Pallier Karine, Cazes Aurélie, El Khattabi Laila, Lecchi Cristina, Desroches Marine, Danel Claire, Riquet Marc, Fabre-Guillevin Elizabeth, Laurent-Puig Pierre, Blons Hélène
UMR-S775, INSERM, 45 Rue des Saints Pères, Paris 75006, France.
Tumour Biol. 2012 Feb;33(1):41-51. doi: 10.1007/s13277-011-0239-5. Epub 2011 Oct 11.
Genes, active during normal development, are frequently reactivated during neoplastic transformation and may be related to progression. One of them, the transcription factor TP63, is crucial for pulmonary epithelial development and a possible target of the recurrent 3q amplifications in lung squamous cell carcinoma (SCC). Here, we explored whether TP63 reactivation could be associated to cancer progression in lung SCC through an epithelial to mesenchymal transition. We studied TP63 amplification and TP63 expression at RNA and protein levels and we analyzed the ΔNTP63/TATP63 ratio that quantifies the proportion of the isoform lacking the transactivation domain/the isoform containing the transactivation domain. We correlated TP63 status to survival and to the expression of epithelial (E-cadherin and plakoglobin) and mesenchymal (N-cadherin, vimentin, TWIST1, and SNAIL) markers. We found that high ΔN/TA TP63 ratio was related to high E-cadherin and plakoglobin mRNA levels (P < 0.05) and that E-cadherin mRNA level was the only marker related to survival. Kaplan-Meier survival curves stratified according to the expression level of E-cadherin showed, as already reported in breast cancer, that patients with low (first quartile) or high (last quartile) E-cadherin expression had a worse survival with respect to patients with intermediate E-cadherin expression. Altogether, our results indicate that a reactivation of ΔNTP63 is linked to the maintenance of epithelial markers and suggest that E-cadherin has a dual role in lung SCC.
在正常发育过程中活跃的基因，在肿瘤转化过程中经常会重新激活，并且可能与肿瘤进展相关。其中之一，转录因子TP63，对肺上皮发育至关重要，并且可能是肺鳞状细胞癌（SCC）中常见的3q扩增的一个靶点。在此，我们探究了TP63的重新激活是否可能通过上皮-间质转化与肺SCC的癌症进展相关。我们研究了TP63在RNA和蛋白质水平的扩增及表达情况，并分析了ΔNTP63/TATP63比值，该比值用于量化缺乏反式激活结构域的异构体/含有反式激活结构域的异构体的比例。我们将TP63状态与生存率以及上皮标志物（E-钙黏蛋白和桥粒斑蛋白）和间质标志物（N-钙黏蛋白、波形蛋白、TWIST1和SNAIL）的表达进行关联分析。我们发现高ΔN/TA TP63比值与高E-钙黏蛋白和桥粒斑蛋白mRNA水平相关（P < 0.05），并且E-钙黏蛋白mRNA水平是唯一与生存率相关的标志物。根据E-钙黏蛋白表达水平分层的Kaplan-Meier生存曲线显示，正如乳腺癌中已报道的那样，E-钙黏蛋白表达低（第一四分位数）或高（最后四分位数）的患者相对于E-钙黏蛋白表达中等的患者生存率更差。总之，我们的结果表明ΔNTP63的重新激活与上皮标志物的维持相关，并提示E-钙黏蛋白在肺SCC中具有双重作用。
