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系統識別號 U0026-2806201111134800
論文名稱(中文) 利用生物資訊學暨實驗方法找尋並研究一個新穎腫瘤胚胎基因-LRRC16B
論文名稱(英文) Using a combined bioinformatics and experimental approach to identify LRRC16B as a novel oncofetal gene with transforming enhancing capability
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 徐中濟
研究生(英文) Chung-Chi Hsu
學號 s5892143
學位類別 博士
語文別 英文
論文頁數 105頁
口試委員 指導教授-何中良
口試委員-林聖哲
口試委員-賴明德
口試委員-劉校生
口試委員-錢宗良
口試委員-鄭永銘
中文關鍵字 腫瘤胚胎基因  生物整合資料庫 
英文關鍵字 oncofetal gene  Expressed sequence tags  LRRC16B 
學科別分類
中文摘要 在人類基因體計畫中,利用電腦軟體分析大量的基因庫資料並快速及極準確尋找有趣的基因,並且得到相關的資訊是目前生物資訊研究的一個主題。本實驗室則是利用Expressed sequence tags (EST) 作為一個基因資料庫,然後建構了一個具擴展性的生物整合資料庫(bio-database)。而本實驗室則是運用在找尋腫瘤發生相關的基因。之前的研究指出,腫瘤胚胎基因會在胚胎發育時會表現的基因在腫瘤發生的過程中會表現;而在正常的組織中表現量少或是不表現。所以我們想利用在這條件之下是否會找到更多符合的基因。基於此想法,本實驗室收集在網路上的EST資料庫並加以分類整理成本實驗室所需要使用的形式。分為三類:正常成年群、腫瘤群、以及未成熟群。以α-fetoprotein (AFP)在正常成人群的資料庫中所呈現數值(normal=10)當作為篩選基因的標準。經過一連串的運算;找到了73個基因。經由文獻查詢後;其中29個是已知功能的基因;44個是未知功能的基因。在29個是已知功能的基因中,五個屬於腫瘤胚胎的基因、三個屬於表現在特定組織中的基因、還有十二個則有些在控制胚胎發育或是在腫瘤發生的訊息傳遞中扮演重要角色的基因;其他有九個基因是都不符合上述條件的基因。LRRC16B利用RT-PCR以及Real-time PCR的表現結果顯示類似於腫瘤胚基因表現。為了確定LRRC16B為一個可以確實轉譯成蛋白的基因,本實驗室構築出可以表現全長的質體,並經由西方墨點法和螢光照相確認LRRC16B的大小以及在細胞的表現的位置。結果發現LRRC16B的確可以轉譯成蛋白並大量表現在細胞質中。在LRRC16B的生物功能方面,我們在293T 和BHK 細胞株上篩選了可以穩定表現LRRC16B-EGFP 融合蛋白的細胞株。本實驗室發現在穩定表現LRRC16B-EGFP以及LRRC16B-myc的細胞株經由增加cyclin B1的表現量而影響其生長速率。重要的是;在研究腫瘤轉型上;在soft agar中我們發現穩定表現LRRC16B-EGFP細胞株可以增加生長的數量以及增加colony 的體積;而在RNAi 的實驗中則得到把LRRC16B抑制之後則會影響細胞的生長以及transformation的能力。此外在活體xenograft中穩定表現LRRC16B-EGFP的細胞株可以增加腫瘤的體積以及重量。更有趣的是;LRRC16B在由酵母菌雙雜合系統、蛋白質體學、以及免疫螢光染色等分析得到LRRC16B是會與細胞骨架結合並且會影響細胞爬行或是侵襲的能力。由以上的結果顯示LRRC16B不但有類似腫瘤胚基因的表現型並且可能在腫瘤發生中扮演重要的角色。
英文摘要 The wide availability of human genome data has accelerated the use of computational tools to explore essential biological processes. Expressed sequence tags (ESTs) are randomly selected clones sequenced from cDNA libraries, and are a powerful tool to select the genes in which we are interested. Recent reports have indicated that embryos or fetuses genes may be re-expressed in cancer cells and down-regulated in normal adult cells. In order to screen for novel oncofetal genes systematically, we collected EST information from the NCBI databases, and divided the genes into three categories: mature group, the tumor group, and the immature group. We chose the values of α-fetoprotein (AFP) in the mature group (normal = 10) as the exclusion criteria. After a series of bioinformatic analyses; 73 candidate genes were found. By literature review, the final gene list included 29 genes with known functions and 44 genes with unknown functions In the 29 known genes, five were known oncofetal genes, three were tissue-specific genes or genes with limited tissue distribution, and twelve genes were related to oncogenesis or embryogenesis. Only nine genes did not have interesting expression patterns or functions. The functionally unknown genes were screened for their expression in cancer cell lines, normal tissues, tumor tissues and rat tissues. We also collected some human tumor/ non-tumor tissues derived from various organs such as ovarian cancer, hepatic cancer, and colon cancer to carry out gene analysis. One of the genes, LRRC16B, was found to be up-regulated in many tumors and had an oncofetal-like expression pattern. LRRC16B is a functionally unknown gene. In order to study the functions of LRRC16B, we cloned the full-length construct and established an HEK293T pool stably expressing LRRC16B-EGFP and LRRC16B-myc. Western blot experiments were carried out to confirm these constructs. After transfecting these constructs into HEK293T cells, the green fluorescent signal showed that the LRRC16B-EGFP fusion proteins were present diffusely in the cytosol, and formed dot-like structures in the nucleus. In our study, the biological function of LRRC16B, overexpression of LRRC16B-EGFP and LRRC16B-myc significantly increased cell growth by increasing the cyclin B1 expression of HEK293T stale pool cells. To investigate whether LRRC16B affected cell tumorigenesis, we performed colony formation assays and xenografts. LRRC16B overexpression in an HEK293T pool stably expressing LRRC16B-EGFP fusion proteins resulted in increased colonogenicity and tumorigenesis. In an RNAi experiment, knockdown LRRC16B inhibited cell proliferation and transformation in an ovarian tumor cell line, BG-1. More interestingly, using a yeast two-hybrid system, proteomic analysis, and immunocytochemistry, we observed that LRRC16B seemed to interact with the cytoskeleton. LRRC16B affected cell migration and invasion. Therefore, LRRC16B is not only an oncofetal-like gene expression pattern, but also may play an important role in carcinogenesis.
論文目次 Content
Abstract………………………………………………………………………………….1
Chinese……………………………………………………………………………….1
English………………………………………………………………………………..2
Acknowledgement.............................4
Content.................................6
Abbreviation……………………………………………………………….....................11
Introduction………………………………………………………………......................14
Oncofetal genes/proteins.........................15
AFP: α-fetoprotein................................15
β-HCG: Human chorionic gonadotropin.............16
GPC3: Glypican 3...........................16
H19……………………………………………………….……...........................17
IMP family: IGF2 mRNA-binding protein……………….....…........18
HMGA2: High mobility group A2 …….………………...….......19
How to find interesting oncofetal genes? ...............19
Expressed sequence tags: EST …………………..……..........21
Materials and methods……………………...………………............23
Bioinformatic analysis……………...…...………………………....23
Cell cultures ......................24
Animal and tissue specimens………………………………………………………..23
Animals…………………………………………………………………………...25
Tissue samples………………………………………………………………..…..25
RNA analysis………………………………………………………………………..26
RNA preparation……………………………………………………………….....26
RT-PCR……….……………..26
Real–time PCR…………….…………………..29
Northern blot……………………………………………………………………...29
Full-length and siRNA plasmid construction and generation of stable clones……...29
Generation of full length LRRC16B expressed plasmids.. 29
Generation of LRRC16B shRNA expressed plasmids…………………………30
Transient transfection…………………………………………………………….30
Generation of LRRC16B full length and shRNA stable clones…31
Western blot, Mass spectrometry, Immunoprecipitation, Immunohistochemistry, and Immunocytochemistry……………………31
Western blot………………………………………………………………………31
Immunoprecipitation, IP………………………………………………………….32
Mass spectrometry………………………………………………………………..33
Silver Stain…………………………………………………………………….33
Immunohistochemistry………………………………...…………………………34
Immunofluoresence………………………………………………………………34
In vitro and in vivo growth properties analysis…………………….35
XTT proliferation assay…………………………………………………………..35
BrdU incorporation assay………………………………………………………...35
DNA content analysis…………………………………………………………….35
Migration assay…………………………………………………………………...36
Wound healing assay…………………………………………………………..36
Transwell migration assay……………………………………………………..36
Invasion assay…………………………………………………………………….37
Soft agar assay……………………………………………………………………37
Induction of Tumor Xenografts in Mice………………………………38
Statistics………………………………………………………………………….…..38
Results……………………………………………………………………………………39
Bioinformatic analysis of the EST database for oncofetal genes…….........................39
RT-PCR screening of the unknown genes for potential oncofetal expression patterns………………………………………………….…….39
Downregulation of LRRC16B in adult tissue……………………....…..40
Expression of LRRC16B at different developmental stages in rat…………….……..41
Expression of LRRC16B in ovarian, hepatic, and colorectal cancers………………..42
LRRC16B gene cloning, sequence analysis, and in vitro expression..42
LRRC16B promotes cell proliferation in 293T cells………………………43
Knocking down endogenous LRRC16B inhibited proliferation……44
Transforming potential of LRRC16B in vitro and in vivo…………46
Distinct Roles for LRRC16B in Cell Migration……………………………….47
Cytoskeleton may interact with LRRC16B………………………………………..…48
Disscussion……………………………………………………………………………….49
Conclusion……………………………………………………………………………….55
Reference…………………..………………………………………….57
Tables…………………..…………………………………………………………….68
Figures…………………..…………………………………………………………….77
Author…………………..…………………………………………………………….105
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