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博碩士論文 etd-0125106-030141 詳細資訊
Title page for etd-0125106-030141
論文名稱
Title
細胞週期相關基因在人類食道鱗狀上皮細胞癌發生機轉之角色探討
The Role of Cell Cycle Associated Genes in Carcinogenesis of Human Esophageal Squamous Cell Carcinoma
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
115
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2006-01-10
繳交日期
Date of Submission
2006-01-25
關鍵字
Keywords
癌化機轉、基因、細胞週期、食道鱗狀上皮細胞癌
Esophageal Squamous Cell Carcinoma, Carcinogenesis, Genes, Cell Cycle
統計
Statistics
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中文摘要
食道癌是上消化道惡性腫瘤中常見的癌症,在所有食道惡性腫瘤中,食道鱗狀上皮細胞癌與食道腺細胞癌是兩大主要的組織細胞形態,儘管在過去的二十年中,食道腺細胞癌的發生率在西方國家有快速攀升的現象,目前食道鱗狀上皮細胞癌依舊是世界上最常見的食道癌組織細胞形態。在臺灣,食道癌佔據國人癌症死亡原因的第九位的位置,也是男性癌症死亡原因的第六位。在所有食道癌的治療方式中,外科手術依舊是治療食道癌患者最主要的方式,在食道癌患者接受外科手術治療預後的研究中顯示,食道癌患者接受手術切除治療後,其五年的平均存活率大約維持在20%左右。然而,這些相關研究的結果大多都是將不同細胞形態的食道癌的患者全部包括在內加以分析比較。因此,外科手術的治療方式對於食道鱗狀上皮細胞癌患者所帶來的風險與助益,目前並無廣泛的研究與明確的結論。
為了探討外科手術治療在食道鱗狀上皮細胞癌患者預後上所扮演的角色以及不同的手術方式對食道鱗狀上皮細胞癌患者所造成的影響,本研究以回溯性的方式從1991到2003年,總共收集了166個接受剖胸式食道切除術(Transthoracic esophagectomy)及50個接受剖腹式食道切除術(Transhiatal esophagectomy)治療的病患加以分析比較。所有患者的住院死亡率是7.9%,術後併發症的發生率為49%,手術治療後的五年存活率是16.8%。剖腹式食道切除術所需的手術時間顯著地短於剖胸式食道切除術的手術時間(p<0.001)。然而,兩種手術方式的手術死亡率、術後併發症發生率、平均住院天數、術中失血量與輸血量,以及五年存活率彼此之間並無顯著性差異。傳統採用之腫瘤分期系統(TNM)僅對接受剖胸式食道切除術治療的患者具有預後預測的效果,對於接受剖腹式食道切除術治療的患者而言,腫瘤的位置(Middle vs. upper/lower; p=0.0085)與腫瘤的長度(> 5cm vs. < 5cm; p=0.0118)則具有顯著地預後評估的效果。從上述的研究結果發現食道鱗狀上皮細胞癌患者即使接受手術治療後,其治療效果仍然令人非常的沮喪,因此如何有效預防此一腫瘤的發生將是延長患者壽命的重要課題之一。
在許多流行病學的研究結果中顯示,食道鱗狀上皮細胞癌的發生具有非常明顯的地區分布的差異性,此一地區分布的差異性反映著不同環境中某些特殊的環境因子在食道癌的發生上扮演著重要的角色,然而目前對於這些致病因子的瞭解卻是非常的有限。在臺灣最近發現,除了吸煙、喝酒以外,嚼食檳榔的習慣與食道鱗狀上皮細胞癌的發生具有顯著的相關性,然而嚼食檳榔在食道鱗狀上皮細胞癌發生過程中的作用機轉到目前為止還不是非常的瞭解。過去在口腔癌的相關研究報告中曾經指出,嚼食檳榔與口腔癌組織中p53基因變異的發生具有顯著的相關性,為了瞭解嚼食檳榔與食道鱗狀上皮細胞癌組織中p53基因變異發生彼此間的相關性,我們在216位接受手術治療的食道癌患者中,收集了75例原發性食道鱗狀上皮細胞癌患者的組織標本,運用聚合酵素連鎖反應技術與直接定序的方法分析比較食道癌組織中p53基因突變的情形,結果顯示,總共有37個p53基因的變異發生在45.5% (34/75)的組織標本中,這些變異多發生在p53基因exon 5 (21/37)的區域。而p53基因變異的發生與病患的臨床相關特性、組織病理診斷、病患的預後、患者抽煙與喝酒習慣等等相關因子間沒有顯著的相關性。可是在有吃檳榔習慣的食道鱗狀上皮細胞癌患者的食道癌組織中,p53基因發生變異的機率遠高於沒有吃檳榔習慣的患者(67.6% vs. 32.4%, p=0.007)。若是將煙、酒等與食道癌發生有關的危險因子加以控制後再加以分析比較,依舊可以發現食道癌組織中p53基因發生變異的機率與患者是否有吃檳榔的習慣間存在著顯著的相關性(RR=4.233; 95% CI, 1.317-13.603)。此外,我們發現A:T to G:C transition (8/37, 21.6%) 與 G:C to T:A transversion (6/37, 16.2%)的基因變換是食道鱗狀上皮細胞癌組織中最常見的兩種p53基因變異型態,其中所有A:T to G:C transition的變異型態都發生在同時具有抽煙及吃檳榔習慣的患者身上。值得注意的是,喝酒習慣會增加食道癌組織中此一特殊變異型態發生的機會。綜觀以上的結果可以發現,p53基因在臺灣食道鱗狀細胞癌中發生突變的機率非常的高,而且p53基因可能是檳榔中相關致癌成分引發產生食道鱗狀細胞癌作用機轉中的主要分子標的物之一。
對於p53基因在臺灣食道鱗狀細胞癌組織中發生突變的狀況有了初步了解後,我們便再進一步探討食道鱗狀細胞癌組織中p53基因的突變與細胞週期調控相關基因間的相關性,以及這些基因的改變對食道鱗狀上皮細胞癌患者預後的有何影響?於是,利用其中40位食道鱗狀上皮細胞癌患者急速冷凍的組織標本以及蠟塊包埋組織分析食道癌組織中細胞週期分布的狀況、細胞中去氧核醣核酸含量的改變情形、及p16、pRb、p21waf1/cip1、p53等細胞週期相關基因蛋白質的表現情形、以受比較p53基因變異與p21waf1/cip1和p53蛋白表現間的相關性。在這一部分的研究中發現,腫瘤組織中細胞週期的S-phase有非常顯著的增加,在75%腫瘤組織中的去氧核醣核酸的含量呈現單倍套數(aneuploidy)。另外在免疫染色實驗中發現,62.5% (25/40)的癌組織中可偵測到p53蛋白的表現,p21waf1/cip1蛋白則可在50%的癌組織中偵測得到,但p16蛋白在80%的腫瘤組織中無法偵測到,而直得注意的是pRb蛋白幾乎可在所有的癌組織中偵測得到。基於pRb蛋白被視為抑癌蛋白的一種,卻能表現在所有的癌組織中,此一結果非常令人好奇,因此在對pRb磷酸化的情形作更進一步分析研究後,發現所有癌組織中的偵側到的pRb蛋白皆為磷酸化狀態的蛋白,此結果顯示pRb在食道鱗狀細胞癌組織中,在功能上是處於無法抑制癌細胞的細胞週期進行的狀態。
然而,p16、p21waf1/cip1及pRb蛋白的表現情形與p53基因變異的發生,彼此間沒有顯著的相關性。但是,p21waf1/cip1蛋白過度的表現卻與腫瘤組織中單倍套數去氧核醣核酸含量呈現的異常狀態彼此間存在著顯著的相關性(p=0.028)。在單變項分析中,晚期的癌病變、淋巴腺的轉移以及p21waf1/cip1蛋白過度的表現,呈現出是食道癌患者不良預後的重要指標(p值分別是0.013, 0.045 及 0.017) 。在多變項的分析中,癌症分期(IIB/III/IV vs. I/IIA; p=0.024)與p21waf1/cip1蛋白過度的表現(positive vs. negative; p=0.035)卻是食道癌患者顯著獨立的預後評估因子。令人驚訝的是,在p53基因發生突變的狀況下,p21waf1/cip1蛋白的過度表現會顯著性的降低食道癌患者的存活率(p=0.035),可是當p53基因沒有發生突變時,p21waf1/cip1蛋白的過度表現所產生的不良效應即不復存在(P=0.175)。由上結果吾人可知在某些食道鱗狀上皮細胞癌患者身上,食道癌組織中的p21waf1/cip1蛋白過度表現與染色體的不穩定性有顯著的相關性,而p21waf1/cip1蛋白的過度表現所產生的不良預後的效果與p53基因變異的發生有顯著的相關性。
由於在細胞進行分裂與增長過程中DNA是不可或缺的重要元素,而在DNA的合成途徑上Ribonucleotide Reductase(RNR)卻是負責提供DNA合成所需原料dNTP合成過程中不可缺少的酵素蛋白。一般所知,Ribonucleotide Reductase是由RRM1與RRM2兩次單元聚合而成的酵素蛋白。研究發現RRM2的表現與RNR功能的強弱、腫瘤細胞的侵襲性及抗藥性有關。最近又在人類細胞中發現一種與RRM2功能相似的蛋白,p53R2,此一蛋白可受p53的調控,參與細胞中受損基因的修復工作,然而此一蛋白在p53發生突變後的腫瘤細胞中所扮演的角色為何?目前並不是非常的清楚。為了進一步探討Ribonucleotide Reductase、RRM2與p53R2在癌組織中表現的情形,於是在這一部份的研究中,收集了85位食道鱗狀上皮細胞癌患者的組織加以分析,發現Ribonucleotide Reductase含量在食道鱗狀上皮細胞癌組織中有異常之表現。在94.1% (80/85)的食道鱗狀上皮細胞癌組織中可偵測到RRM2蛋白的表現,而p53R2僅在55.3% (47/85) 的食道鱗狀上皮細胞癌組織中被偵測到,p53R2蛋白的表現與食道癌患者不良預後的結果有顯著的相關性。
基於上述之結果發現,食道鱗狀上皮細胞癌組織中細胞週期相關基因功能異常的表現在食道鱗狀上皮細胞癌的發生上扮演者非常重要的角色,而食道鱗狀上皮細胞癌組織中RRM2與p53R2特殊的表現狀態,將有助於日後設計有效的相關基因療法,運用在食道鱗狀上皮細胞癌患者的治療上,增加食道鱗狀上皮細胞癌患者的存活率。
Abstract
The esophageal squamous cell carcinoma (ESCC) is known to be one of the most difficult malignancies to treat among digestive carcinomas. The esophageal squamous cell carcinoma and adenocarcinoma are the two most common cell types of esophageal cancer in the world. Even though the incidence of esophageal adenocarcinoma has been dramatically increasing in Western populations during the past two decades, esophageal squamous cell carcinoma remains the predominant type of esophageal malignancy in the remainder of the world. In Taiwan, ESCC is the ninth leading cause of cancer deaths, the 6th among male. In spite of advances in surgical techniques and perioperative management in recent decades, current modalities of therapy for this disease still offer poor survival and cure rates. Even in resectable diseases, the 5-year survival rates were only less than 20%. Recently, esophageal squamous cell carcinoma and adenocarcinoma were increasingly recognized as two entities with different biologic behavior and outcome. Consequently, the surgical risks and oncologic benefits of esophagectomies for esophageal squamous cell carcinoma patients are controversial and not confessed.
From 1991 to 2003, 216 esophageal squamous cell carcinoma patients underwent esophagectomy were enrolled and analyzed retrospectively. Among these patients, 166 patients underwent transthoracic esophagectomy and 50 patients underwent transhiatal esophagectomy. The overall hospital mortality and postoperative complication rates were 9.7% and 49%, respectively. The overall 5-year survival rate was 16.8%. The hospital mortality rate, postoperative complication rate, length of hospital stay and amount of intra-operative blood loss or transfusion were not significantly different between both groups. But, shorter operative time was noticed in transhiatal group (p<0.001). Patients underwent either transthoracic or transhiatal esophagectomy had comparable long-term survival. The pTNM stage was independent prognostic factors for patients underwent transthoracic esophagectomy. However, location of tumors (p=0.0085) and pathologic tumor length (p=0.0118) were significant predictors for patients underwent transhiatal esophagectomy. In this part of study, we found that both transthoracic and transhiatal esophagectomies could provide comparable survival benefits for esophageal squamous cell carcinoma patients. However, the traditional pTNM staging system might underestimate the severities of ESCC patients who underwent transhiatal esophagectomy.
Due to the dismal results of ESCC patients after surgery and the findings of multi-environmental and/or genetic factors involved in the carcriogenesis of ESCC, further realizing the molecular mechanisms of carcinogens in the development of esophageal squamous cell carcinoma is crucial for prevention and treatment for this disease. Epidemiological analysis showed that the prevalence of esophageal squamous cell carcinoma varied in different geographic areas. The various prevalence of disease in different parts of the world reflects different forms and extents of exposure to these etiological agents involving the development of this disease. In stead of tobacco and alcohol, recent reports indicated that betel quid (BQ) chewing also significantly correlated with the occurrence of esophageal squamous cell carcinoma in Taiwanese. The mechanisms behind the BQ-related esophageal squamous cell carcinoma in Taiwan are worthy for further investigation. Previous studies have shown that certain carcinogens may induce a “fingerprint-like” – like pattern of mutations at the p53 gene, both in terms of mutation type and codon specificity. However, the role of p53 mutation in the etiology of esophageal squamous cell carcinoma has not been rigorously studied in Taiwan. The incidence of p53 mutations in ESCC associated with risk factors has not been explored in Taiwanese. Accordingly, 75 primary esophageal squamous cell carcinoma specimens were collected for examining the incidence of mutations in the conserved regions of p53 gene by using polymerase chain amplification and direct sequencing of amplified products. There were 37 mutations of p53 gene detected in 45.5% (34/75) of tumor specimens. These mutations significantly clustered in exon 5 (21/37) of p53 gene. The incidence of p53 mutations didn’t associate with clinicopathological characteristics and habits of cigarette smoking or alcohol drinking. However, BQ chewer exhibited significantly higher incidence of p53 gene mutations than non-chewer (67.6% vs. 32.4%, p=0.007). After controlling confounding factors of cigarette smoking and alcohol drinking, BQ chewing still showed significant impact on the incidence of p53 mutation in esophageal squamous cell carcinomas (RR=4.233; 95% CI, 1.317-13.603). The A:T to G:C transition (8/37, 21.6%) and G:C to T:A transversion (5/23, 13.5%) were the prevalent spectrum of p53 gene mutations. All A:T to G:C transitional mutations occurred in patients with habits of betel quid chewing and cigarette smoking. Noticeably, alcohol drinking could enhance this peculiar spectrum of p53 mutation in esophageal squamous cell carcinoma. Therefore, p53 gene might be one of the molecular targets of betel quid carcinogens in the development of esophageal squamous cell carcinoma in Taiwanese. Determination of the importance of p53 gene mutation in ESCC requires further study.
To elucidate the role of cell cycle associated genes in ESCC, 40 primary esophageal squamous cell carcinoma patients were included in this part of study. Tissue samples were analyzed for cell proliferation, DNA content, mutation of p53 gene, and expression of p16, p21waf1/cip1, pRb and p53 proteins. In this part of study, 75% of tumors exhibited aneuploid DNA content. Significantly higher S-phase fractions were detected in tumor samples (p<0.001). The p53 immunostaining was detected in 62.5% (25/40) of tumor tissues and 50% of tumors were p21waf1/cip1 overexpression. The p16 protein was only detected only in 8 of the 40 ESCC (20.0%) tissue samples by immunohistochemistry. The nucleus stained Rb protein was detected in 38 ESCC tissue samples and all of them were phosporylated status. The phosphorylation of pRb at Ser-795, Ser-789 and Ser-807/811 was detected in 87.5% (35/40), 72.5 (29/40) and 42.5% (17/40) of ESCC tissue samples, respectively. Expression of p16 protein, total pRb or phospho-Rb expression status did not correlate with the clinicopathological parameters of patients. The overexpression of p21waf1/cip1 protein didn’t correlate with p53 gene status, but significantly correlated with the existence of abnormal DNA content (P=0.028). Advanced pTNM stage, lymph node metastasis and p21waf1/cip1 overexpression conferred survival disadvantages in univariate analysis (P=0.013, 0.045 and 0.017, respectively). A Cox multivariable analysis revealed pTNM stage (IIB/III/IV vs. I/IIA; p=0.024) associated with p21waf1/cip1 overexpression (positive vs. negative; p=0.035) as independent prognostic factors in esophageal squamous cell carcinomas. Surprisingly, p21waf1/cip1 overexpression significantly compromised the survival of patients with mutated p53 gene (p=0.035). However, no significant dismal effect of p21waf1/cip1 overexpression can be seen in patients with wild-type p53 gene (P=0.175). Consequently, overexpression of p21waf1/cip1 is correlated with chromosomal instability and serves as an adverse prognostic predictor for esophageal squamous cell carcinoma patient. Its dismal effect is more prominent when p53 gene is mutated.
The ribonucleotide reductase (RNR) is an S phase-specific dimeric enzyme and is the rate-limiting enzyme of DNA synthesis pathway responsible for the reduction of all four ribonucleotides to their corresponding deoxyribonucleotides (dNTPs), which are the building blocks for DNA replication and repair in all living cells. The RNR enzyme was formed by the association of RRM1 and RRM2 subunits. Normally, the levels of RRM2 expression modulate the RNR enzymatic activity. However, RRM2 also plays an important role in other aspects of the malignant phenotype such as tumor development and drug resistance. Recently, the p53-inducible ribonucleotide reductase small subunit homologue, p53R2, has been isolated and shown to play a crucial role in DNA repair after DNA damage. However, the function of p53R2 is still unclear especially in tumor cells. By immunohistochemistry, the expression of RRM2 and p53R2 proteins were detected in 94.1% (80/85) and 55.3% (47/85) of ESCCs tissue samples, respectively. No significant correlation could be found between RRM2 protein expression and gender, depth of tumor invasion, lymph-node involvement and pTNM stage. The p53R2 expression status also did not correlate with the gender of patients and the depth of tumor invasion. However, the presence of p53R2 protein expression significantly correlated with pTNM stages of tumors (p=0.027) and lymph node metastasis (p=0.009). In Cox multivariable regression analysis, p53R2 expression (positive vs. negative; p=0.011, HR: 3.096, 95% CI: 1.294-7.407) together with pTNM stage (IIB/III/IV vs. I/IIA; p=0.005, HR: 2.496, 95% CI: 1.320-4.719) was shown to have independent prognostic impact on survival of ESCC patients.
Accordingly, in the analysis of cell cycle associate genes, the p53 mutations associated with loss of Rb pathway function would be the critical event in the development of human esophageal squamous cell carcinoma. In ESCC, loss of p53 pathway function is attributable to p53 mutations. However, the Rb pathway might be perturbed by inactivation of p16 and over-expressed p21waf1/cip1 protein in ESCC tissues. Consequently, the perturbed Rb function results in up-regulation ribonucleotide reductase activity, causing DNA precursors overproduction and cell proliferation. Using immunohistochemistry, our findings provide the first evidence of RRM2 and p53R2 expression in human ESCCs. We identified the different prognostic effects of RRM2 and p53R2 expression in human ESCCs. The identification of different roles of p53R2 and RRM2 involved in the carcinogenesis of esophageal squamous cell carcinomas might be useful for designing more effective RRM2 or p53R2 specific target therapy for esophageal squamous cell carcinoma to improve the clinical outcome of patients with esophageal carcinoma.
目次 Table of Contents
Table of Contents
Chapter 1.Introduction and Literature review.............1
1.1 Epidemiology of Esophageal Squamous Cell Carcinoma...1
1.2 Etiology of Esophageal Squamous Cell Carcinoma.......1
1.3 Management and Outcome Of ESCC Patients..............2
1.4 Molecular Aspects of Esophageal Squamous Cell Carcinogenesis...........................................4
1.5 The P53 Gene Mutations and Expression Of p21waf1/cip1 Protein In ESCCS.........................................9
Chapter 2. Research Motive and Objectives...............11
Chapter 3. Patients and Methods.........................13
3.1 Patients............................................13
3.2 Surgical technique..................................13
3.3 Follow-up...........................................14
3.4 Tissue preparation..................................14
3.5 Flow Cytometry Analysis.............................14
3.6 Extraction of RNA and RT-PCR amplification..........15
3.7 Genomic DNA extraction and amplification............16
3.8 Direct sequencing...................................16
3.9 Western blot analysis...............................16
3.10 Immunohistochemistry...............................17
3.11 Statistics.........................................17
Chapter 4. Results......................................19
4.1 Outcome of ESCC patients underwent esophagectomy....19
4.2 Mutational profile of p53 gene in ESCC in Taiwanese and its correlation with habitual of cigarette smoking, alcohol drinking and Betel Quid chewing.................22
4.3 Molecular aspects of cell cycle associated suppressor genes in ESCCs..........................................24
4.4 Prognostic effects of cell cycle associated p53, p21waf1/cip1 proteins in human ESCCs....................25
4.5 Prognostic effects of cell cycle associated RRM2 and p53R2 proteins in human ESCCs...........................28
Chapter 5. Discussion...................................30
Chapter 6. Summary and Future Directions................42
References..............................................45
Tables..................................................59
Figures and Legends.....................................79
Abbreviations..........................................104
Publications related to this thesis....................105
參考文獻 References
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