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Characterization of long non-coding RNA H19 in epithelial to mesenchymal transition: 長非編碼RNA H19在上皮間充質轉化中的功能探究 / 長非編碼RNA H19在上皮間充質轉化中的功能探究 / CUHK electronic theses & dissertations collection / Characterization of long non-coding RNA H19 in epithelial to mesenchymal transition: Chang fei bian ma RNA H19 zai shang pi jian chong zhi zhuan hua zhong de gong neng tan jiu / Chang fei bian ma RNA H19 zai shang pi jian chong zhi zhuan hua zhong de gong neng tan jiuJanuary 2014 (has links)
Colorectal cancer (CRC), with an estimated 1.2 million new cases annually, is the third leading cause of cancer incidence and death worldwide. Generally, the majority of CRC patients are diagnosed at the advanced stages with poor prognosis and unfavorable response to multiple therapeutic drugs. In spite of increasing knowledge of the molecular mechanism for the tumorigenesis in CRC patients, the translation from basic science into clinical therapy has been limited for quite a long time. In order to develop novel treatment strategies against CRC, intensive and extensive attempts have been made in the past decades. / The epithelial to mesenchymal transition (EMT) is a multi-step process characterized by the loss of cell polarity, decreased cell-cell adhesion as well as enhanced migration and invasion capacity. It is well documented that EMT is essential for a variety of cellular biological events ranging from embryogenesis to tumor progression. The field of lncRNA is developing rapidly and currently it is one of the most intensively studied fields in the biomedical sciences. Emerging evidence indicates that the majority of human genome encodes thousands of non-protein-coding RNA transcripts, nevertheless, the function of long non-coding RNAs (lncRNAs) in orchestrating EMT progression remains elusive. Historically, the lncRNA H19 was the first identified imprinted non-coding RNA transcript in human, and the H19/IGF2 locus acted as an ideal paradigm for the investigation of genomic imprinting genes. In recent years, the expression profiling and functional characterization of the H19 gene in a variety of human diseases has been extensively studied. / In our studies, H19 was characterized as a novel regulator of EMT in colon cancer. We first observed significant mesenchymal characteristics in the methotrexate-resistant HT-29 cells. Interestingly, significant upregulation of H19 was observed in mesenchymal-like MTX resistant HT-29 cells. We subsequently demonstrated that after treatment of TGF-β1, one of the most widely used EMT inducers, H19 presented dramatic increase during the EMT progression. To further investigate the functional role of H19 in EMT, we generated the stable cell lines overexpressing H19 in colon cancer cells using retroviral infection. Stable overexpression of H19 significantly promoted EMT progression in two epithelial colon cancer cell lines HT-29 and HCT-116. However, overexpression of H19 did not affect cell proliferation as well as cell cycle progression. Further proteomics studies screened out that ectopic expression of H19 upregulated the protein level of Vimentin, a vital biomarker for mesenchymal cells. By using the bioinformatics study in combination with luciferase reporter assays, we demonstrated that H19 potentiated the expression of several core marker genes essential for mesenchymal cells by serving as a competing endogenous RNA(ceRNA), which builds up the missing link between the regulatory miRNA network and EMT progression. According to the results from xenograft tumor model and soft agar assay, stable expression of H19 reinforced the in vitro and in vivo tumor growth. Moreover, the investigation of clinical specimens verified that H19 RNA level was significantly increased in colon cancer tissues compared with corresponding adjacent normal tissues. Taken together, the above observations imply that the lncRNA H19, by acting as a competing endogenous RNA, is an important regulator which tightly modulated the expression of multiple important genes involved in EMT and it could probably serve as a novel therapeutic target against colon cancer. / 大腸癌每年有一百二十萬新增個案,是世界第三大癌症殺手。通常情況下,大部分大腸癌病人發現時已經處於晚期,該時期的癌症病人對多種臨床治療藥物已無法治愈。盡管關於大腸癌發病的分子生物學機制已經不斷完善,但如何從基礎研究轉化為臨床治療手段在很長一段時間內不可實現。為了進一步研究新的抗擊大腸癌治療手段,廣泛且深入的研究已經不斷開展。 / 上皮間充質轉化是一個多步驟的過程,該過程的典型特徵為失去細胞的極性,細胞間粘連減弱以及細胞爬行遷移能力的不斷加強。目前科學家已經知道上皮間充質轉化對於從胚胎發育到腫瘤發展都起著重要的作用。近年來,長非編碼RNA的研究不斷快速發展,已然成為醫學研究中最激烈的領域之一。眾多證據表明人體基因組編碼數以千計不編碼蛋白質的RNA轉錄體。然而,這些RNA轉錄體在上皮間充質轉化中的功能依然所知甚少。長非編碼RNA H19是人體內第一個被鑒別出來參與到基因印記的非編碼RNA。資料表明H19/IGF2位點是一個非常理想的研究基因印記的位點。近年來,H19在眾多癌症中的表達以及功能學研究已不斷湧現,同時也不斷取得令人鼓舞的研究成果。 / 在我們的研究中,H19被鑒定為大腸癌裏上皮間充質轉化過程中一個重要的參與者。通過研究甲氨蝶呤耐藥大腸癌HT-29細胞株,我們發現該HT-29耐藥細胞株有著顯著的間充質細胞特性。有趣的是,H19在該細胞株中有著顯著升高。我們隨後用經典的上皮間充質轉化誘導劑TGF-β1處理兩株大腸癌細胞,處理後H19亦有著顯著升高。為了進一步研究H19在上皮間充質轉化,通過使用逆轉錄病毒,我們建立H19的穩定表達細胞株。穩定表達H19顯著地促進了HT-29以及SW620大腸癌細胞株的上皮間充質轉化。然後,高水平表達(過表達)H19並不影響細胞的生長以及細胞周期的進程。進一步的蛋白質組學研究表明,過表達H19能促進間充質細胞一個重要標記基因Vimentin的表達。通過生物信息學以及熒光素酶報告基因實驗,我們證明了H19通過其競爭內源性RNA的作用,能夠促進間充質細胞所需的幾個重要基因的表達。該發現建立起了miRNA網絡以及上皮間充質轉化進程的交流網絡。通過異位移植以及軟瓊脂實驗,我們發現過表達H19能夠促進腫瘤細胞的生長。而在臨床大腸癌病人組織中,我們更發現H19在大腸癌病人組織中高表達。綜上所述,我們的結果證明H19這一長非編碼RNA,能夠通過其競爭內源性RNA的作用機制,從而調控上皮間充質轉化過程中的關鍵基因。同時H19亦有可能成為治療大腸癌的臨床新靶點。 / Liang, Weicheng. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 95-124). / Abstracts also in Chinese. / Title from PDF title page (viewed on 24, October, 2016). / Liang, Weicheng.
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Identification of candidate tumor suppressor genes at 11q for nasopharyngeal and esophageal carcinoma.January 2007 (has links)
Wang, Yajun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 118-126). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgements --- p.v / Table of Contents --- p.vi / List of Figures --- p.xi / List of Tables --- p.xii / Abbreviations and Symbols --- p.xiii / List of Publications and Sequence Submissions during the Study --- p.xv / Chapter Chapter One: --- General Introduction --- p.1 / Chapter Chapter Two: --- Literature Review --- p.8 / Chapter 2.1 --- DNA methylation --- p.8 / Chapter 2.1.1 --- Epigenetic changes --- p.8 / Chapter 2.1.2 --- Differential methylation pattern in normal and tumor cells --- p.10 / Chapter 2.2 --- TSGs --- p.13 / Chapter 2.2.1 --- "Cancer initiation, progression and cancer genes" --- p.13 / Chapter 2.2.2 --- TSGs could be inactivated through promoter hypermethylation --- p.14 / Chapter 2.3 --- NPC --- p.17 / Chapter 2.3.1 --- Epidemiology ofNPC --- p.18 / Chapter 2.3.2 --- Molecular genetic and epigenetic studies ofNPC --- p.19 / Chapter 2.3.3 --- NPC and chromosome 11q --- p.21 / Chapter 2.4 --- ESCC --- p.21 / Chapter 2.4.1 --- Epidemiology of ESCC --- p.22 / Chapter 2.4.2 --- Genetic and epigenetic studies of ESCC --- p.23 / Chapter 2.4.3 --- ESCC and chromosome 11q --- p.24 / Chapter 2.5 --- Chromosome 11q and other carcinomas --- p.24 / Chapter 2.5.1 --- Breast cancer --- p.24 / Chapter 2.5.2 --- Ovarian cancer --- p.25 / Chapter 2.5.3 --- Neuroblastoma --- p.26 / Chapter 2.5.4 --- Melanoma --- p.27 / Chapter 2.5.5 --- Multiple myeloma --- p.27 / Chapter 2.5.6 --- Lung Cancer --- p.27 / Chapter 2.6 --- Important candidate genes located at the project study 1 lq region --- p.28 / Chapter 2.6.1 --- ETS1 --- p.28 / Chapter 2.6.2 --- FLI1 --- p.29 / Chapter 2.6.3 --- P53AIP1 --- p.30 / Chapter 2.6.4 --- RICS --- p.30 / Chapter 2.6.5 --- BARX2 --- p.30 / Chapter 2.6.6 --- ST14 --- p.32 / Chapter 2.6.7 --- ADAMTS8 --- p.33 / Chapter 2.6.8 --- ADAMTS15 --- p.35 / Chapter 2.6.9 --- HNT --- p.36 / Chapter 2.6.10 --- OPCML --- p.36 / Chapter Chapter Three: --- Materials and Methods --- p.37 / Chapter 3.1 --- Cell lines and primary tumor samples --- p.37 / Chapter 3.2 --- Cell line demethylation treatment --- p.38 / Chapter 3.3 --- DNA and RNA extraction from cell lines and tissues --- p.39 / Chapter 3.4 --- Semiquantitative RT-PCR --- p.41 / Chapter 3.5 --- DNA bisulfite treatment --- p.42 / Chapter 3.6 --- Promoter analysis and identification of 5' CpG islands of target genes --- p.45 / Chapter 3.7 --- Methylation-Specific PCR (MSP) --- p.45 / Chapter 3.8 --- Bisulfite Genomic Sequencing (BGS) --- p.46 / Chapter 3.8.1 --- BGS PCR reaction --- p.46 / Chapter 3.8.2 --- TA cloning of the PCR products into the sequencing vector --- p.47 / Chapter 3.8.3 --- Plasmid mini-preparation on 96-well plate --- p.48 / Chapter 3.8.4 --- Plasmid sequencing --- p.49 / Chapter 3.9 --- Homozygous deletion detection --- p.50 / Chapter 3.10 --- Construction of expression plasmids --- p.51 / Chapter 3.10.1 --- The strategy of full length cDNA cloning --- p.51 / Chapter 3.10.2 --- Obtaining of full length covered cDNA by cloning PCR --- p.53 / Chapter 3.10.3 --- Ligation and transformation --- p.54 / Chapter 3.10.4 --- Mini preparation of plasmid in Eppendorf tubes --- p.54 / Chapter 3.10.5 --- Verification of correct inserts in the plasmid --- p.55 / Chapter 3.10.6 --- Subcloning --- p.55 / Chapter 3.10.7 --- Bacteria storage --- p.57 / Chapter 3.11 --- Colony formation assays (CFA) --- p.57 / Chapter 3.11.1 --- Midiprep of the transfection grade plasmid --- p.57 / Chapter 3.11.2 --- Transfection --- p.58 / Chapter 3.11.3 --- Selection of the transfected cells with G418 --- p.59 / Chapter 3.11.4 --- Colony staining --- p.60 / Chapter 3.12 --- Statistical analysis --- p.60 / Chapter Chapter Four: --- Results --- p.61 / Chapter 4.1 --- Narrow down the candidate genes for further study --- p.61 / Chapter 4.1.1 --- Define the study chromosome region --- p.61 / Chapter 4.1.2 --- Database search of all candidate genes --- p.61 / Chapter 4.1.3 --- Transcriptional expression analysis of the candidate genes --- p.63 / Chapter 4.1.4 --- Selection of the genes with tumor specific expression downregulation for further intensive study --- p.64 / Chapter 4.2 --- Further characterization of ADAMTS8 --- p.69 / Chapter 4.2.1 --- Tissue transcriptional expression panel --- p.69 / Chapter 4.2.2 --- Semiquantitative RT-PCR results in tumor cell lines --- p.70 / Chapter 4.2.3 --- Promoter CpG island identification and promoter methylation study --- p.70 / Chapter 4.2.4 --- Transcription reactivation by demethylation treatment --- p.72 / Chapter 4.2.5 --- High resolution promoter methylation analysis by BGS --- p.72 / Chapter 4.2.6 --- Detection of homozygous deletion --- p.73 / Chapter 4.2.7 --- Analysis of ADAMTS8 promoter methylation in clinical samples --- p.74 / Chapter 4.2.8 --- ADAMTS8 full length cDNA cloning --- p.74 / Chapter 4.2.9 --- Colony formation assay --- p.75 / Chapter 4.3 --- Further characterization of HNT --- p.80 / Chapter 4.3.1 --- Tissue transcriptional expression panel --- p.80 / Chapter 4.3.2 --- Semiquantitative RT-PCR results in tumor cell lines --- p.80 / Chapter 4.3.3 --- Promoter CpG island identification and promoter methylation study --- p.81 / Chapter 4.3.4 --- Transcription reactivation by demethylation treatment --- p.82 / Chapter 4.3.5 --- HNT full length cDNA cloning --- p.82 / Chapter 4.4 --- Further characterization of BARX2 --- p.87 / Chapter 4.4.1 --- Tissue transcriptional expression panel --- p.87 / Chapter 4.4.2 --- Semiquantitative RT-PCR results in tumor cell lines --- p.87 / Chapter 4.4.3 --- Promoter CpG island identification and promoter methylation study --- p.88 / Chapter 4.4.4 --- Transcription reactivation by demethylation treatment --- p.89 / Chapter 4.4.5 --- BARX2 full length cDNA cloning --- p.89 / Chapter 4.5 --- Further study of other downregulated genes --- p.92 / Chapter 4.5.1 --- FLII --- p.92 / Chapter 4.5.2 --- ADAMTS15 --- p.94 / Chapter 4.5.3 --- P53AIP1 --- p.97 / Chapter Chapter Five: --- Discussion --- p.100 / Reference List --- p.118 / Appendix I: Reagents Preparation Recipe --- p.127 / Appendix II: PCR Primers for cDNA Cloning --- p.129
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Identification of novel candidate tumor suppressor genes at 11q and 15q for esophageal squamous cell carcinoma and nasopharyngeal carcinoma via integrative cancer epigenetics and genomics. / 通過整合擬遺傳學與基因組學策略在食管鱗狀細胞癌及鼻咽癌中鑒定位於人類11及15號染色體長臂上的新候選抑癌基因的研究 / CUHK electronic theses & dissertations collection / Tong guo zheng he ni yi chuan xue yu ji yin zu xue ce lüe zai shi guan lin zhuang xi bao ai ji bi yan ai zhong jian ding wei yu ren lei 11 ji 15 hao ran se ti chang bei shang de xin hou xuan yi ai ji yin de yan jiuJanuary 2010 (has links)
In brief, mRNA expression profiling of candidate genes in each locus was performed using semi-quantitative RT-PCR in a panel of ESCC and NPC cell lines, normal tissues and immortalized epithelial cell lines. Genes downregulated in cancer cells but with high expression in normal tissues and immortalized epithelial cells were subjected to promoter methylation analysis using methylation-specific PCR (MSP), bisulfite genomic sequencing (BGS) and pharmacological demethylation treatment. Genes with tumor-specific downregulation and methylation were further selected as candidates and their tumor suppressive roles were verified via functional studies. / In conclusion, RAB39 and WDRX, epigenetically silenced in multiple cancer cell lines, were identified as novel TSG candidates in this study. Meanwhile, the tumor suppressive functions of ADAMTS8 were further validated, proving the efficiency of this integrative approach. Further study on these novel TSG candidates may help to elucidate the detailed molecular mechanisms for ESCC and NPC, and provide novel therapeutic targets and biomarkers. / In this study, RAB39 and WDRX were identified as candidate TSGs in 11q22.3 and 15q21.3, respectively. Both genes were broadly expressed in normal tissues and immortalized epithelial cell lines, but significantly downregulated and methylated in multiple cancer cell lines. Demethylation treatment with 5-Aza-2'-deoxycytidine restored their mRNA expression, indicating that CpG methylation directly contributed to their transcriptional inactivation. Methylation of RAB39 and WDRX was detected in primary ESCC and NPC, but rarely observed in normal tissues, implicating that their tumor-specific methylation might be used as biomarkers. Ectopic expression of both genes significantly inhibited the clonogenicity of multiple cancer cell lines, supporting their potential roles as functional TSGs. Moreover, WDRX repressed WNT/beta-catenin signaling, underscoring a possible anti-tumorigenic mechanism for it. In addition, ADAMTS8 was revealed to inhibit clonogenicity of NPC and ESCC cell lines, acting as a negative modulator for ERK pathway and a potential pro-apoptotic metalloprotease. / Inactivation of tumor suppressor genes (TSGs) contributes to the genesis of cancers including esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC), two prevalent causes of death in Hong Kong. Apart from genetic abnormalities, epigenetic disruptions including CpG methylation represent another major mechanism for TSG inactivation. Promoter methylation of multiple TSGs was detected in different cancer types, suggesting that it could be utilized as therapeutic target or biomarker for disease diagnosis and prognosis. / TSGs are often located at frequently deleted chromosomal regions and subjected to tumor-specific methylation, making it possible to use an integrative epigenetic and genomic approach combining array comparative genomic hybridization (aCGH) with epigenetic profiling to screen for novel TSGs. Previous aCGH revealed that several loci in 11822.3, 15q14, 15q21.1 and 15q21.3 underwent frequent copy number loss in ESCC cell lines. Loss of heterozygosity (LOH) of these regions was also reported in other cancers, indicating that TSGs might reside within them. The aim of this study was thus to identify the candidate TSGs in these loci and study their anti-tumorigenic roles. In addition, the tumor suppressive function of ADAMTS8, a silenced 11q25 candidate TSG previously identified in our lab via this approach, was also studied. / Li, Jisheng. / Adviser: Qian Tao. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 136-159). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
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Anti-tumor mechanisms of cyclooxygenase inhibitors and a c-Jun-N-terminal kinase inhibitor in gastrointestinal cancersHe, Hua, 何華 January 2004 (has links)
published_or_final_version / abstract / toc / Medicine / Master / Master of Philosophy
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Promoter hypermethylation of tumor related genes in the progression of colorectal neoplasia.January 2005 (has links)
Bai Hsing Chen. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 89-94). / Abstracts in English and Chinese. / Acknowledgments --- p.ii / Publication --- p.iii / List of Abbreviations --- p.iv / List of Tables --- p.v / List of Figures --- p.vi / Abstract --- p.vii / 摘要 --- p.x / Table of Contents --- p.xii / Chapter Chapter 1 --- INTRODUCTION / Chapter 1.1 --- Molecular Biology in Cancer Development --- p.2 / Chapter 1.1.1 --- Cell Cycle and Cancer --- p.2 / Chapter 1.1.2 --- Oncogenes and Tumor Suppressor Genes --- p.4 / Chapter 1.1.3 --- Epigenetic Alteration in Tumor Cells --- p.6 / Chapter 1.2 --- Colorectal Cancer Development --- p.9 / Chapter 1.2.1 --- Epidemiology of Colorectal Cancer --- p.9 / Chapter 1.2.2 --- Adenoma-Carcinoma Sequence --- p.11 / Chapter 1.2.2.1 --- Hyperplastic (metaplastic) Polyps --- p.11 / Chapter 1.2.2.2 --- Aberrant Crypt Foci (ACF) --- p.13 / Chapter 1.2.2.3 --- Adenomas --- p.13 / Chapter 1.2.2.4 --- Serrated adenomas --- p.15 / Chapter 1.2.2.5 --- Colorectal Carcinomas --- p.16 / Chapter 1.2.3 --- Genetic alterations in CRC --- p.18 / Chapter 1.2.4 --- Epigenetic alterations in CRC --- p.21 / Chapter 1.2.5 --- Staging of Colorectal Cancer --- p.23 / Chapter 1.3 --- Hypothesis --- p.25 / Chapter 1.4 --- Aim of Study --- p.26 / Chapter Chapter 2 --- MATERIALS and METHODES / Chapter 2.1 --- Patient Populations --- p.28 / Chapter 2.2 --- Microdissection and Immunohistochemistry --- p.29 / Chapter 2.3 --- DNA Isolation and Modification --- p.31 / Chapter 2.3.1 --- DNA Extraction from Microdissected Tissues --- p.31 / Chapter 2.3.2 --- DNA Extraction from Frozen Biopsy --- p.31 / Chapter 2.3.3 --- Bisulfite Modification of DNA --- p.32 / Chapter 2.4 --- Detection of K-ras Mutation --- p.33 / Chapter 2.5 --- Methylation-specific PCR (MSP) --- p.36 / Chapter 2.6 --- Bisulfite DNA Sequencing --- p.42 / Chapter 2.7 --- Statistical analysis --- p.44 / Chapter Chapter 3 --- RESULTS / Chapter 3.1 --- Promoter Hypermethylation of Tumor Related Genes in the Progression of Colorectal Neoplasia --- p.46 / Chapter 3.1.1 --- Clinico-Pathological parameters --- p.46 / Chapter 3.1.2 --- "Frequencies of Promoter Hypermethylation in Colorectal Cancers, Adenomas and Normal Colonic Tissues" --- p.47 / Chapter 3.1.3 --- Promoter Hypermethylation in Multiple Genes --- p.50 / Chapter 3.1.4 --- Promoter Hypermethylation in Advanced vs. Non-advanced Adenoma --- p.50 / Chapter 3.1.5 --- Methylation Patterns in Paired Adjacent Tissues from Cancer Patients --- p.53 / Chapter 3.1.6 --- Immunohistochemistry --- p.55 / Chapter 3.1.7 --- K-ras mutation --- p.61 / Chapter 3.1.8 --- Clinicopathological Correlations with Promoter Hypermethylation --- p.64 / Chapter 3.2 --- DNA Methylation Spread within HLTF CpG Island in Colorectal neoplasia --- p.67 / Chapter Chapter 4 --- DISCUSSION / Chapter 4.1 --- Methylation is an early event in Colorectal Carcinogenesis --- p.72 / Chapter 4.1.1 --- Methylation is frequently detected in both adenoma and carcinoma --- p.74 / Chapter 4.1.2 --- Concurrent methylation in multiple genes --- p.76 / Chapter 4.1.3 --- Methylation in advanced and non-advanced colorectal adenomas --- p.76 / Chapter 4.1.4 --- Relationship between K-ras mutation and methylation --- p.78 / Chapter 4.1.5 --- Methylation in adjacent tissues --- p.80 / Chapter 4.2 --- DNA Methylation Spread in HLTF gene --- p.81 / Chapter 4.2.1 --- HLTF is Frequently Methylated in Gastrointestinal Neoplasm --- p.82 / Chapter 4.2.2 --- Methylation Spread Patterns in Cancers and Adenomas --- p.83 / Chapter 4.2.3 --- Age Dependent Methylation Spread --- p.85 / Chapter Chapter 5 --- CONCLUSION --- p.87 / References --- p.89
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Functional epigenetics identifies novel KRAB-ZNF tumor suppressors in ESCC, NPC and multiple tumors. / CUHK electronic theses & dissertations collectionJanuary 2010 (has links)
First, expression profiling of ZNFs with CpG islands at 10 clusters of Chr19 was examined in a panel of NPC and ESCC cell lines by semi-quantitative RT-PCR, with adult normal tissues - larynx and esophagus as controls. Several down-regulated genes were identified, and I further focused on 5 candidates: ZNF382, ZNF545, ZFP30, ZNFT1 and ZNFT2. These genes were frequently downregulated in NPC, ESCC, lung, gastric, colon and breast carcinomas. Their promoters were frequently methylated in multiple downregulated cell lines but less in non-tumor cell lines as revealed by methylation-specific PCR (MSP) and bisulfite genomic sequencing (BGS). Their expression could be restored by pharmacologic or genetic demethylation, suggesting that DNA methylation was directly involved in their silencing. The frequent methylation of these genes indicated they could act as potential biomarkers. / In conclusion, several novel candidate TSGs epigenetically silenced in tumor cells were identified in this study. Their downregulation by promoter methylation was tumor-specific, which could be use as epigenetic biomarkers for diagnosis. / More functional studies were done for ZNF382 and ZNF545, I found that ectopic expression of ZNF382 and ZNF545 in tumor cells lacking endogenous expression could inhibit tumor cell clonogenicity, proliferation and induce apoptosis. I found that ZNF382 suppressed tumorigenesis through mediating heterochromatin formation, as ZNF382 was revealed to be co-localized and interacts with heterochromatin protein. For ZNF545, I found that it is a transcriptional repressor. I further showed that ZNF545 was located in the nucleus and sequestered in the nucleolus. ZNF545 could inhibit tumorigenesis at least partially through downregulating the transcription of target genes or regulating nucleolus function such as ribosome biogenesis. / The development of a tumor from a normal cell is a complex and multi-step process. A large number of oncogenes, tumor suppressor genes (TSGs) and signal transduction pathways are involved in this process. Tumor-specific methylation of TSGs in multiple tumors indicated that it could be used as epigenetic biomarker for molecular diagnosis and therapeutics. / The functions of KRAB-containing proteins are critical to cell differentiation, proliferation, apoptosis and neoplastic transformation. A large number of ZNF genes are located in 10 clusters at chromosome 19. Some of the KRAB-ZNF may function as potential TSGs with epigenetic alterations. Thus, I try to identify silenced novel KRAB-ZNF candidate TSGs through screening chromosome 19. / Cheng, yingduan. / Adviser: Tao Qian. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 110-136). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
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Molecular genetics of colorectal cancer and its relevance to epidemiology in Chinese populationYuen, Siu-tsan, Thomas., 袁兆燦. January 2003 (has links)
published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine
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Functional study of the EBV-encoded RNAs (EBERs) in nasopharyngeal epithelial cellsWong, Hing-lok., 黃慶樂. January 2005 (has links)
published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy
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The role of Id-1 on the proliferation, motility and mitotic regulationof prostate epithelial cellsDi, Kaijun., 狄凱軍. January 2007 (has links)
published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy
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Potential oncogenic role of FOXGI in ovarian cancerTo, Man-yan., 杜汶欣. January 2007 (has links)
published_or_final_version / abstract / Obstetrics and Gynaecology / Master / Master of Philosophy
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