DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung
DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung
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DOI：
10.1038/onc.2010.217
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发表时间：
2010-08-01
期刊：
影响因子：
8
通讯作者：
Hirohashi, S.
中科院分区：
文献类型：
--
作者：
Shibata, T.;Kokubu, A.;Hirohashi, S.
肺癌具有不同的组织学亚型。大细胞神经内分泌细胞癌和小细胞肺癌具有相似的组织学特征和临床表现，可归类为肺的高级别神经内分泌癌（HGNEC）。在这里，我们阐明了肺内分泌肿瘤的分子分类的拷贝数分析。我们比较了拷贝数的改变与HGNEC的临床结果，并确定了与不良预后显著相关的DEK癌基因位点（6p22.3）的染色体获得。我们进一步证实，DEK过表达与更大范围的HGNEC预后不良相关。通过小发夹RNA下调DEK导致体外集落形成、体内致瘤性和化疗耐药性的显著降低，并且与肺癌干细胞标志物的丢失相关。基因表达谱分析显示，DEK下调与转录调节因子的表达改变有关，这些转录调节因子特别包括造血肿瘤中染色体间易位的已知靶点，这些表观遗传修饰因子的敲低影响集落形成活性。我们的研究表明，DEK过表达，部分通过其基因剂量的增加，介导的全球转录调节因子的活性，并与肿瘤的起始活动和预后不良的HGNEC。Oncogene（2010）29，4671-4681; doi：10.1038/onc.2010.217; 2010年6月14日在线发表
Lung cancer shows diverse histological subtypes. Large-cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical behaviors, and can be classified as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Here we elucidated the molecular classification of pulmonary endocrine tumors by copy-number profiling. We compared alterations of copy number with the clinical outcome of HGNEC and identified a chromosomal gain of the DEK oncogene locus (6p22.3) that was significantly associated with poor prognosis. We further confirmed that DEK overexpression was associated with poor prognosis in a larger set of HGNEC. Downregulation of DEK by small hairpin RNA led to a marked reduction of in vitro colony formation, in vivo tumorigenicity and chemo-resistance, and was associated with loss of lung cancer stem cell markers. Gene expression profiling revealed that DEK downregulation was associated with altered expression of transcriptional regulators, which specifically include known targets of interchromosomal translocations in hematopoietic tumors, and knockdown of these epigenetic modifiers affected colony formation activity. Our study showed that DEK overexpression, partly through an increase in its gene dose, mediates the activity of global transcriptional regulators and is associated with tumor initiation activity and poor prognosis in HGNEC. Oncogene (2010) 29, 4671-4681; doi:10.1038/onc.2010.217; published online 14 June 2010