LIM-class homeobox gene Lim1, a novel oncogene in human renal cell carcinoma.
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.
INSERM U682, Section of Kidney Cancer and Renal Physiopathology, University of Strasbourg, School of Medicine, Strasbourg, France.
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Dormoy
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Béraud
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Lindner
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Thomas
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Coquard
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Barthelmebs
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Jacqmin
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Lang
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Massfelder
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors
D018398:Homeodomain Proteins; C085473:LHX1 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors