Role of inflammation in epigenetic alterations of metastatic cancer cells

炎症在转移性癌细胞表观遗传改变中的作用

• 批准号: 10262250
• 负责人: Li Yang
• 金额: $ 98.55万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262250
• 关键词: Affect; Binding Sites; Biological Assay; Cancer Biology; Cancer Patient; Carcinoma; Cause of Death; Cyclin-Dependent Kinase 4 Inhibitor B; DNA Damage; Development; Disseminated Malignant Neoplasm; Distant; Down-Regulation; Epigenetic Process; Epithelial; Epithelium; Fibroblasts; Genetic; Genomic Instability; Genomics; Goals; Heterogeneity; Homeostasis; In Vitro; Inflammation; Inflammatory; Malignant Neoplasms; Mediating; Mediator of activation protein; Methylation; Molecular; Molecular Biology; Mutation; Neoplasm Metastasis; Organ; PTGS2 gene; Promoter Regions; Role; Signal Transduction; TP53 gene; Tumor Suppressor Genes; Variant; attenuation; cancer cell; cancer prevention; carcinogenesis; effective therapy; in vivo; metastatic process; mouse model; neoplastic cell; pressure; therapeutic target; tumor; tumor initiation; tumor microenvironment

Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelia homeostasis. The precise molecular mediators remain to be identified. We found that stromal deletion of Tgfbr2 resulted in genetic and epigenetic changes in the adjacent epithelia including a loss of the cyclin dependent kinase (CDK) inhibitors p15 and p16. In addition, there was increased methylation at the p53-binding site of the p21 promoter region in the tumor cells. The mechanisms mediating the crosstalk between the epithelia and the stroma involved COX-2-mediated inflammation. Our studies demonstrate that attenuation of stromal TGFb signaling induces inflammation that, in turn, causes DNA damage as well as epigenetic and genetic alterations in epithelia. Therefore, therapeutic targeting of inflammation and the tumor microenvironment may be useful in treating cancers with downregulation of TGFb signaling in the stroma. Wa are currently investigating how cancer associated inflammation affect metastatic cancer cell colonization through epigenetic reprogramming.

间质成纤维细胞中肿瘤抑制基因的缺失诱导上皮癌的发展，这表明间质在上皮内环境稳定中的重要作用。精确的分子介质仍有待确定。我们发现Tgfbr 2的基质缺失导致邻近上皮细胞的遗传和表观遗传变化，包括细胞周期蛋白依赖性激酶（CDK）抑制剂p15和p16的丢失。此外，在肿瘤细胞中，p21启动子区域的p53结合位点的甲基化增加。介导上皮和间质之间的串扰的机制涉及考克斯-2介导的炎症。我们的研究表明，基质TGF β信号转导的减弱诱导炎症，这反过来又导致上皮细胞中的DNA损伤以及表观遗传和遗传改变。因此，炎症和肿瘤微环境的治疗靶向可用于治疗基质中TGF β信号转导下调的癌症。我们目前正在研究癌症相关炎症如何通过表观遗传重编程影响转移性癌细胞的定植。