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    請使用永久網址來引用或連結此文件: http://libir.tmu.edu.tw/handle/987654321/59397


    題名: TMEM240基因在大腸直腸癌之甲基化及臨床相關性研究
    Methylation Alteration Analysis of TMEM240 Gene and Its Clinical Significance in Colorectal Cancer
    作者: 陳建宇
    Chen, Jian-Yu
    貢獻者: 林美香
    關鍵詞: TMEM240;大腸直腸癌;DNA甲基化
    TMEM240;colorectal cancer;DNA methylation
    日期: 2015-07-06
    上傳時間: 2020-08-19 16:21:24 (UTC+8)
    摘要: 背景: 台灣大腸直腸癌發生率位居十大癌症第一名，儘管非侵入性的大腸癌篩檢(例如:糞便潛血) 已逐漸普及，糞便潛血檢測受限於偽陽性、低敏感度和缺乏大腸癌專一性的結果，使得學者積極開發更精確的大腸癌篩檢方式，期望運用在臨床檢測上。DNA甲基化生物標記使用在大腸癌早期偵測已被廣泛研究，惟臨床上尚無大腸癌專一的生物標記。
    研究目的: 在目前研究我們已檢測大腸癌病患檢體，並分析在腫瘤組織和正常組織特定基因的DNA甲基化變異，抑癌基因啟動子CpG島異常的高度甲基化導致大腸直腸癌發生，開發新穎的抑癌基因和DNA甲基化生物標記有助於研究大腸直腸癌分子機轉異常及開發診斷和預後評估的方式。
    實驗設計: Illumina’s Infinium HumanMethylation450 BeadChip arrays檢測台灣26對大腸直腸癌病人癌症組織和正常組織挑選高度甲基化CpG位點。以Quantitative methylation specific real-time PCR (QMSP)，real-time RT-PCR (QPCR) 和免疫螢光染色實驗協助分析基因變異。同時比較西方國家The Cancer Genome Atlas (TCGA) 資料庫TMEM240基因甲基化變異。短暫轉染TMEM240基因或剔除內生性基因表現確認TMEM240基因在大腸癌細胞株的功能。
    結果: Methylation arrays確認TMEM240基因高度甲基化CpG位點。QMSP結果顯示有96.69% (146/151) 大腸癌病患TMEM240高度甲基化。TMEM240 mRNA低度表現比例66.67% (14/21)。在106位大腸癌病患TMEM240高度甲基化有較差的整體生存率 (p=0.027) 和腫瘤無復發死亡率 (p=0.012)。TCGA資料庫中腫瘤組織和正常組織TMEM240甲基化程度差異大，特別是基因啟動子及外顯子區域的CpG。短暫轉染TMEM240或剔除內生性TMEM240發現TMEM240抑制大腸癌細胞增生和爬行能力，誘導大腸癌細胞停滯在G1期。其蛋白質主要表現在細胞膜上與細胞質內。
    結論: 候選的TMEM240基因的其DNA甲基化變異是具潛力的大腸直腸癌早期偵測及癌症轉移與復發的生物標記。
    Background: Colorectal cancer (CRC) remains the most common cancer in Taiwan. Though noninvasive colorectal cancer screening such as fecal occult blood test has been widespread, its imprecise detection and false positive results restrain its potency. DNA methylation biomarkers for prediction of colorectal cancer have been extensively studied. Different panels have been reported, attempting to improve current implementation in clinical practice, although no definite biomarkers have been established.
    Purpose: In the present study, we have examined patient biopsies starting from a comprehensive analysis of DNA methylation differences between paired normal and tumor samples in known cancer-related genes, aiming to select the best performing candidates informative for CRC diagnosis in blood and stool samples. Aberrant promoter hypermethylation of CpG islands associated with tumor suppressor genes (TSGs) contributes to colorectal tumorigenesis. To characterize CRC and to develop new tools for diagnosis and prognosis, identifying novel critical TSGs and DNA methylation markers is mandatory.
    Experimental Design: HumanMethylation450 BeadChip arrays were used to
    identify novel hypermethylated CpG sites in 26 colorectal tumors and 26 paired non-neoplastic tissues. Quantitative methylation specific real-time PCR (QMSP), real-time RT-PCR (QPCR) and immunofluorescence analyses were performed. The Cancer Genome Atlas (TCGA) data set was used to analyze alteration of TMEM240 in western countries. Transient transfection of TMEM240 and/or si-TMEM240 was performed to verify the function of TMEM240 in colon cancer cells.
    Results: Methylation arrays were used to define highly methylated CpG sites in the TMEM240 gene. The QMSP revealed that 96.69% (146/151) of CRCs had hypermethylated TMEM240. TMEM240 mRNA expression was down-regulated in 66.67% (14/21). Hypermethylation of TMEM240 was associated with poor QS and recurrence free survival for 106 CRC patients (p = 0.027 & 0.012). DNA methylation differ greatly between paired normal and tumor samples in TMEM240 gene from TCGA data set, especially in promotor and exon 1 regions. Transient transfection of TMEM240 and/or si-TMEM240 found that TMEM240 inhibits colon cancer cell proliferation, migration and induces colon cancer cell arrest in G1 phase. TMEM240 protein was observed in cell membrane and cytoplasm.
    Conclusions: Methylation alteration in the candidate tumor suppressor gene TMEM240 is a potential marker for early prediction and prognosis.
    描述: 碩士
    指導教授:林美香
    委員:阮麗蓉
    委員:徐駿森
    委員:張偉嶠
    資料類型: thesis
    顯示於類別:[藥學系] 博碩士論文

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