Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer.
Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer.
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DOI：
10.2353/ajpath.2009.081004
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发表时间：
2009-09
期刊：
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通讯作者：
T. Yazawa;Hanako Sato;H. Shimoyamada;K. Okudela;Tetsukan Woo;M. Tajiri;T. Ogura;N. Ogawa;Takehisa Suzuki;Hideaki Mitsui;Jun Ishii;Chie Miyata;Masashi Sakaeda;Kazuya Goto;K. Kashiwagi;M. Masuda;Takashi Takahashi;H. Kitamura
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文献类型：
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作者：
T. Yazawa;Hanako Sato;H. Shimoyamada;K. Okudela;Tetsukan Woo;M. Tajiri;T. Ogura;N. Ogawa;Takehisa Suzuki;Hideaki Mitsui;Jun Ishii;Chie Miyata;Masashi Sakaeda;Kazuya Goto;K. Kashiwagi;M. Masuda;Takashi Takahashi;H. Kitamura
小细胞肺癌（SCLC）表现出胰岛素样生长因子依赖性生长。SCLC是已知的体内肺癌中最具侵袭性的，而与非SCLC（NSCLC）相比，SCLC的体外生长反常地缓慢。在这项研究中，我们证明，SCLC细胞过表达胰岛素样生长因子结合蛋白（IGFBP）-2通过NeuroD，神经内分泌细胞特异性转录因子。染色质免疫沉淀、电泳迁移率改变和IGFBP-2启动子测定均显示NeuroD与IGFBP-2 5 '非翻译区的E-box结合。气道上皮细胞和NSCLC细胞中的NeuroD转基因上调IGFBP-2的转录并延缓细胞生长。重组IGFBP-2以剂量依赖性方式抑制气道上皮细胞和NSCLC细胞的生长。NeuroD特异性小干扰RNA抑制SCLC中IGFBP-2的表达，中和IGFBP-2和IGFBP-2特异性小干扰RNA增加SCLC细胞生长。与NSCLC相比，SCLC的病理样品也大量表达IGFBP-2，并且仅显示罕见的（8%）IGFBP-2启动子甲基化，而IGFBP-2启动子在71%的腺癌和29%的鳞状细胞癌中甲基化。这些发现表明1）SCLC具有与NSCLC不同的IGFBP-2过表达机制，2）分泌的IGFBP-2有助于体外SCLC的缓慢生长，3）IGFBP-2启动子的表观遗传学改变有助于体内SCLC和NSCLC之间IGFBP-2表达的显著差异。
Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 promoter assays all revealed that NeuroD binds to the E-box in the 5'-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2 and retarded cell growth. Recombinant IGFBP-2 repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2 expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2 promoter methylation, whereas the IGFBP-2 promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2 overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2 promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo.