肝硬化在原发性肝癌的发生过程中所起作用的分子机制研究
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摘要
原发性肝癌作为最常见的恶性肿瘤之一，对人类的健康和生存构成了极大的危害。每年肝癌发病总数为56.4万人。肝癌发病占全球各种癌症的第五位，死亡占全癌死亡的第三位。在我国和某些亚非国家具有较高的发病率，我国肝癌约占全球肝癌的40％～45％。由于我国是肝炎高发国家，近年来肝癌的发病率和死亡率有逐年升高的趋势，IARC2001年度报告，中国肝癌发病男性世界人口标化率(ASR)为35.17／10万，排位第三，仅次于肺癌和胃癌；女性肝癌发病ASR为13.34／10万，排位第四，仅次于胃癌、乳腺癌、肺癌。肝癌死亡率男性为34.44／10万，女性为13.03／10万；肝癌死亡占所有癌症死亡的22.1％，超过肺癌，居第1位。
近年来的研究表明，肝癌的发生是多基因参与、多步骤改变的复杂过程，其分子调控机制仍未完全阐明。我国的肝癌患者多数都有乙型肝炎病史，然而大量乙肝感染而无肝硬化者，其肝癌发生率远远低于有肝炎后肝硬化者，并且肝硬变在HCC中并发率达84.6％，而肝硬变后HCC发生率达49.9％，因此提示多数情况下，HBV是通过肝炎后肝硬化发生肝癌的。因此，检测硬化肝脏中原癌基因和抑癌基因表达状况，对发现肝癌发生前早期阶段的基因异常有着重要意义，并有助于揭示肝癌的发生机理。
天津医科大学博士学位论文
目前，国内外关于肝硬化在肝癌的发生过程中所起作用的研究少
有报道〔5一“〕，多是针对个别已知的癌基因或抑癌基因，进行大规模差
异基因的筛选并构建cDNA文库的未见有报道。本研究应用抑制消减
杂交技术(SSH)，对肝硬化组织与正常肝组织差异表达基因进行筛选，
构建差异表达基因的削减cDNA文库，并对部分克隆〔70个)进行质
粒酶切和PCR双重鉴定，并对其中16个阳性克隆进行基因序列分析、
同源性检索，为进一步研究肝硬化在肝癌发生发生过程中的作用奠定
了分子水平的基础。
第一部分
伴肝细胞癌的肝硬化组织与正常肝组织差异表达基因的筛选
目的:筛选伴肝细胞癌的肝硬化组织与正常肝组织差异表达基因。
方法:采用抑制削减杂交技术，以3例正常肝组织及3例有肝癌背景
的肝硬化组织作为对比材料分离出mRNA，经反转录成双链cDNA后，
分成驱动子与检测子，将检测子连接上特定的接头，通过两轮不平衡
杂交、两次PCR，筛选并扩增出两种组织间所有差异表达的基因。并
进行了削减效率的验证。
结果:mRNA提取检测、cDNA酶切消化检测、接头连接效率检测、
PCR削减效率检测均达到实验设计要求。
结论:采用抑制削减杂交技术首次成功地分离出全部伴肝细胞癌的肝
硬化组织与正常肝组织所有差异表达的基因。
第二部分
差异表达基因的cDNA文库的构建及差异表达基因的初步鉴定
目的:构建差异表达基因的cDNA文库及初步筛选差异表达的基因
方法:采用TOPO T/A克隆技术，将第一部分所得到的差异表达基因
与TOPOT质粒载体连接，转化TOP10大肠杆菌，构建含全部差异表
达的基因cDNA文库。通过蓝白斑试验筛选出部分阳性重组子(70个)，
进一步扩增，通过提取质粒进行酶切以及PCR法双重鉴定验证重组子
中插入了差异表达的基因。并进一步选择其中的16个阳性重组于进行
序列测定，BLAST同源性检索。
结果：质粒酶切以及PCR法双重鉴定验证了差异表达的基因成功的
插入了重组子，CDNA文库构建成功。16个差异表达的基因序列测定，
BLAST同源性检索显示，1个为载体序列，15个均在 genebank中找到，
有五对是相同基因，共 10个不同的基因，涉及到 Wilm＼ 肿瘤相关蛋
白（QM）mRNA，载脂蛋白 H mRNA，纤维蛋白原 a链 mRNA，甲胎
蛋白 mRNA，chromosome 5 clone CTC－278HI，膜连蛋白 V（ANX）gene，
17一日羟类固醇脱氢酶IV型 mRNA，核糖体蛋白 L6 mRNA，CGI．31
蛋白mRNA，p53诱导蛋白PIGPCI
结论：用SSH和T／A克隆技术成功构建了正常肝组织与肝硬化组织差
异表达基因的削减。DNA文库。该文库的建立为进一步筛选、鉴定出
肝癌的发生过程中的相关的调控基因奠定了基础，也有助于阐明肝硬
化在肝癌发生过程中所起的作用。对差异表达基因的初步筛选鉴定中
发现，肝硬化阶段的确发生了基因的改变，涉及到的基因包括与肝组
织密切相关的如：AFP、APOH等，而且还有一些新近发现的和其他肿
瘤相关的基因如：Wi link肿瘤相关蛋白，THW基因等，以及一些在功
能上仍不很明确的基因，如 CGI上 protein mRNA。进一步验证了肝癌
的发生是多基因参与、多步骤改变的复杂过程。
Hepatocellular carcinoma(HCC) as one of the most frequent tumors is life threatening to human being.There are 564,000 new cases every year. The incidence rate of HCC ranks the fifth among all tumors in the world,and the mortality ranks the third. High rates are seen in China and some Asia- Africa countries. The cases in China account for 40-45% of those in the world.
As a country with high incidence rate of hepatitis ,the incidence and mortality rate of HCC increase steadily recently in China, IARC reports in 2001 shows age-standardised rate (ASR) of Chinese male is 35.17 per 100,000, ranks the third after lung cancer and gastric cancer;that of female is 13.34 per 100,000, ranks the fouth after gastric cancer breast cancer and lung cancer ; the death cases accout for 22.1% of those of all tumors ,exceeding lung cancer ,ranks the first.
Recent researches shows HCC carcinogenesis is a multi-gene and multi-step complicated process. The mechanism of molecular regulation is not completely clear. Most of the patients of HCC in China have hepatitis B history, but the incidence rate of HCC in patients of hepatitis B without cirrhosis is far lower than that with cirrhosis. Nearly 84.6% of HCC come with cirrhosis, whereas 49.9% of cirrhosis will develop into HCC, which hints HBV, cirrhosis, HCC is a three-step
process.Therefore, to detect the expression of oncogene and suppressor gene in cirrhotic liver is not only essential to find the gene changes in HCC early stage but also helpful to expound the carcinogenesis of HCC. There are little reports on the effect of liver cirrhosis on HCC carcinogenesis, most of which are mainly focus on known individual oncogene or suppressor gene. There is no reports on screening of differentially expressed genes in large scale and construction of cDNA library. In our study , the differentially expressed genes between normal liver and liver cirrhosis tissue accompanied with hepatocellular carcinoma were screened by suppression subtractive hybridization (SSH), and cDNA library was constructed, 70 colonies (parts of library)were analyzed by restriction enzyme analysis and PCR, 16 of positive colonies were sequenced further and aligned by BLAST(Basic Local Alignment Search Tool) in NCBI ,which set up the foundation of the study on the effect of liver cirrhosis in HCC carcinogenesis.
Part I : Screening of differentially expressed genes
between normal liver and liver cirrhosis tissue
accompanied with hepatocellular carcinoma
Aim: To screen the differentially expressed genes between normal liver and liver cirrhosis tissue accompanied with hepatocellular carcinoma Methods: 3 normal liver and 3 liver cirrhosis tissue accompanied with hepatocellular carcinoma as comparative materials ,SSH was used. The populations of mRNA was isolated first and reverse transcripted to cDNA, the samples were divided into tester and driver, specific adaptors were ligated to tester .Two-round unbalanced hybridization and nested polymerase chain reaction were performed .The differentially expressed
genes between two tissues were acquired . The subtraction efficiency was also tested.
Results: Tests of quantity and quality of mRNA populations , Rsal digestion of cDNA , ligation efficiency of adaptors and Subtraction Efficiency all reached the standards of experimental design. Conclusion: The differentially expressed genes between normal liver and liver cirrhosis tissue accompanied with hepatocellular carcinoma were separated successfully first .
Part II: Construction of a subtracted cDNA library of differentially expressed genes and primary identification
Aim: To construct a subtracted cDNA library of differentially expressed genes and identify primarily.
Methods: TOPO T/A Cloning technique was used, the differentially expressed genes acquired in part I were inserted into TOPO T vector, and transform TOP10 One Shot Competent Cells ( E.Coli), a subtracted cDNA library containing all differentially expressed genes between normal liver and liver cirrhosis tissue with HCC background
近年来的研究表明，肝癌的发生是多基因参与、多步骤改变的复杂过程，其分子调控机制仍未完全阐明。我国的肝癌患者多数都有乙型肝炎病史，然而大量乙肝感染而无肝硬化者，其肝癌发生率远远低于有肝炎后肝硬化者，并且肝硬变在HCC中并发率达84.6％，而肝硬变后HCC发生率达49.9％，因此提示多数情况下，HBV是通过肝炎后肝硬化发生肝癌的。因此，检测硬化肝脏中原癌基因和抑癌基因表达状况，对发现肝癌发生前早期阶段的基因异常有着重要意义，并有助于揭示肝癌的发生机理。
天津医科大学博士学位论文
目前，国内外关于肝硬化在肝癌的发生过程中所起作用的研究少
有报道〔5一“〕，多是针对个别已知的癌基因或抑癌基因，进行大规模差
异基因的筛选并构建cDNA文库的未见有报道。本研究应用抑制消减
杂交技术(SSH)，对肝硬化组织与正常肝组织差异表达基因进行筛选，
构建差异表达基因的削减cDNA文库，并对部分克隆〔70个)进行质
粒酶切和PCR双重鉴定，并对其中16个阳性克隆进行基因序列分析、
同源性检索，为进一步研究肝硬化在肝癌发生发生过程中的作用奠定
了分子水平的基础。
第一部分
伴肝细胞癌的肝硬化组织与正常肝组织差异表达基因的筛选
目的:筛选伴肝细胞癌的肝硬化组织与正常肝组织差异表达基因。
方法:采用抑制削减杂交技术，以3例正常肝组织及3例有肝癌背景
的肝硬化组织作为对比材料分离出mRNA，经反转录成双链cDNA后，
分成驱动子与检测子，将检测子连接上特定的接头，通过两轮不平衡
杂交、两次PCR，筛选并扩增出两种组织间所有差异表达的基因。并
进行了削减效率的验证。
结果:mRNA提取检测、cDNA酶切消化检测、接头连接效率检测、
PCR削减效率检测均达到实验设计要求。
结论:采用抑制削减杂交技术首次成功地分离出全部伴肝细胞癌的肝
硬化组织与正常肝组织所有差异表达的基因。
第二部分
差异表达基因的cDNA文库的构建及差异表达基因的初步鉴定
目的:构建差异表达基因的cDNA文库及初步筛选差异表达的基因
方法:采用TOPO T/A克隆技术，将第一部分所得到的差异表达基因
与TOPOT质粒载体连接，转化TOP10大肠杆菌，构建含全部差异表
达的基因cDNA文库。通过蓝白斑试验筛选出部分阳性重组子(70个)，
进一步扩增，通过提取质粒进行酶切以及PCR法双重鉴定验证重组子
中插入了差异表达的基因。并进一步选择其中的16个阳性重组于进行
序列测定，BLAST同源性检索。
结果：质粒酶切以及PCR法双重鉴定验证了差异表达的基因成功的
插入了重组子，CDNA文库构建成功。16个差异表达的基因序列测定，
BLAST同源性检索显示，1个为载体序列，15个均在 genebank中找到，
有五对是相同基因，共 10个不同的基因，涉及到 Wilm＼ 肿瘤相关蛋
白（QM）mRNA，载脂蛋白 H mRNA，纤维蛋白原 a链 mRNA，甲胎
蛋白 mRNA，chromosome 5 clone CTC－278HI，膜连蛋白 V（ANX）gene，
17一日羟类固醇脱氢酶IV型 mRNA，核糖体蛋白 L6 mRNA，CGI．31
蛋白mRNA，p53诱导蛋白PIGPCI
结论：用SSH和T／A克隆技术成功构建了正常肝组织与肝硬化组织差
异表达基因的削减。DNA文库。该文库的建立为进一步筛选、鉴定出
肝癌的发生过程中的相关的调控基因奠定了基础，也有助于阐明肝硬
化在肝癌发生过程中所起的作用。对差异表达基因的初步筛选鉴定中
发现，肝硬化阶段的确发生了基因的改变，涉及到的基因包括与肝组
织密切相关的如：AFP、APOH等，而且还有一些新近发现的和其他肿
瘤相关的基因如：Wi link肿瘤相关蛋白，THW基因等，以及一些在功
能上仍不很明确的基因，如 CGI上 protein mRNA。进一步验证了肝癌
的发生是多基因参与、多步骤改变的复杂过程。
Hepatocellular carcinoma(HCC) as one of the most frequent tumors is life threatening to human being.There are 564,000 new cases every year. The incidence rate of HCC ranks the fifth among all tumors in the world,and the mortality ranks the third. High rates are seen in China and some Asia- Africa countries. The cases in China account for 40-45% of those in the world.
As a country with high incidence rate of hepatitis ,the incidence and mortality rate of HCC increase steadily recently in China, IARC reports in 2001 shows age-standardised rate (ASR) of Chinese male is 35.17 per 100,000, ranks the third after lung cancer and gastric cancer;that of female is 13.34 per 100,000, ranks the fouth after gastric cancer breast cancer and lung cancer ; the death cases accout for 22.1% of those of all tumors ,exceeding lung cancer ,ranks the first.
Recent researches shows HCC carcinogenesis is a multi-gene and multi-step complicated process. The mechanism of molecular regulation is not completely clear. Most of the patients of HCC in China have hepatitis B history, but the incidence rate of HCC in patients of hepatitis B without cirrhosis is far lower than that with cirrhosis. Nearly 84.6% of HCC come with cirrhosis, whereas 49.9% of cirrhosis will develop into HCC, which hints HBV, cirrhosis, HCC is a three-step
process.Therefore, to detect the expression of oncogene and suppressor gene in cirrhotic liver is not only essential to find the gene changes in HCC early stage but also helpful to expound the carcinogenesis of HCC. There are little reports on the effect of liver cirrhosis on HCC carcinogenesis, most of which are mainly focus on known individual oncogene or suppressor gene. There is no reports on screening of differentially expressed genes in large scale and construction of cDNA library. In our study , the differentially expressed genes between normal liver and liver cirrhosis tissue accompanied with hepatocellular carcinoma were screened by suppression subtractive hybridization (SSH), and cDNA library was constructed, 70 colonies (parts of library)were analyzed by restriction enzyme analysis and PCR, 16 of positive colonies were sequenced further and aligned by BLAST(Basic Local Alignment Search Tool) in NCBI ,which set up the foundation of the study on the effect of liver cirrhosis in HCC carcinogenesis.
Part I : Screening of differentially expressed genes
between normal liver and liver cirrhosis tissue
accompanied with hepatocellular carcinoma
Aim: To screen the differentially expressed genes between normal liver and liver cirrhosis tissue accompanied with hepatocellular carcinoma Methods: 3 normal liver and 3 liver cirrhosis tissue accompanied with hepatocellular carcinoma as comparative materials ,SSH was used. The populations of mRNA was isolated first and reverse transcripted to cDNA, the samples were divided into tester and driver, specific adaptors were ligated to tester .Two-round unbalanced hybridization and nested polymerase chain reaction were performed .The differentially expressed
genes between two tissues were acquired . The subtraction efficiency was also tested.
Results: Tests of quantity and quality of mRNA populations , Rsal digestion of cDNA , ligation efficiency of adaptors and Subtraction Efficiency all reached the standards of experimental design. Conclusion: The differentially expressed genes between normal liver and liver cirrhosis tissue accompanied with hepatocellular carcinoma were separated successfully first .
Part II: Construction of a subtracted cDNA library of differentially expressed genes and primary identification
Aim: To construct a subtracted cDNA library of differentially expressed genes and identify primarily.
Methods: TOPO T/A Cloning technique was used, the differentially expressed genes acquired in part I were inserted into TOPO T vector, and transform TOP10 One Shot Competent Cells ( E.Coli), a subtracted cDNA library containing all differentially expressed genes between normal liver and liver cirrhosis tissue with HCC background
引文
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46．吴岚军，毛秉智，王升启．人胃癌抑制消减cDNA文库的构建及文库质量分析．军事医学科学院院刊，2001，25(1)：9-13
47. Kostic C, Shaw PH. Isolation and characterization of sixteen novel p53 response genes. Oncogene, 2000, 19(35):3978-3987
48．郭俊明，陶莎、周俊宜，庄苦，谢金卫，罗超权．应用抑制性消减杂交方法分析结肠癌相关基因．癌症，2001，20(7)：743-747
49. Robles-Diaz G, Duarte-Rojo A. Pancreas: a sex steroid-dependent tissue. Isr Med Assoc J,2001,3(5):364-368
50．郭树彬，伍东升，陆星华，钱家鸣．胰腺癌抑制消减eDNA文库的构建及质量．胰腺病学，2002，2(2)：66-70
51．周津，刘芝华，王秀琴，丁芳，张春林，毛学正，韩而芳，吴旻．抑制消减杂交及反Northern结合高通量筛选食管癌中差异表达基因．科学通报，2001，46(3)：222-226
52. Miyasaka Y, Enomoto N, Nagayama K, et,al. Analysis of differentially expressed genes in human hepatocellular carcinoma using suppression subtractive hybridization. Br J Cancer,2001,85(2):228-234
53．李靖，徐晓霞，韩本立等．正常肝组织与肝癌组织差异表达基因消减cDNA文库的构建．中华肝脏病杂志，2001，9(6)：346-348
54. Adams MD, Kelley JM, Gocayne JD, et, al. Complementary DNA sequencing: expressed sequence tags and human genome project. Science ,1991,252(5013):1651-1656
55．彭宏，赵彤，姚开泰．EST在克隆新基因中的应用．国外医学分子生物学分册，2001，23(1)：55-57
56. Li Z, Yao K, Cao Y. Molecular cloning of a novel tissue-specific gene from human nasopharyngeal epithelium. Gene, 1999, 237(1):235-240
57．张天泽，主编．肿瘤学．天津，天津科技出版社，1996．
58． Miettinen M, Mustonen M, Poutanen M, et,al. 17Beta-hydroxysteroid dehydrogenases in normal human mammary epithelial cells and breast tissue. Breast Cancer Res Treat , 1999, 57(2) :175-182
59． Mustonen MV, Poutanen MH, Isomaa VV, et,al. Cloning of mouse 17beta-hydroxysteroid dehydrogenase type 2, and analyzing expression of the mRNAs for types 1, 2, 3, 4 and 5 in mouse embryos and adult tissues. Biochem J, 1997,325 ( Pt 1) :199-205
60． de Launoit Y, Adamski J. Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome. J Mol Endocrinol , 1999 Jun, 22(3) :227-240
61． Koh E, Noda T, Kanaya J,et,al. Differential expression of 17beta-hydroxysteroid dehydrogenase isozyme genes inprostate cancer and noncancer tissues. Prostate , 2002 1;53(2) :154-159
62． Green VL, Speirs V, Landolt AM, et,al. 17Beta-hydroxysteroid dehydrogenase type 1, 2, 3, and 4 expression and enzyme activity in human anterior pituitary adenomas. J Clin Endocrinol Metab , 1999 ,84(4) :1340-1345
63． English MA, Hughes SV, Kane KF,et,al. Oestrogen inactivation in the colon: analysis of the expression and regulation of 17beta-hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer. Br J Cancer, 2000 ,83(4) :550-558
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65． Lin YW, Lee IN, Chen CH, et,al. Deletion mapping of chromosome 16q24 in hepatocellular carcinoma in Taiwan and mutational analysis of the 17-beta-HSD gene localized to the region. Int J Cancer , 2001 ,93(1) :74-79
66． Narasaka T, Moriya T, Endoh M,et,al. 17Beta-hydroxysteroid dehydrogenase type 2 and dehydroepiandrosterone sulfotransferase in the human liver. Endocr J, 2000 ,47(6) :697-705
67． Niessen HW, Lagrand WK, Rensink HJ, et,al. Apolipoprotein H, a new mediator in the inflammatory changes ensuring in jeopardised human myocardium. J Clin Pathol, 2000 53(11) ,863-867
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71． 谢桂岚，李志样．白血病细胞凝固异常中膜联蛋白V作用的研究．中华实用医学，2002，4(17) ：15-17
72． Crumpton MJ, Dedman JR. Protein terminology tangle. Nature , 1990 , 345 (6272) :212
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74． Gong ZJ, De, Meyer S, van Pelt J,et,al. Transfection of a rat hepatoma cell line with a construct expressing human liver annexin V confers susceptibility to hepatitis B virus infection. Hepatology ,1999,29(2) :576-584
75． De Meyer S, Depla E, Maertens G,et,al. Characterization of small hepatitis B surface antigen epitopes involved in binding to human annexin V. J Viral Hepat ,1999 ,6(4) :277-285
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