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研究生:梁慕理
研究生(外文):Muh-Lii Liang
論文名稱:兒童高度惡性膠質瘤的微型核醣核酸/核醣核酸互動組與腦室管膜瘤放射線抗性之機轉及探討
論文名稱(外文):The Mechanism of MicroRNAs/mRNAs Interactomes in Pediatric High-grade Gliomas and Radio-resistance in Pediatric Ependymomas
指導教授:楊慕華楊慕華引用關係王學偉王學偉引用關係
指導教授(外文):Muh-Hwa YangHsei-Wei Wang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:英文
論文頁數:116
中文關鍵詞:兒童惡性膠質瘤腦室管膜瘤微型核醣酸137微型核醣酸6500-3p細胞週期蛋白D1
外文關鍵詞:pediatrichigh-grade gliomaependymomamiR-137miR-6500-3pcyclin D1
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高惡性度膠質瘤及腦室管膜瘤是兩個極具挑戰的惡性腫瘤,也是好發在孩童主要的中樞神經系統腫瘤。除了以手術做最大範圍的安全切除及效果有限的化療外,運用輔助放射線照射對這些惡性腫瘤扮演重要的角色。然而,對於年紀小的幼童,殘餘或復發腫瘤的頑固性,以及長期對智能的後遺症,仍是放射線治療的主要阻礙。
最近十年來,隨著高產量次世代基因定序及分子群集分析技術的進步,大幅提升了神經腫瘤在分子層次的診斷及治療標靶的研究。為了辨識有潛力的標靶以期發展新的治療策略,在第一個研究中,以微型核醣核酸定序及基因表現微陣列技術為基礎,我們比較兒童低度及高惡性度膠質瘤的微型核醣核酸組及轉錄組。透過整合生物資訊分析及實驗驗證,我們辨識出在兒童高惡性度膠質瘤顯著降低的微型核醣核酸137及微型核醣核酸6500-3p。微型核醣核酸137或微型核醣核酸6500-3p過度表現噵致兒童高惡性度膠質瘤細胞株SF188及WU479的增殖降低。關於核醣核酸與微型核醣核酸的交互作用,我們也確認出CENPE、KIF14及NCAPG基因是微型核醣核酸137或微型核醣核酸6500-3p的直接標靶,且在兒童高惡性度膠質瘤有顯著表現上升。更進一步,剔除CENPE、KIF14及NCAPG基因合併帝盟多藥物治療,對兒童高惡性度膠質瘤細胞株的增殖有合併抑制的效果,有潛力發展新的藥物合併治療策略。
第二個研究,聚焦在了解放射線抗性導致治療腦室管膜瘤失效的機制,並且證實細胞週期蛋白D1過度表現對兒童腦室管膜瘤的進展及放射線抗性的關鍵角色。我們分析82例小於20歲兒童腦室管膜瘤的臨床及病理因子中,31例 (37.8%)為小於3歲幼童。10年疾病無復發率及整體存活率為38%及60%。在多變項分析中,手術全切除是較佳的10年無復發及整體存活率的單一顯著預後因子(P<0.05)。我們也證明,24例原發 (92%) 及16例 (95%) 復發腦室管膜瘤的細胞週期蛋白D1過度表現,並且在復發的腦室管膜瘤中7對中的5對細胞週期蛋白D1也過度表現。剔除細胞週期蛋白D1降低細胞增殖、抑制細胞週期S期關聯基因並且抑制去氧核醣核酸修復。當細胞接受放射線照射治療時H2AX上昇,但去氧核醣核酸同源性重組及修復也因細胞週期蛋白D1缺少而降低。當腦室管膜細胞以palbociclib加上放射線治療後24小時,H2AX上昇,CDC6、MCM2、MAD2L1、CDK2、BRCA2 及 RAD51基因顯著受抑制且降低細胞增殖。
綜上所述,我們的發現辨識出兒童高惡性度膠質瘤新的核醣核酸與微型核醣核酸交互作用,以及在兒童腦室管膜瘤細胞週期蛋白D1在調節細胞增殖及放射線抗性的強大角色,提供對放射線抗性的關聯機制的深入了解以及對這兩種惡性腫瘤有潛力的治療標靶。
High-grade gliomas and ependymomas are two main challenging malignancies in children, and which composed of a majority of central nervous system (CNS) tumors of young patients. In addition to maximal safe surgical resection and limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for the tumor treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy.
The advancement of high-throughput next-generation sequencing and molecular clustering technologies largely promoted the study of neuro-oncology from diagnosis based molecular to therapeutic targets in the last decade. In order to identify potential targets for the development of new therapeutic strategies, we compared the miRNome and transcriptome of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively in the first study. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p are significantly downregulated in pHGGs. Overexpression of miR-137 or miR-6500-3p reduced cell proliferation in two pHGG cell lines, SF188 and UW479. We also identified mRNA/miRNA interactions and confirmed that CENPE, KIF14 and NCAPG levels were direct targets of miR-137 or miR-6500-3p and were significantly higher in pHGGs than pLGGs. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. These targets combined with chemotherapy are also potential therapeutic strategy.
In the secondary study, we focused on the mechanism of therapeutic failure caused by radio-resistance and identified the significance of cyclin D1 overexpression in progression and radio-resistance of pediatric ependymomas. Here we analyze clinic-pathological factors in 82 cases of ependymoma less than 20 years old and 31 out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross-total resection is the single significant prognostic factor for longer 10 years progression free survival (PFS) and overall survival (OS) in the multi-variant analysis (p<0.05). We demonstrated that 24 primary (92%) and 16 recurrent (95%) ependymomas were up-regulated, and 5 out of 7 paired samples exhibited higher CCND1 expression in recurrent tumors. Knocking down CCND1 reduced cell proliferation and repressed genes associated with S-phase and DNA repair. Homologous recombination activities of DNA repair were significantly decreased in CCND1-deficient cells while the level of H2AX was increased after irradiation. We treated ependymoma cells with palbociclib plus irradiation significantly suppressed expression of CDC6, MCM2, MAD2L1, CDK2, BRCA2 and RAD51 genes, and induced higher H2AX level after 24 hours and also reduced cell proliferation.
In summary, our findings identify novel mRNA/miRNA interactions in pediatric high-grade gliomas and also suggest a robust role of CCND1 in regulating cell proliferation and radio-resistance in ependymomas, which providing insight of mechanism related to the radio-resistance and the potential therapeutic targets for both pediatric high-grade gliomas and ependymomas.
Acknowledgments ----------------------- 1
Abstract ------------------------------- 3
中文摘要 ------------------------- 5
Contents -------------------------------- 7
List of Abbreviations ---------------------- 11

1. Introduction
1.1 Molecular Era in the Diagnosis of Neuro-Oncology----14
1.2 New Molecular Classifications of High-grade Gliomas ----------------------------------------------------------15
1.3 Key differences between Pediatric and Adult High-grade Gliomas-------------------------------------------------17
1.4 Present Therapeutic Challenging in Pediatric High-grade Gliomas ------------------------------------------18
1.5 MicroRNAs in Pediatric High-grade Gliomas -------19
1.6 MicroRNA137 & MicroRNA6500-3p--------------------19
1.7 Impact of Novel mRNA/microRNA interactome in Gliomas--20
1.8 New Molecular Classifications of Ependymomas--------21
1.9 Present Therapeutic Challenges in Pediatric Ependymomas --------------------------------------------22
1.10 Factors affecting the Prognosis of Pediatric Ependymomas --------------------------------------------23
1.11 Expression of CCND1 in Ependymomas ----------------24
1.12 Mechanism of Therapeutic Resistance in Ependymomas --24
2. Materials and methods
2.1 Biological samples ---------------------------------26
2.2 Cell cultures --------------------------------------26
2.3 Plasmids--------------------------------------------27
2.4 Gene expression microarray (GEM) and computational analyses -----------------------------------------------27
2.5 Small RNA sequencing (smRNA-Seq) and data analysis -28
2.6 RNA and reverse transcription-quantitative PCR -----29
2.7 Immunoblotting -------------------------------------30
2.8 MTT assay -----------------------------------------30
2.9 Cell cycle analysis---------------------------------31
2.10 in vitro drug sensitivity assay -------------------31
2.11 Luciferase reporter assay -------------------------32
2.12 Homologous Recombination detection ----------------32
2.13 Immunohistochemistry ------------------------------33
2.14 Statistics ----------------------------------------33
3. Results
3.1.1 Clinical characteristics of pediatric gliomas ----35
3.1.2 Differentially expressed genes between pLGGs and pHGGs --------------------------------------------------35
3.1.3 Significant down-regulated miR-137 and miR-6500-3p in pHGGs and increase
cell proliferation in pHGG cell lines ------------------36
3.1.4 miR-137 or miR6500-3p suppress cell proliferation and have a combined effect
with temozolomide treatment -------37
3.1.5 Identifying the pLGG and pHGG miRNA-mRNA interactomes -------------------------------------------37
3.1.6 Potential targets CENPE of miR-137, KIF14 and NCAPG of miR-6500-3p -----------------------------------------38
3.1.7 Confirmation of downstream targets with reporter assays -------------------------------------------------39
3.1.8 CENPE, KIF14 or NCAPG knockdown also reduced cell proliferation ------------------------------------------39
3.1.9 shCENPE, shKIF14 or shNCAPG suppress cell proliferation and have a combined
effect with temozolomide treatment ---------------------40
3.1.10 Mechanisms of miRs/mRNAs interaction and combined anti-proliferative
effect in the presence of temozolomide in pediatric high-grade gliomas-------------------------------------------40
3.2.1 Clinical factors affecting outcome of pediatric ependymomas --------------------------------------------41
3.2.2 Differentially expressed genes between normal and ependymomas --------------------------------------------42
3.2.3 DNA damages related genes sorted out and analyzed by Gene ontology ------------------------------------------43
3.2.4 Overexpression of Cyclin D1 in primary and recurrence ependymomas ---------------------------------43
3.2.5 Overexpression of radiation-related genes CCND1 and RAD51---------------------------------------------------45
3.2.6 Cyclin D1 is associated with cell proliferation and DNA repair in ependymomas ------------------------------45
3.2.7 CDK4/6 inhibitor, Palbociclib, reduced cell proliferation in ependymoma-----------------------------46
3.2.8 Mechanisms of overexpression CCND1 affecting progression and radio-
resistance in pediatric ependymomas --------------------48
4. Discussion
4.1.1 Unique transcriptome and interactome characteristics in pHGGs -----------------------------------------------49
4.1.2 Potential therapeutic targets for novel molecular agents in pHGGs ----------------------------------------50
4.2.1 Role of overexpressed CCND1 in primary and recurrent ependymoma ---------------------------------------------51
4.2.2 Potential therapeutic target of CCND1 in epedymomas --------------------------------------------------------53
5. Conclusions -----------------------------------------54
6. Perspectives ----------------------------------------55
References ---------------------------------------------56
Figures ------------------------------------------------68
Tables ------------------------------------------------104
Supplemental Tables -----------------------------------107
Publications ------------------------------------------113
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