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: 9153803
• 负责人: Li Yang
• 金额: $ 57.02万
• 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/9153803
• 关键词: Affect; Binding Sites; Biological Assay; Bone Marrow; Cancer Biology; Cancer Patient; Cause of Death; Cells; Cyclin-Dependent Kinase 4 Inhibitor B; DNA Damage; Development; Disseminated Malignant Neoplasm; Distant; Down-Regulation; Epigenetic Process; Epithelial; Epithelium; Fibroblasts; Genes; 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; Strategic Planning; Tumor Suppressor Genes; Variant; Yang; attenuation; cancer cell; cancer prevention; carcinogenesis; effective therapy; in vivo; metastatic process; mouse model; neoplastic cell; pressure; therapeutic target; tumor; tumor initiation; tumor microenvironment; tumor progression

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. In a mouse model in which the Tgfbr2 gene in stromal fibroblasts was inactivated, 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 these findings affect cancer metastatic process.

间质成纤维细胞中肿瘤抑制基因的缺失可诱导上皮癌的发生，提示间质在上皮细胞动态平衡中起重要作用。确切的分子介体仍有待确定。在基质成纤维细胞中TGFBR2基因失活的小鼠模型中，我们发现基质中TGFBR2的缺失会导致相邻上皮细胞的遗传和表观遗传学变化，包括细胞周期蛋白依赖激酶(CDK)抑制物p15和p16的丢失。此外，肿瘤细胞中p21启动子区域的P53结合部位的甲基化增加。介导上皮和基质之间的串扰的机制涉及COX-2介导的炎症。我们的研究表明，基质TGFb信号的减弱会诱导炎症，进而导致DNA损伤以及上皮细胞的表观遗传和遗传改变。因此，针对炎症和肿瘤微环境的治疗靶点可能有助于通过下调间质中的TGFb信号来治疗癌症。西澳目前正在调查这些发现如何影响癌症转移过程。