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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊雅倩(Ya-Chien Yang) | |
| dc.contributor.author | Tzu-Ming Jao | en |
| dc.contributor.author | 饒梓明 | zh_TW |
| dc.date.accessioned | 2021-06-16T07:03:06Z | - |
| dc.date.available | 2019-10-09 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-14 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57778 | - |
| dc.description.abstract | 在臺灣及美國大腸直腸癌都位居癌症死因的第三位。百分之75的大腸直腸癌屬於偶發性，而其中有85%是由染色體變異所導致。染色體變異常造成大片段的基因漏失導致抑癌基因缺失而使癌症生成。利用失異合性(Loss of heterozygosity)方法分析第四號染色體，本實驗室先前研究發現PCDH10可能是大腸直腸癌的抑癌基因。PCDH10缺失不但與腫瘤進程及遠端轉移有關，而且可作為預測病人較差存活率的獨立因子。為進一步確認PCDH10具有抑癌功能，本研究將針對此基因進行抑癌功能鑑定並探討其抑癌的分子機制。利用反轉錄聚合酶鏈鎖反應偵測12個大腸直腸癌細胞株及53對臨床檢體發現：PCDH10表現量於12個大腸直腸癌細胞株無表現，而在41個腫瘤組織則是低表現，此結果再度支持PCDH10可能為抑癌基因。為證實PCDH10的抑癌功能，我們於大腸直腸癌細胞HCT116篩選穩定表現PCDH10之細胞株，並進行細胞體外及小鼠體內之抑癌功能測試。重新表現PCDH10於HCT116可以抑制癌細胞增生、胞落形成、移行及侵犯能力。利用皮下及脾臟注射之小鼠模式，發現PCDH10的表現可抑制HCT116於小鼠體內的生長及肝臟轉移能力；重要的是：脾臟注射表現PCDH10之癌細胞的小鼠其存活率較長。於分子機制方面，PCDH10可藉由降低AKT磷酸化並抑制beta-catenin核轉移而抑制癌細胞上皮間質轉化(Epithelial-to-Mesenchymal Transition)，進而降低癌細胞之轉移能力；再者，PCDH10可使p53表現量增加而減緩細胞週期進行，進而抑制癌細胞之增生能力。 | zh_TW |
| dc.description.abstract | Colorectal cancer (CRC) is the third leading cause of cancer deaths in Taiwan and United States. Seventy-five percent of CRC is sporadic and 85% of them suffered chromosomal instability (CIN). Loss-of-function of tumor suppressor gene or gain-of-function of oncogene is a hallmark during tumor development. CIN results in frequent allelic loss and then loss of tumor suppressor genes. Our previous study showed that Protocadherin 10 (PCDH10), a novel tumor suppressor gene in human cancers, is located in one common deleted region at chromosome 4q28 in CRC. The genetic loss of PCDH10 was significantly associated with tumor progression and distant metastasis, as well as was an independent predictor of poor survival for CRC patients. This study aimed to explore the tumor suppressor function and molecular mechanisms of PCDH10. Expression of PCDH10 gene was silenced or markedly down-regulated in all of 12 CRC cell lines and 41 of 53 colorectal carcinomas compared with their matched normal mucosae. In addition, tumor suppressor activity of PCDH10 was identified by in vitro cell models and mouse xenograft tumor models. Ectopic expression of PCDH10 reduced cancer cell proliferation, anchorage-independent growth, migration, and invasion in vitro. Subcutaneous injection of PCDH10-expressing CRC cells in SCID mice showed alleviated tumor growth when compared with mock-inoculated mice. More importantly, via intrasplenic implantation, re-expression of PCDH10 in silenced cells restrained liver metastasis, and also improved survival in SCID mice. PCDH10 blockades epithelial-to-mesenchymal transition through inhibition of AKT phosphorylation and nuclear translocation of beta-catenin. In addition, PCDH10 suppresses cancer proliferation through up-regulation of p53 signaling and retardation of cell cycle progression. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T07:03:06Z (GMT). No. of bitstreams: 1 ntu-103-D97424006-1.pdf: 9256026 bytes, checksum: db62591ba27a623e9d33c8d459e6035b (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 誌謝 I
中文摘要 II Abstract III List of Figures VII List of Tables IX Abbreviation X Chapter 1 Introduction 1 1.1 Colorectal cancer 1 1.2 Staging for colorectal cancer 1 1.3 Genetic and epigenetic alteration in colorectal tumorigenesis 3 1.4 Canonical Wnt signaling pathway in CRC 4 1.5 Epithelial-to-mesenchymal transition in CRC 6 1.6 PCDH10 is a candidate tumor suppressor gene in CRC 8 1.7 Protocadherin family 9 1.8 Nonclustered PCDHs 11 1.9 Protocadherin 10 (PCDH10, OL-PCDH) 14 1.10 Specific aims 15 Chapter 2 Materials and Methods 16 2.1 Antibodies 16 2.2 Cell lines and reagents 16 2.3 Generation of constitutive or inducible PCDH10-expressing stable clones 17 2.4 Generation of lentivirus vectors 17 2.5 DNA and RNA preparation 18 2.6 Semi-quantitative and quantitative real-time RT-PCR 18 2.7 Plasmid construction 19 2.8 Animal 19 2.9 Proliferation assay 19 2.10 Anchorage-independent growth assay 20 2.11 Wound healing assay 20 2.12 Matrigel invasion assay 20 2.13 Western blotting 21 2.14 Subcutaneous tumor model in SCID mice 21 2.15 Intrasplenic implantation in SCID mice 22 2.16 Immunofluorescence staining 22 2.17 Immunohistochemical staining 23 2.18 cDNA microarray analysis 23 2.19 TOPFlash reporter assay 24 2.20 Statistical analysis 24 Chapter 3 Results 25 3.1 PCDH10 is down-regulated in CRC cell lines and primary colorectal carcinomas 25 3.2 Establishment of constitutive and inducible PCDH10-expressing clones 25 3.3 PCDH10 inhibits cell proliferation, anchorage-independent growth, migration, and invasion in vitro 26 3.4 PCDH10 suppresses tumorigenesis in the immunodeficient mouse model of subcutaneous xenograft 27 3.5 PCDH10 restrains liver metastasis and prolongs survival in the immunodeficient mouse model of intrasplenic xenograft 27 3.6 Cytoplasmic domain of PCDH10 is responsible for tumor suppressor functions 28 3.7 Identification of PCDH10-mediated molecular mechanisms by cDNA microarray 29 3.8 PCDH10 represses | |
| dc.language.iso | en | |
| dc.subject | PCDH10 | zh_TW |
| dc.subject | 肝臟轉移 | zh_TW |
| dc.subject | 抑癌基因 | zh_TW |
| dc.subject | 分子機制 | zh_TW |
| dc.subject | PCDH10 | en |
| dc.subject | tumor suppressor gene | en |
| dc.subject | liver metastasis | en |
| dc.subject | molecular mechanism | en |
| dc.title | Protocadherin 10於大腸直腸癌之抑癌功能鑑定及其分子機制探討 | zh_TW |
| dc.title | Identification of Protocadherin 10 as a tumor suppressor and its molecular mechanisms in colorectal cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 蔡明宏(Ming-Hong Tsai),蔡錦華(Ching-Hwa Tsai),林淑華(Shu-Wha Lin),何元順(Yuan-Soon Ho),俞松良(Sung-Liang Yu) | |
| dc.subject.keyword | PCDH10,抑癌基因,肝臟轉移,分子機制, | zh_TW |
| dc.subject.keyword | PCDH10,tumor suppressor gene,liver metastasis,molecular mechanism, | en |
| dc.relation.page | 86 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-14 | |
| 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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