Sox9 signaling in lung adenocarcinoma

肺腺癌中的 Sox9 信号传导

• 批准号: 9479728
• 负责人: Sharon R. Pine
• 金额: $ 4万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9479728
• 关键词: Adenocarcinoma Cell; Adult; Automobile Driving; Binding; Binding Sites; Biological Assay; Bypass; Cancer cell line; Cell Line; Cellular Morphology; Cessation of life; Cisplatin; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Developmental Gene; Doxycycline; E-Cadherin; Embryo; Embryonic Development; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Event; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Growth; Guide RNA; Human; Human Development; In Vitro; Knock-out; Laboratories; Lead; Lung; Lung Adenocarcinoma; Lung Adenoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mesenchymal; Molecular; Morphogenesis; Mus; Mutation; NF-kappa B; NOTCH1 gene; Nature; Oncogenes; Oncogenic; Pathway interactions; Patients; Phenotype; Play; Polyadenylation; Regulation; Reporting; Repression; Resistance; Role; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; System; Technology; Testing; Therapeutic; Toxic effect; Transcriptional Regulation; Translating; Treatment Efficacy; Xenograft procedure; addiction; antitumor effect; cancer survival; cancer therapy; carcinogenesis; cell motility; chromatin immunoprecipitation; disorder control; improved; in vivo; loss of function; lung carcinogenesis; lung tumorigenesis; man; mouse model; mutant; notch protein; novel; novel therapeutic intervention; novel therapeutics; overexpression; p65; promoter; public health relevance; targeted treatment; therapy resistant; transcription factor; translational approach; tumor; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Tumors frequently enlist developmental genes to translate oncogenic signals into drivers of tumor progression. To gain a better understanding of the molecular mechanisms behind lung carcinogenesis and progression, we are focusing on the potential role of Sox9, a transcription factor required for human development. We found that Sox9 is barely expressed in normal lung tissue, but is overexpressed in primary human and murine lung tumors as well as lung cancer cell lines. We determined that Sox9 is not only a direct target gene of Notch1 signaling, but it is also a key mediator of Notch1-induced mesenchymal-like cellular morphological changes, E- cadherin repression, cell motility, and invasion in lung cancer. Our studies suggest that Sox9 is downstream of other oncogenic pathways. We propose that Sox9 is a terminal hub for convergence of upstream oncogenic signals, and plays a central role in mediating their contribution to lung tumorigenesis and progression. Therefore, targeting Sox9 expression could alleviate the resistance often invoked by redundant oncogenic pathways during treatment with targeted therapies. The overall goals of this proposal are to validate the pathways regulating Sox9 expression and mediating Sox9's role in the induction of cell motility and invasion. We will test the function of Sox9 during murine lun carcinogenesis. Using patient-derived lung tumor xenografts and a validated platform to target Sox9 in vivo, we will test if Sox9 repression has anti-tumor activity. This study will help in understanding the regulation of lung tumor progression by a novel embryonic developmental gene and develop a strategy for potentially circumventing therapeutic resistance.

描述（由申请人提供）：肿瘤经常利用发育基因将致癌信号转化为肿瘤进展的驱动因素。为了更好地了解肺癌发生和进展背后的分子机制，我们重点关注 Sox9（人类发育所需的转录因子）的潜在作用。我们发现Sox9在正常肺组织中几乎不表达，但在原发性人和小鼠肺肿瘤以及肺癌细胞系中过度表达。我们确定Sox9不仅是Notch1信号传导的直接靶基因，而且还是Notch1诱导的间充质样细胞形态变化、E-钙粘蛋白抑制、细胞运动和肺癌侵袭的关键介质。我们的研究表明 Sox9 是其他致癌途径的下游。我们认为 Sox9 是上游致癌信号汇聚的终端枢纽，并在介导其对肺部肿瘤发生和进展的贡献中发挥核心作用。因此，靶向 Sox9 表达可以减轻靶向治疗过程中由冗余致癌途径引起的耐药性。该提案的总体目标是验证调节 Sox9 表达和介导 Sox9 在诱导细胞运动和侵袭中的作用的途径。我们将测试 Sox9 在小鼠肺癌发生过程中的功能。使用患者来源的肺肿瘤异种移植物和体内靶向 Sox9 的经过验证的平台，我们将测试 Sox9 抑制是否具有抗肿瘤活性。这项研究将有助于了解新型胚胎发育基因对肺肿瘤进展的调节，并制定潜在规避治疗耐药性的策略。