Transcriptome and epigenetics regulation in pediatric brain tumors

• Main Authors: Tsung-Han Hsieh, 謝宗翰
• Other Authors: Hsei-Wei Wang
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/52213555676707482035

博士 === 國立陽明大學 === 微生物及免疫學研究所 === 102 === Pediatric central nervous system (CNS) tumors are a heterogeneous group of neoplasm and are the second prevalent cancer in childhood. Embryonal tumors and intracranial germ cell tumors (iGCTs) rank the number 2 and 3, respectively, most common brain tumors that occur in childhood. Embryonal tumors represent a highly malignant tumor group of medulloblastomas (MBs), atypical teratoid/rhabdoid tumors (AT/RTs), and primitive neuroectodermal tumors (PNETs). iGCTs encompass germinomas and non-germinomatous malignant GCTs (NGMGCTs, includes all GCTs except for germinoma & benign mature teratoma). AT/RTs show more undifferentiated cells and are more malignant and aggressive than MB. In contrast, iGCT NGGCTs show more differentiated cells but more malignant than germinoma. The mechanisms underlying theses difference are still unclear. In this doctoral dissertation, I reveal miRNome and methylomes in embryonal tumors and iGCTs by high-throughput sequencing. In embryonal tumors, our findings demonstrate that miR-221 and miR-222 are abundantly expressed in AT/RT but not in MB, and these 2 microRNAs contribute to the malignancy of embryonal tumors. MiR-221/-222 target SUN2, a newly discovered tumor suppressor, directly to increase cell proliferation and tumor malignancy in vitro and in vivo. In iGCTs, we found that methylation-regulated miRNAs, miR-335-5p and miR-199a-5p, are highly expressed in NGMGCTs but not in germinomas. Overexpressing miR-335-5p and miR-199a-5p in GCT cell lines contribute the enhancement of cisplatin resistance through targeting two important stemness factors, Oct4 and Nanog. Our findings illustrate new pathogenesis and therapeutic tactics towards pediatric brain tumors. In addition, our sequencing data also provide a roadmap for further pediatric brain tumor research.