Loss of expression of TIMP3 in clear cell renal cell carcinoma. - Archive ouverte HAL Access content directly
Journal Articles European Journal of Cancer Year : 2010

Loss of expression of TIMP3 in clear cell renal cell carcinoma.

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Abstract

AIMS: In clear cell renal cell carcinoma (CCRCC), vascular endothelial growth factor (VEGF) represents the central positive mediator of tumour angiogenesis while VEGF receptor (VEGFR) is the primary target of anti-angiogenic therapies. TIMP3 is a physiological VEGFR-2 antagonist and thus could be considered as an anti-angiogenic factor. We therefore determined the status of this physiological inhibitor in CCRCC. PATIENTS AND METHODS: Archival tumour from 105 patients was studied. TIMP3 expression was analysed using immuno-histochemistry and real-time RT-PCR. Results were correlated with clinicopathological variables. To analyse the mechanisms of gene silencing involved, we performed Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA (MS-MLPA). At last, we evaluated the main upstream pathway described implicating TGFbetaRII, which induces TIMP3 expression. RESULTS: A down-expression of TIMP3, determined by immunohistochemistry, affected 100/105 renal cancers (95.2%). TIMP3 mRNA levels were significantly lower in high-grade tumours. Loss of heterozygosity of the TIMP3 gene was observed in 8 tumours (7.6%) and the 5'CpG island of the TIMP3 promoter was found to be methylated in 25 tumours (23.8%). A down-expression of TGFbetaRII was found in 85/105 CCRCCs (80.9%). A significant correlation was found between TIMP3 expression and TGFbetaRII expression. CONCLUSIONS: This is the first demonstration that the loss of TIMP3 expression is observed in almost all CCRCCs. This loss of expression is a common molecular event in CCRCC. It may be an important initiation step for tumour development in a complex process implicating loss of heterozygosity on chromosome 22q, promoter hyper-methylation and inactivation of the TGFbetaRII pathway.
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Dates and versions

inserm-00462176 , version 1 (08-03-2010)

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Cite

Damien Masson, Nathalie Rioux-Leclercq, Patricia Fergelot, Florence Jouan, Stéphanie Mottier, et al.. Loss of expression of TIMP3 in clear cell renal cell carcinoma.. European Journal of Cancer, 2010, 46 (8), pp.1430-7. ⟨10.1016/j.ejca.2010.01.009⟩. ⟨inserm-00462176⟩
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