Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer
Insulinoma-Associated Protein 1 Is a Crucial Regulator of Neuroendocrine Differentiation in Lung Cancer
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DOI：
10.1016/j.ajpath.2015.08.018
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发表时间：
2015-12-01
影响因子：
6
通讯作者：
Ito, Takaaki
中科院分区：
文献类型：
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作者：
Fujino, Kosuke;Motooka, Yamato;Ito, Takaaki
胰岛素瘤相关蛋白1(INSM1)仅在胚胎发育中的神经内分泌(NE)组织中表达。INSM1基因的表达是小细胞肺癌(SCLC)所特有的，与ASCL1和一些去甲肾上腺素(NE)分子如嗜铬粒素A、突触素和神经细胞黏附分子1一起表达。然而，INSM1在肺癌中的潜在生物学作用仍不清楚。我们首先展示了手术切除的小细胞肺癌样本特异性地表达INSM1。在腺癌细胞株(H358和H1975)中强制表达INSM1基因可诱导ASCL1、脑-2(Brn2)、嗜铬粒蛋白A、突触素和神经细胞黏附分子1的表达，而在小细胞肺癌(H69和H889)中通过siRNA敲除INSM1基因可降低它们的表达。然而，ASCL1和Brn2的强制/下调表达并不影响INSM1的表达。染色质免疫沉淀研究表明，INSM1结合在ASCL1基因的启动子区域。Tet-on INSM1基因转染腺癌细胞系的异种移植实验表明，INSM1诱导NE分化和生长抑制。此外，我们还发现INSM1在非小细胞肺癌和一些表达Notch1-Hes1的小细胞肺癌细胞系中不表达。通过强制/敲除Notch1或Hes1基因的表达，我们发现Notch1-Hes1信号抑制了INSM1，以及ASCL1和Brn2。INSM1仅在小细胞肺癌中表达，是小细胞肺癌去甲肾上腺素分化的重要调节因子，受Notch1-Hes1信号通路调控。
Insulinoma-associated protein 1 (INSM1) is expressed exclusively in embryonic developing neuroendocrine (NE) tissues. INSM1 gene expression is specific for small-cell lung cancer (SCLC), along with achaetescute homolog-like 1 (ASCL1) and several NE molecules, such as chromogranin A, synaptophysin, and neural cell adhesion molecule 1. However, the underlying biological role of INSM1 in lung cancer remains largely unknown. We first showed that surgically resected SCLC samples specifically expressed INSM1. Forced expression of the INSM1 gene in adenocarcinoma cell lines (H358 and H1975) induced the expression of ASCL1, brain-2 (BRN2), chromogranin A, synaptophysin, and neural cell adhesion molecule 1; in contrast, knockdown of the INSM1 gene by siRNA in SCLC (H69 and H889) decreased their expression. However, forced/knockdown expression of ASCL1 and BRN2 did not affect INSM1 expression. A chromatin immunoprecipitation study revealed that INSM1 bound to the promoter region of the ASCL1 gene. A xenotransplantation assay using tet-on INSM1 gene-transfected adenocarcinoma cell Lines demonstrated that INSM1 induced NE differentiation and growth inhibition. Furthermore, we found that INSM1 was not expressed in non small-cell lung cancer and some SCLC cell lines expressing Notch1-Hes1. By forced/knockdown expression of Notch1 or Hes1 genes, we revealed that Notch1-Hes1 signaling suppressed INSM1, as well as ASCL1 and BRN2. INSM1, expressed exclusively in SCLC, is a crucial regulator of NE differentiation in SCLCs, and is regulated by the Notch1-Hes1 signaling pathway.