Genetic and epigenomic studies of testicular tumor

睾丸肿瘤的遗传学和表观基因组研究

• 批准号: 8351208
• 负责人: Owen Rennert
• 金额: $ 11.89万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 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/8351208
• 关键词: Adhesives; Affect; Age; Antigens; Cancer Cell Growth; Chromatin Structure; Chromosomes, Human, Pair 1; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Development; Disease; Dynamin III; Embryonal Carcinoma; Epigenetic Process; Functional RNA; Genetic; Genome Stability; Genomics; Germ Cell Cancers; Goals; Human Resources; Hypermethylation; Introns; Link; Malignant Neoplasms; Malignant neoplasm of testis; Maps; Mediating; Methylation; MicroRNAs; Mutation; Neoplasm Metastasis; Pathogenesis; Promoter Regions; Proteins; Reporting; Role; Subgroup; Testicular Germ Cell Tumor; Testicular Neoplasms; Tumor Cell Line; bisulfite; cancer cell; epigenomics; genome-wide; male; migration; novel; overexpression; podocalyxin; tumor progression; tumorigenesis

Epigenetic inactivation of microRNA in male germ cell cancer Personnel: Lee, Cheung, Chan, Rennert MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been shown to be deregulated in many diseases including cancer. An intertwined connection between epigenetics and miRNAs has been supported by the recent identification of a specific subgroup of miRNAs called "epi-miRNAs" that can directly and indirectly modulate the activity of the epigenetic machinery. Using a genome-wide approach for studying differential methylation in testicular germ cell tumor cell line, we previously identified a novel hypermethylated locus on chromosome 1. Genomic mapping revealed that the hypermethylated region overlapped with a mircroRNA candidate, miR-199a and its upstream promoter region. Bisulfite sequencing and treatment with DNA methyltransferase inhibitor 5-aza in the Ntera-2 testis cancer cells confirmed the same observation in the tiling microarray data. Changes in DNA methylation are a hallmark of cancer, and are frequently associated with cancer progression. Epigenomic profiling revealed a conserved region in intron-14 of dynamin 3, located at 1q24.3; its hypermethylation correlated with testicular cancer progression, and silencing of miR-199a. Re-expression of miR-199a in testicular cancer cells suppressed cell growth, cancer migration, invasion, and metastasis. miR-199a-5p, one of two mature miRNA species derived from miR-199a, is associated with cancer progression. We identified an embryonal carcinoma antigen, podocalyxin-like protein 1 (PODXL), as a target of miR-199a-5p. PODXL is an anti-adhesive protein overexpressed in aggressive testicular cancer. Knockdown of PODXL suppressed cancer invasion. The inverse relationship between PODXL and miR-199a-5p expression suggests that PODXL is one of the downstream effectors mediating cancer invasion and metastasis. This report links DNA methylation, miR-199a dysregulation, and PODXL expression as a mechanism to explain testicular cancer progression.

男性生殖细胞癌中微小RNA的表观遗传失活 人员：Lee，Cheung，Chan，Rennert MicroRNA（miRNAs）是一类小的非编码RNA，其已被证明在包括癌症在内的许多疾病中失调。表观遗传学和miRNA之间的相互交织的联系已经得到最近鉴定的称为“表观-miRNA”的miRNA的特定亚组的支持，所述表观-miRNA可以直接和间接地调节表观遗传机制的活性。利用全基因组方法研究睾丸生殖细胞肿瘤细胞系中的差异甲基化，我们先前在1号染色体上发现了一个新的高甲基化位点。基因组图谱显示，高甲基化区域与microRNA候选物miR-199 a及其上游启动子区域重叠。亚硫酸氢盐测序和用DNA甲基转移酶抑制剂5-aza处理Ntera-2睾丸癌细胞证实了平铺微阵列数据中的相同观察结果。 DNA甲基化的变化是癌症的标志，并且经常与癌症进展相关。表观基因组分析揭示了发动蛋白3内含子14中的一个保守区域，位于1q24.3;其高甲基化与睾丸癌进展和miR-199 a沉默相关。miR-199 a在睾丸癌细胞中的重新表达抑制了细胞生长、癌症迁移、侵袭和转移。 miR-199 a-5 p是来源于miR-199 a的两种成熟miRNA之一，与癌症进展相关。我们鉴定了胚胎癌抗原，足细胞萼蛋白样蛋白1（PODXL），作为miR-199 a-5 p的靶点。PODXL是一种在侵袭性睾丸癌中过度表达的抗粘附蛋白。PODXL的敲除抑制了癌症侵袭。PODXL和miR-199 a-5 p表达之间的负相关性表明PODXL是介导癌症侵袭和转移的下游效应物之一。 该报告将DNA甲基化，miR-199 a失调和PODXL表达作为解释睾丸癌进展的机制。