human clear cell renal cell carcinoma (CCC) remains resistant to therapies. The transcription factor LIM-class homeobox gene Lim1 is required for normal organogenesis, including nephrogenesis, by regulating cell movements, differentiation and growth. Its expression is controlled partly by the sonic hedgehog-Gli signaling pathway, which we have recently shown to be reactivated in human CCC. So far, no study has assessed whether Lim1 may be associated with tumorigenesis. Using a panel of human CCC cell lines expressing or not the von Hippel-Lindau tumor suppressor gene and 44 tumor/normal tissues pairs, we found that Lim1 is constitutively and exclusively reexpressed in tumors. Through Lim1 silencing or overexpressing, we show that Lim1 is a growth and survival factor in human CCC, at least through the activation of oncogenic pathways including the phosphoinositide kinase-3/Akt and nuclear factor-kappaB pathways. More importantly, in nude mice bearing human CCC tumors, Lim1 silencing abolished tumor growth through the same mechanism as in vitro. In Lim1-depleted cells and tumors, cell movements were substantially impaired because of the inhibition of expression of various proteins involved in metastatic spread, such as paxillin or tenascin-C. These findings establish that the developmental marker Lim1 acts as an oncogene in cancer cells and targeting Lim1 may constitute an innovative therapeutic intervention in human CCC.

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Abbreviations

CCC:

clear cell renal cell carcinoma

Lhx1:

LIM-class homeobox gene 1

SHH:

sonic hedgehog

VHL:

von Hippel-Lindau

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Acknowledgements

This study was sponsored by INSERM (Institut National de la Santé Et de la Recherche Médicale), by University of Strasbourg and by the French Ligue Contre le Cancer (Comités du Bas-Rhin et du Haut-Rhin et Comité National, recipient TM). We thank Dr A Donai for helpful suggestions, Dr J Barths for allowing us to perform FACS analysis and RA Hanna for text correction.

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Authors and Affiliations

  1. INSERM U682, Section of Kidney Cancer and Renal Physiopathology, University of Strasbourg, School of Medicine, Strasbourg, France

    V Dormoy, C Béraud, L Thomas, C Coquard, M Barthelmebs & T Massfelder

  2. Department of Pathology, Hôpital de Mulhouse, Mulhouse, France

    V Lindner

  3. Department of Urology, Nouvel Hôpital Civil de Strasbourg, Strasbourg, France

    D Jacqmin & H Lang

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  1. V Dormoy
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  2. C Béraud
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  3. V Lindner
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  4. L Thomas
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  6. M Barthelmebs
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  7. D Jacqmin
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  8. H Lang
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Correspondence to T Massfelder.

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Dormoy, V., Béraud, C., Lindner, V. et al. LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma. Oncogene 30, 1753–1763 (2011). https://doi.org/10.1038/onc.2010.557

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