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研究生:張世慶
研究生(外文):Shih-Ching Chang
論文名稱:基因不穩定及粒線體改變在大腸直腸癌癌化過程的角色
論文名稱(外文):Genetic Instability and Mitochondrial Alteration in Colorectal Carcinogenesis
指導教授:戚謹文林楨國林楨國引用關係
指導教授(外文):Chin-Wen ChiJen-Kou Lin
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:149
中文關鍵詞:大腸直腸癌染色體不穩定微衛星不穩定缺氧粒線體
外文關鍵詞:colorectal cancerchromosomal instabilitymicrosatellite instabilityhypoxiamitochondria
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背景:在西方國家大腸直腸癌高居癌症死亡率第二位,在台灣,大腸直腸癌為發生率及死亡率第三高的癌症,在過去幾年的研究,一般認為大腸癌的癌起源(carcinogenesis)可以有二主要途徑:1.染色體不穩定,約有60∼90%大腸癌會出現染色體不穩定,這一類的癌症特性在於有較差的預後,及和抑癌基因缺失有關。2.微衛星不穩定現象。微衛星不穩定現象,係因DNA修補蛋白質失去功能造成,約有10∼15%大腸癌有如此現象。和結腸癌病人預後關係最密切的就是癌是否轉移。由於轉移的過程非常的複雜,因此被認為應包含了累積許多調控生長,組織穩定性的基因改變。另一方面,腫瘤中新生的血管有嚴重的功能及結構的缺陷,造成血液供應不足而逐漸產生病態的生理環境包括低氧環境。 缺氧環境可以篩選出一些細胞凋亡基因有缺損的細胞。半世紀前,Warburg即提出癌細胞利用能量的方式以糖解作用(Glycolysis)產生ATP為主和正常細胞以粒線體氧化磷酸化(Oxidative phosphorylation)為主有所不同。本論文所探討的是: 1. 以分子生物學方法來分類大腸直腸癌及探討此分類和預後的關係粒線體DNA含量的變化和大腸直腸癌疾病進程的相關性。3. 在低氧環境下培養的結腸癌細胞具有較多的基因改變,粒線體改變及較強的侵襲能力。
實驗材料及方法:分為臨床及實驗驗證二大部份。臨床部份:本論文自1999年1月到2000年12月,共收集了213位在台北榮總直腸外科手術的大腸直腸癌患者。癌症組織於手術取下後,清洗乾淨,取四個不同象限的組織以減少癌症的不均質性(heterogeneity),另外取下附近離腫瘤10公分以上的正常組織,萃取DNA進行Loss of heterozygosity (LOH)及Microsatellite instability (MSI)分析,流式細胞儀分析染色體套數的改變,及細胞內粒線體DNA 拷貝數之定量。體外實驗部份:(1)在1﹪氧氣環境下培養HCT116(野生型p53)。經至少二十次繼代培養,挑選具抵抗缺氧能力之細胞。(2)以比較基因雜交法(Comparative genomic hybridization)來比較基因缺損情形。(3)以定量PCR決定粒線體DNA的量。(4)以流式細胞儀測定粒線體質量,膜電位變化,及活性氧分子的量。(5)分析和粒線體相關的蛋白質變化。(6)分析缺氧狀態前後細胞株侵襲能力。
結果:臨床部份:在流式細胞儀的分析中,有71例為雙套染色體佔1/3。而142例為異套染色體佔2/3。高比率微衛星不穩定的有19例,佔全部病例8.9%。p53基因的突變有96例,佔45.1%。89例出現Ki-ras突變(41.8%),其中大部分發生在codon 12 (71/89,79.8%), BRAF出現突變的機率為4.23%,共9例。在19例MSI-H腫瘤的臨床病理特性1.年紀較輕(57歲);2.右側居多(31.6%);3. 分化較差(26.3%);4. mucin產生較多,而在分子生物分析中,MSI-H腫瘤有較高BRAF突變,及較少LOH (1.6 ± 1.0)。根據染色體套數的結果,可以將微衛星穩定的腫瘤,分為MSS-diploid及MSS-aneuploid兩類,其中MSS-diploid有56例,MSS-aneuploid有138例。而MSS-diploid的腫瘤特性為分化較差(14.3%),右側比例多(26.8%),較類似於MSI-H腫瘤。而MSS-aneuploid的分子特性為p53突變多(58%)及LOH頻率高(2.5 ± 1.5)。在LOH的分析中,在11個標記中有170例出現至少1個LOH。在第一期大腸癌中,每個腫瘤出現1.68個LOH (23%),到了第四期則為2.88個LOH (48%)。利用定量PCR的方法來測量腫瘤及其附近正常組織的粒線體DNA量,在153個腫瘤組織中,粒線體DNA拷貝數為981±1564 (95% CI為731-1231),明顯高於正常組織的593±723 (95% CI為477-408),在22個第一期癌症中,腫瘤的mtDNA拷貝數為正常組織的3.43倍。而在33例第四期癌症中則下降為1.28倍。而和4年總存活率及無疾病存活率有關的有:癌症分期;癌指數(CEA); p53突變及較多的LOH。而粒線體DNA拷貝數變化和病人預後相關性較低。
實驗驗證部份:經低氧環境培養下的細胞出現細胞大小不一致,形狀不規則,顆粒性增加。在CGH 分析中,低氧培養下的細胞出現11q13, 12q24.2-24.3, 14q32, 及17p13增加的現象。在這些DNA拷貝數增加的位置中,本論文發現低氧培養的細胞中,fibulin-4的mRNA明顯較對照組增加。粒線體DNA拷貝數變化 由原來細胞的7920 下降為低氧培養細胞的 820 。蛋白質的表現則為:HSP60及β-F1-ATPase下降為原來細胞的10%及5%。 而GAPDH 則上升為原來細胞的 500%。但以流式細胞儀測粒線體質量的結果則是低氧培養細胞為原來的2.5倍。粒線體膜電位及活性氧分子為原來的2-3倍。 低氧培養的細胞內ATP含量僅為對照組的三分之一。利用穿透式電子顯微鏡發現低氧培養細胞的粒線體喪失了crista,呈現空泡狀。而在Matrigel的分析中,發現細胞侵襲能力由原來的 5% 上升為 8%。
結論:基因不穏定及粒線體功能的改變在大腸直腸癌的癌形成佔有相當重要的角色。
Background: Colorectal cancer is the third most common cancer in Taiwan. It has been suggested that destabilization of the genome may be a prerequisite early in carcinogenesis. This "mutator phenotype" is best understood in colorectal cancer, in which there are two separate destabilizing pathways. The more common of these mutational pathways involves chromosomal instability, characterized by allelic losses (loss of heterozygosity). In the second mutational pathway, colorectal cancers display increased rates of intragenic mutation, characterized by generalized instability of short, tandemly repeated DNA sequences known as microsatellites. The most important prognostic factor in CRC patients is tumor metastasis. Tumor hypoxia has been associated with treatment resistance, poor outcome, increased invasiveness, and enhanced metastatic potential. Over half a century ago, Warburg proposed that cancer cells undergo mitochondrial respiratory alterations by converting glucose to lactate, via the reduction of pyruvate. Mitochondria play important role in apoptosis, production of ROS and energy provider. Impairment in mitochondria respiratory function not only reduces the supply of energy, which may prevent energy-dependent apoptosis, but also enhances ROS production that may induce mutation and oxidative damage to mitochondria DNA(mtDNA) In this study I will describe the molecular profiles of sporadic colorectal cancer and clarify the relationship between molecular profiles and prognosis of CRC patients. Second, I will explore the change of mtDNA copy number in colorectal cancers. Third, I make a hypothesis that microenvironment of CRC such as hypoxia might promote more genetic change, and alteration of mitochondria, further more aggressive behavior of tumors.
In the clinical analysis: A total of 213 colorectal tumors who received tumor resection in Taipei-Veterans General Hospital since 1999 were collected for analysis of DNA ploidy, MSI, loss of heterozygosity (LOH), mutation of p53 (exons 5 to 9), Ki-ras (exons 1 and 2), and BRAF (V599E). MSI-H existed in 19 tumors (8.9%), which were more likely to be right-sided (31.6%) with poor differentiation (26.3%).71 (33.3%) tumors were diploid and 142 (66.7%) were aneuploid. Mutations in p53, Ki-ras and BRAF were found in 45.1%, 41.8% and 4.2% of tumors, respectively. Based on MSI, and CIN, three classes were defined: 1) MSI-H tumors: young age, high CEA level, right colon, poorly differentiated, mucin production, high BRAF mutation, lower allelic loss and relatively good prognosis; 2) MSS diploid tumors: right colon, poorly differentiated, less infiltrative tumor, mucin production, lower allelic loss, and low p53, BRAF mutation; 3) MSS aneuploid tumors: more infiltrative invasion, greater allelic loss, and high p53 mutation. According to multivariate analysis, tumor stage and p53 mutation were significantly associated with disease progression. The MSS diploid and MSS aneuploid CRCs could be subtyped with p53 mutation and had different prognostic outcome and molecular profiles.
Mitochondrial DNA copy number (mtDNA) was analyzed in a total of 153 colorectal tumors by real-time PCR. Of the stage I disease, the mtDNA copy number in cancer tissue was 3.43 times of those in normal mucosa, but decreased to 1.28 in stage IV disease. In the meantime, the frequency of LOH increased from 25% to 48%. In the multivariate analysis, change of mtDNA copy number was not an independent prognostic factor. Therefore it is concluded that as the disease progression of colorectal cancer, more genetic change developed, in contrast that mtDNA copy number decreased.
In the in-vitro experiment, this study established a hypoxia model. The derived cells were collected for analysis of genomic change, mitochondrial change, adaptation of energy use, and invasiveness of cells. After at least 20 passages, the morphology of the derived cells became irregular, and the glandularity increased. Also the cells became smaller with various sizes. The hypoxia treated cells had more aberration in CGH result including the gain of 11q13, 12q24.2-24.3, 14q32, and 17p13. By matrigel analysis, in the hypoxia condition, the invasiveness of the HCT116 cells (control) was 5.16% and significantly lower than the hypoxia treated HCT116 cells 7.94% (p=0.004).Western blot analysis of expression Hsp60 in hypoxia treated HCT116 cells revealed a 90% decrease in this structural mitochondrial protein relative to controls. A highly significant down-regulation of the β-F1-ATPase protein in hypoxia treated cells was also found when compared with the controls (5.4% vs. 100%). In the hypoxia treated cells, the mtDNA level was 820 and it was only one-tenth in controls (7920; P <0.001). In contrast, a highly significant up-regulation of the glycolytic GAPDH was found as compared with the controls. Flow cytometry with NAO-stained hypoxia treated cells and controls indicated that the average fluorescence emission in hypoxia treated cells was 3 folds of that in controls. The mitochondrial membranous potential (MMP) in hypoxia-treated cells was 2.5 and 3.1 folds in controls by flowcytometry with rhodamine123 and JC-1 stain. Also the concentration of ROS was determined by DCFH-DA fluorescence, ROS production in hypoxia treated cells was 2.65 folds in controls, which is in parallel to elevation of MMP. The intracellular ATP production in the hypoxia treated cells was only one-third of controls (p<0.01). Furthermore transmission electron microscopy demonstrate that hypoxia treated cells appeared to have loss of cristae patterns with empty or ‘ghost like’ mitochondrial scaffolding.
Conclusion: The results obtained from clinical data together with experimental evidence suggested that the genetic alteration and mitochondrial change were associated with disease progression of colorectal cancer. These changes seemed to be associated with tumor hypoxia.
目錄
中文摘要……………………………………………… 1-4
英文摘要……………………………………………… 5-7
縮寫表………………………………………………… 8,9
壹、緒綸
癌生成(carcinogenesis)的模式…………………… 10
分子醫學及基因的證據……………………………… 10-16
細胞遺傳學的證據…………………………………… 17,18
低氧環境造成癌轉移的可能機制…………………… 19-21
粒線體與癌症………………………………………… 22-25
粒線體和細胞凋亡…………………………………… 26,27
貳、研究目的………………………………………… 28
参、實驗藥品與材料………………………………… 29-32
肆、儀器……………………………………………… 33,34
伍、實驗方法與步驟………………………………… 35-53
陸、結果
一、以分子生物學方法來分類大腸直腸癌及探討此
分類和預後的關係…………………………………… 54-56
二、粒線體DNA的改變和大腸直腸癌分期的關係… 57,58
三、低氧造成基因改變,粒線體功能改變的模式… 59-63
柒、討論……………………………………………… 64-73
捌、結論……………………………………………… 74
玖、參考文獻………………………………………… 75-90
拾、圖表……………………………………………… 91-129
拾壹、附錄…………………………………………… 130-149
玖、參考文獻
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