Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Res. 2011 Oct 1;71(19):6165-73. doi: 10.1158/0008-5472.CAN-11-1020. Epub 2011 Aug 19.
Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition.
具有神经内分泌 (NE) 特征的肺癌通常具有很强的侵袭性，但潜在的分子机制仍不清楚。转录因子 ASH1/ASCL1 是肺 NE 细胞发育的主要调节因子，参与具有 NE 特征的肺癌 (NE 肺癌) 的发病机制。在这里，我们报告了 microRNA miR-375 的定义，作为 ASH1 在 NE 肺癌细胞中功能的关键下游效应物。miR-375 在肺癌细胞中被 ASH1 显著诱导，足以诱导 NE 分化。miR-375 的上调是 ASH1 介导的诱导 NE 特征的前提条件。转录共激活因子 YAP1 被确定为 miR-375 的直接靶标。YAP1 在一系列肺癌细胞系中与 miR-375 呈负相关，并在 NE 肺癌细胞中具有生长抑制活性。我们的研究结果阐明了 NE 肺癌中 ASH1 效应轴，该轴在控制 NE 特征和减轻 YAP1 介导的生长抑制方面具有功能重要性。
