NEURAL TRANSCRIPTION FACTOR IN LUNG CANCER EVOLUTION

描述（改编自研究者摘要）：本资助提案 重点是一个基本的螺旋环螺旋转录因子的作用，人类 hASH 1在调节大多数表型中的作用 侵袭性和高转移性的人肺肿瘤，小细胞肺 癌（SCLC）。 hASH 1是果蝇的人类对应物， AS-C是一个保守的转录因子家族 对原始神经前体细胞的形成至关重要。 研究人员已经确定hASH 1在肺癌中表达， 模式与神经内分泌表型的存在密切相关 包括典型的小细胞肺癌细胞 基因操作模拟了 SCLC和非SCLC表型之间的转换导致了 hASH 1表达。 鲍尔博士还证明了该基因在 正常胎肺内分泌细胞，群集于神经上皮小体。 由于肺内分泌细胞是最早分化的细胞， 类型出现在肺气道上皮的发展，这 表达模式将hASH 1置于介导重要过程的位置 在肺发育和SCLC表型的建立中。 一 胎儿肺内分泌细胞和SCLC的标志是 成簇的、紧密组织的、不依赖于锚定的聚集体的细胞。 在 果蝇神经系统发育，AS-C触发因子的表达 聚集事件和细胞间信号传导， 单个优势神经母细胞和相邻细胞中AS-C的下调 细胞，然后假设上皮的命运。 许多信号 分子和转录因子参与了这一横向 抑制过程现在已知有哺乳动物同源物;一个引人注目的 功能同源性的程度也正在出现。 一系列 转染实验，他们已经表明，外源表达的 hASH 1在不内源性表达该基因的肺癌细胞中， 诱导细胞在还原血清中以密集漂浮聚集体生长。 等 发现表明hASH 1可能对SCLC表型至关重要， 包括其特有的聚集行为。 建议的系列 目前的研究试图确定：1）肺癌的神经内分泌特征 分化和生长，特别是与 旁分泌生长因子，其可由hASH 1调节; 2）分子 可能是hASH 1基础的表面粘附分子的事件和变化 肺癌中介导的细胞-细胞粘附; 3）调节hASH 1的途径 肺癌中的基因表达，重点是进化保守 果蝇神经发生的因素; 4）hASH 1表达在 正常肺发育中的肺内分泌细胞和对 实验性肺损伤 这些研究将提供一个强有力的方法， 了解SCLC的起源和分化关系， 将这种肿瘤与其他主要疾病联系起来， 从而发现了肺癌的新治疗靶点。

DESCRIPTION (adapted from the investigator's abstract): This grant proposal focuses on the role of a basic-helix-loop-helix transcription factor, human achaete-scute homolog-1 (hASH1) in regulating the phenotype of the most aggressive and highly metastatic of human lung tumors, small cell lung carcinoma (SCLC). hASH1 is a human counterpart to the Drosophila achaete-scute complex (AS-C), a conserved family of transcription factors that are essential for the commitment of primitive neural precursor cells. The investigator has determined that hASH1 is expressed in lung cancers in a pattern tightly correlated with the presence of the neuroendocrine phenotype including classic SCLC cells. Genetic manipulations which mimic a transition between SCLC and non-SCLC phenotypes resulted in extinction of hASH1 expression. Dr. Ball has also demonstrated expression of the gene in normal fetal pulmonary endocrine cells, clustered in neuroepithelial bodies. Since pulmonary endocrine cells are among the first differentiated cell types to appear in development of the pulmonary airway epithelium, this expression pattern places hASH1 in a position to mediate essential processes in both lung development and establishment of the SCLC phenotype. A hallmark of both fetal pulmonary endocrine cells and SCLC is the growth of cells in clustered, tightly organized, anchorage-independent aggregates. In Drosophila nervous system development, expression of the AS-C triggers clustering events and cell-cell signaling which results in emergence of a single dominant neuroblast and down-regulation of the AS-C in adjoining cells, which then assume an epithelial fate. Many of the signaling molecules and transcription factors that participate in this lateral inhibition process are now known to have mammalian homologs; a striking degree of functional homology is also now emerging. In a series of transfections experiments, they have shown that exogenous expression of hASH1 in lung cancer cells which do not endogenously express this gene can induce growth of cells in dense floating aggregates in reduced serum. Such findings indicate that hASH1 may be critical to the SCLC phenotype, including its characteristic aggregative behavior. The proposed series of studies now seek to determine: 1) features of lung cancer neuroendocrine differentiation and growth, particularly related to the function of paracrine growth factors, that may be modulated by hASH1; 2) the molecular events and changes in surface adhesion molecules that may underlie hASH1 mediated cell-cell adhesion in lung cancer; 3) the pathways regulating hASH1 gene expression in lung cancer, with an emphasis on evolutionary conserved factors from Drosophila neurogenesis; 4) the role of hASH1 expression in pulmonary endocrine cells in normal lung development and in response to experimental lung injury. These studies will provide a powerful approach to understanding the origins of SCLC and the differentiation relationships that link this tumor to the other major forms of this disease, potentially leading to the discovery of novel therapeutic targets in lung cancer.