Maspin expression is transactivated by p63 and is critical for the modulation of lung cancer progression
Maspin expression is transactivated by p63 and is critical for the modulation of lung cancer progression
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DOI：
10.1158/0008-5472.can-04-1657
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发表时间：
2004-10-01
期刊：
影响因子：
11.2
通讯作者：
Park, C
中科院分区：
文献类型：
--
作者：
Kim, S;Han, JH;Park, C
Maspin可抑制某些癌细胞的转移，临床研究已证实在几种癌症类型中，Maspin的缺失与预后不良之间存在相关性。与匹配的正常肺组织相比，Maspin在肺癌组织中显著过表达。然而，maspin表达的调控机制仍不清楚。我们在这里表明，maspin在肿瘤来源的肺癌细胞中的差异表达是在转录水平上调节的。我们发现p63是maspin转录的关键因子，maspin在高侵袭性癌细胞如NCI-H157、NCI-322和NCI-358中缺失。未发现maspin表达与先前相关的转录因子P53、Ets1和Pdef之间的相关性。相反，maspin的表达严格依赖于肺癌组织(P<；0.001)和被测细胞系中p63的存在。反式激活的p63瞬时表达。Maspin启动子在表达TAp63的细胞中有明显的折叠变化，提示TAp63可能是肺癌中maspin启动子的一种新的刺激子。我们还通过凝胶漂移和染色质免疫沉淀实验证明了p63蛋白与先前发现的maspin启动子上的P53结合部位的结合。在肿瘤组织中，除鳞癌外，maspin的表达与淋巴结转移(P=0.035)和肿瘤分期(P=0.063)有关。在功能方面，maspin的异位表达抑制了鳞癌和腺癌的细胞侵袭。综上所述，这些结果将maspin定义为p63的一个新的分子靶点，最终抑制肺癌的侵袭。
Maspin inhibits metastasis of some cancer cells, and clinical studies have identified correlations between maspin loss and poor prognosis in several cancer types. Maspin was found to be significantly overexpressed in lung cancer samples as compared with matched normal lung tissues. However, the regulatory mechanism of maspin expression remains unclear. We show here that differential expression of maspin in carcinoma-derived lung cancer cells is regulated at the transcriptional level. We found that p63 is a critical factor for the transcription of maspin, which is lost in highly invasive cancer cells such as NCI-H157, NCI-322, and NCI-358. No correlation was found between maspin expression and the previously associated transcription factors, p53, Ets1, and Pdef. Instead, maspin expression was strictly dependent on the presence of p63 in lung cancer tissues (P < 0.001) and in the tested cell lines. Transient expression of p63 transactivated. the maspin promoter with remarkable fold changes in cells expressing the TAp63, suggesting that TAp63 might be a novel stimulator of the maspin promoter in lung cancer. We have also demonstrated the binding of p63 protein to a previously identified p53-binding site on the maspin promoter by gel shift and chromatin immunoprecipitation assays. In tumor tissues, maspin expression was associated with lymph node involvement (P = 0.035) and tumor stage (P = 0.063) in all tested cases, except squamous carcinoma. In terms of function, ectopic expression of maspin inhibited cell invasion in squamous carcinoma as well as adenocarcinoma. Taken together, these results define maspin as a new molecular target of p63 that eventually inhibits the invasion of lung cancer.