p63 and p73 Isoform Expression in Non-small Cell Lung Cancer and Corresponding Morphological Normal Lung Tissue
p63 and p73 Isoform Expression in Non-small Cell Lung Cancer and Corresponding Morphological Normal Lung Tissue
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DOI：
10.1097/jto.0b013e31820b86b0
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发表时间：
2011-03-01
影响因子：
20.4
通讯作者：
Scagliotti, Giorgio V.
中科院分区：
文献类型：
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作者：
Lo Iacono, Marco;Monica, Valentina;Scagliotti, Giorgio V.
背景：TP73和TP63基因是p53肿瘤抑制家族的成员，并以不同的N端异构体表达，具有促凋亡（反活化结构域，TA）和抗凋亡（N端截断，Delta N）功能。与p53不同，p73和p63在肿瘤中的作用存在争议。最近有假设认为，Delta N:TA表达比例的改变，而不是单一亚型的过表达，在包括肺癌在内的许多疾病的发病机制中起作用。方法：对手术切除的非小细胞肺癌（nsclc）的匹配癌及相应的正常组织进行异构体特异性实时聚合酶链反应和免疫组化分析，探讨p63和p73各N端异构体的表达水平及其δ N:TA表达比。结果：在p63和p73中，发现了一个改变Delta N:TA异构体平衡的N端特异性调制。特别是，在NSCLC样本中，Delta Np63亚型显著上调，而TAp63则轻微下调。同样，Delta 2p73和Delta 2/3p73是上调的，而Delta Np73和Delta N'p73亚型是下调的。此外，在肿瘤周围的正常组织中检测到较高的TAp63和Delta N'p73转录本表达与患者预后不良相关，是总体生存的独立预后因素（Delta N'p73: p = 0.049，风险比= 3.091,95%可信区间= 1.005-9.524,TAp63: p = 0.001，风险比= 8.091,95%可信区间= 2.259 -29.05）。结论：我们的研究结果表明p63和p73 δ N:TA表达比例的改变可能与非小细胞肺癌的分子发病机制有关。
Background: The TP73 and TP63 genes are members of the p53 tumor suppressor family and are expressed in different N-terminal isoforms either with proapoptotic (transactivation domain, TA) and antiapoptotic (N-terminally truncated, Delta N) function. Unlike p53, the role of p73 and p63 in tumor is controversial. It has been recently hypothesized that altered Delta N:TA expression ratio, rather than single isoform overexpression, plays a role in the pathogenesis of many diseases, including lung cancer.Methods: Isoform-specific, real-time polymerase chain reaction and immunohistochemistry analysis on matched cancer and corresponding normal tissues from surgically resected non-small cell lung cancers (NSCLCs) have been performed aiming to explore the expression levels of each p63 and p73 N-terminal isoforms and their Delta N:TA expression ratio.Results: For both p63 and p73, a N-terminal isoform-specific modulation that alter Delta N:TA isoform balance was identified. In particular, Delta Np63 isoform was significantly up-modulated, whereas TAp63 was slightly down-modulated in NSCLC specimens. Likewise, Delta 2p73 and Delta 2/3p73 were up-modulated, whereas Delta Np73 and Delta N'p73 isoforms were down-modulated. Moreover, a higher TAp63 and Delta N'p73 transcripts expression, detected in the normal tissue surrounding the tumors, correlates with poor patient outcome, representing independent prognostic factors for overall survival (Delta N'p73: p = 0.049, hazard ratio = 3.091, 95% confidence interval = 1.005-9.524 and TAp63: p = 0.001, hazard ratio = 8.091, 95% confidence interval = 2.254-29.05).Conclusion: Our findings suggest that p63 and p73 altered Delta N:TA expression ratio occurs in NSCLC likely contributing to the molecular pathogenesis of this tumor.