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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61843完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊雅倩 | |
| dc.contributor.author | Sheng-Tai Tzeng | en |
| dc.contributor.author | 曾晟泰 | zh_TW |
| dc.date.accessioned | 2021-06-16T13:15:25Z | - |
| dc.date.available | 2016-09-24 | |
| dc.date.copyright | 2013-09-24 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-29 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61843 | - |
| dc.description.abstract | 大腸直腸癌近年為世界最常見的癌症死因之一，而此癌症的發生乃因多步驟的染色體變異逐漸累積、發展而成。許多人類的惡性腫瘤常發生第四號染色體長臂的基因缺失，但目前被鑑定出的抑癌基因卻很稀少。為了探索此區域的抑癌基因，本研究針對114 例大腸直腸癌腫瘤組織，於染色體4q25-4q28.2區域進行刪除圖譜分析。我們定義出一個介於D4S2297及D4S2303位點之間的最小刪除區域，並進一步分析座落其中的NDST4基因(N-deacetylase/ N-sulfotransferase (heparan glucosaminyl) 4)。利用雷射微切除技術，證實NDST4 基因表現於正常大腸黏膜上皮細胞，而此基因於所測試之腫瘤細胞並不表現。為進一步確認NDST4基因缺失是否常見於大腸直腸癌，我們以52例大腸直腸癌檢體進行表現量分析，其中30例 (57.7%) 腫瘤組織的NDST4表現乃明顯下降。此外我們更以174例大腸直腸癌分析NDST4之染色體缺失，發現其與較差的病理分期 (P=0.039) 、存活率 (P=0.036) 有顯著相關。若在人類大腸直腸癌細胞株過度表現NDST4則可顯著抑制其細胞生長、腫瘤形成和肝轉移能力。此外，重新表現NDST4於異種移植腫瘤模式可抑制小鼠皮下及肝轉移之腫瘤生成。為進一步探討NDST4 抑癌的分子機制，我們建立Ndst4 基因剔除小鼠。初步觀察此基因剔除鼠，其發育和生育能力正常，然而於大腸黏膜、胃以及肺臟則發現有輕微病理異常。綜合以上所述，我們發現染色體4q26位點於大腸直腸癌有高頻率缺失現象，而座落於其中的NDST4基因於本研究為首次被提出具腫瘤抑制功能。NDST4缺失與病人預後密切相關，且此基因重新表現於癌細胞亦可抑制其腫瘤特性，顯示其於大腸直腸癌具有重要的抑癌功能。此外，本研究首度發表Ndst4基因剔除小鼠並針對其表現型進行初步分析，對於日後NDST4基因相關的研究將可提供重要的動物模型。 | zh_TW |
| dc.description.abstract | Colorectal cancer (CRC) is one of the most common causes of cancer deaths in the world, and most of CRC arise sporadically by the emergence of multiple chromosomal aberrations. Allelic losses in the long arm of chromosome 4 are commonly encountered in many human malignancies, but few tumor suppressor genes (TSGs) are identified. To explore novel TSGs deleted in CRC, deletion mapping of chromosome 4q25-q28.2 was conducted in 114 sporadic CRC by loss of heterozygosity (LOH) study. One minimal deletion region was delineated between D4S2297 and D4S2303 loci at 4q26. In the region a candidate novel TSG, N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 4 (NDST4), was further investigated. By laser capture microdissection, NDST4 RNA expression was confirmed in colonic epithelial cells, but was undetectable in tumor cells. Gene expression of NDST4 was further investigated in 52 pairs of primary CRC tissues. In total, 30 (57.7%) of 52 colorectal carcinomas showed a dramatic reduction in NDST4 gene expression compared with matched normal mucosae. Allelic loss of NDST4 gene was determined in 174 colorectal carcinomas by LOH analysis. The genetic loss of NDST4 was significantly associated with advanced pathological stage (P = 0.039) and poorer overall survival of patients (P = 0.036). Overexpression of NDST4 in the human CRC cells induced a significant suppression in cell proliferation, anchorage independent growth and invasion. Moreover, re-expression of NDST4 also suppressed subcutaneous and metastatic tumor growth in the mouse xenograft tumor models. To investigate the molecular mechanisms in vivo, we have also generated an Ndst4 knockout (KO) mouse strain, which develops and reproduces normally, but shows minor abnormality in colon, stomach and lung. In conclusion, we identified a novel tumor suppressor region located at 4q26 that is lost in CRC at high frequency. Genetic loss of NDST4 is closely related to prognosis, and NDST4 re-expression inhibits tumor behaviors, suggesting a key suppressor role in colorectal tumorigenesis. In addition, this is the first study to generate Ndst4 KO mice with phenotype characterization. The genetic mouse model would provide a valuable tool for functional study of NDST4. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T13:15:25Z (GMT). No. of bitstreams: 1 ntu-102-D95424001-1.pdf: 7923930 bytes, checksum: 7420a49b24554b91bd1f8fbb5d3ec038 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 口試委員審定書 i
誌謝 ii 摘要 iii ABSTRACT v LIST OF FIGURES x LIST OF TABLES xii Chapter 1 Introduction 1 1.1 Colorectal cancer and tumor staging 1 1.2 Genetic alterations and biomarkers in colorectal cancer 3 1.3 Heparan sulfate proteoglycans 7 1.4 NDST (N-deacetylase/N-sulfotransferase) family and NDST4 9 1.5 Research motive and strategy 10 Chapter 2 Materials and Methods 12 2.1 Patients and tissue specimens 12 2.2 LOH analysis 12 2.3 RNA extraction 13 2.4 Reverse transcription-polymerase chain reaction (RT-PCR) 14 2.5 Quantitative RT-PCR (qRT-PCR) 14 2.6 microRNA 577 expression analysis 15 2.7 Laser capture microdissection 16 2.8 Cloning and stable clone selection 16 2.9 Immunofluorescence staining 17 2.10 Western blot analysis 17 2.11 Cell proliferation assay 18 2.12 Soft agar assay 18 2.13 Wound-healing assay 19 2.14 Cell invasion assay 19 2.15 Subcutaneous xenograft tumor model 20 2.16 Intrasplenic xenograft tumor model 20 2.17 Immunohistochemistry 21 2.18 Targeted recombination of the Ndst4 gene 21 2.19 Southern blotting analysis 22 2.20 Breeding of Ndst4 KO mice 22 2.21 Histological examination of Ndst4 KO mice 23 2.22 Statistical analysis 23 Chapter 3 Results 24 3.1 NDST4 gene is a candidate tumor suppressor gene at chromosome 4q26 24 3.2 NDST4 gene is expressed in normal colonic mucosae and polyps, but is downregulated in colorectal carcinomas 25 3.3 Allelic loss of NDST4 gene is significantly associated with advanced pathological stage and poor survival in CRC 26 3.4 Cloning and re-expression of NDST4 in CRC cell line HCT116 27 3.5 NDST4 suppresses cell growth and invasion in vitro 27 3.6 NDST4 suppresses xenograft tumor growth in vivo 28 3.7 Targeted mutation of Ndst4 in mice 29 3.8 Histological phenotyping of Ndst4 KO mice 30 Chapter 4 Discussion 32 FIGURE 38 TABLE 59 REFERENCE 65 Appendix 75 | |
| dc.language.iso | en | |
| dc.subject | 大腸直腸癌 | zh_TW |
| dc.subject | 4q26 | zh_TW |
| dc.subject | NDST4 | zh_TW |
| dc.subject | 抑癌基因 | zh_TW |
| dc.subject | Ndst4基因剔除鼠 | zh_TW |
| dc.subject | Ndst4 knockout mice | en |
| dc.subject | Colorectal cancer | en |
| dc.subject | 4q26 | en |
| dc.subject | NDST4 | en |
| dc.subject | Tumor suppressor gene | en |
| dc.title | 鑑定NDST4為大腸直腸癌之抑癌基因並製作Ndst4基因剔除小鼠 | zh_TW |
| dc.title | Identification of NDST4 as a tumor suppressor gene in colorectal cancer and generation of Ndst4 knockout mice | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 俞松良,許金玉,蔡明宏,陳志榮,林淑華 | |
| dc.subject.keyword | 大腸直腸癌,4q26,NDST4,抑癌基因,Ndst4基因剔除鼠, | zh_TW |
| dc.subject.keyword | Colorectal cancer,4q26,NDST4,Tumor suppressor gene,Ndst4 knockout mice, | en |
| dc.relation.page | 83 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-07-29 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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