Role of GLI in Tumor progression

GLI 在肿瘤进展中的作用

• 批准号: 6773162
• 负责人: John Michael Ruppert
• 金额: $ 25.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773162
• 关键词: basal cell carcinoma; binding sites; biological signal transduction; chromatin; clinical research; embryo /fetus cell /tissue; epithelium; genetic regulatory element; genetic transcription; genetically modified animals; human tissue; immunoprecipitation; keratinocyte; laboratory mouse; mesenchyme; microarray technology; molecular oncology; neoplastic process; oncogenes; sirolimus; transcription factor

DESCRIPTION (provided by applicant): Signaling by sonic hedgehog (SHH) during development and in normal adult tissues is an important regulatory mechanism for proliferation and morphogenesis. SHH binds to and antagonizes the activity of the tumor suppressor PTCH, a gatekeeper molecule important in basal cell carcinoma of the skin (BCC), medulloblastoma, and rhabdomyosarcoma. Loss-of-function and gain-of-function studies support a role for the GLI family of zinc finger transcription factors in transmission of the hedgehog signal. In BCC, a most common form of carcinoma, GLI expression is consistently induced as a result of mutation of PTCH or of other molecules in the pathway. Expression of GLI or GL12 in mouse skin is sufficient to induce BCC. To better understand the role of GLI in tumor progression, we extensively characterized GLI-expressing RK3E epithelial cells to identify putative target genes. The techniques of suppression subtractive hybridization and microarray analysis were used in combination to identify GLI-induced transcripts. The identified transcripts were not altered in association with transformation by several other oncogenes, including RAS, c-MYC, or GKLF/KLF4. Compared with control cells, mouse embryo cells harboring defective alleles of PTCH exhibited increased expression of several of these transcripts, suggesting that expression of endogenous GLI is sufficient for some of the observed transcriptional effects. mRNA in situ hybridization revealed increased expression of GLI-induced transcripts in GLI-positive hair follicles and in human BCC, compared with GLI-negative hair follicles. Unlike other oncogenes that transform RK3E, GLI specifically induced expression of molecules or oncogenes known to induce epithelial-mesenchymal transition (EMT) in development. Multiple alterations in gene expression previously observed in human BCC were likewise induced by GLI in vitro. We propose to identify transcripts that correspond to direct transcriptional target genes, to determine a role for specific GLI-induced transcripts in a mouse model of BCC, and to characterize specific GLI-induced transcripts as potential effectors of transformation in vitro and in vivo.

描述（由申请人提供）：在发育过程中和在正常成体组织中由声波刺猬（SHH）发出的信号是增殖和形态发生的重要调节机制。 SHH 与肿瘤抑制因子 PTCH 结合并拮抗其活性，PTCH 是一种在皮肤基底细胞癌 (BCC)、髓母细胞瘤和横纹肌肉瘤中发挥重要作用的看门分子。功能丧失和功能获得研究支持锌指转录因子 GLI 家族在刺猬信号传递中的作用。在 BCC（最常见的癌症形式）中，由于 PTCH 或通路中其他分子的突变，GLI 的表达始终被诱导。小鼠皮肤中 GLI 或 GL12 的表达足以诱导 BCC。 为了更好地了解 GLI 在肿瘤进展中的作用，我们广泛表征了表达 GLI 的 RK3E 上皮细胞，以确定假定的靶基因。结合使用抑制消减杂交和微阵列分析技术来鉴定GLI诱导的转录本。所鉴定的转录本并未因其他几个癌基因（包括 RAS、c-MYC 或 GKLF/KLF4）的转化而发生改变。与对照细胞相比，含有 PTCH 缺陷等位基因的小鼠胚胎细胞表现出其中几种转录物的表达增加，表明内源 GLI 的表达足以产生一些观察到的转录效应。 mRNA 原位杂交显示，与 GLI 阴性毛囊相比，GLI 阳性毛囊和人类 BCC 中 GLI 诱导的转录物表达增加。与转化 RK3E 的其他癌基因不同，GLI 特异性诱导已知可诱导发育中上皮间质转化 (EMT) 的分子或癌基因的表达。先前在人类 BCC 中观察到的基因表达的多种改变同样是由 GLI 在体外诱导的。 我们建议鉴定与直接转录靶基因相对应的转录本，以确定特定 GLI 诱导的转录本在 BCC 小鼠模型中的作用，并将特定 GLI 诱导的转录本表征为体外和体内转化的潜在效应子。