河南林州地区同一个体食管癌前病变和癌组织分子变化的特征
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摘要
食管癌是世界上最常见的六大恶性肿瘤之一，显著的地域性分布差异是食管癌流行病学突出特征，高低发区可相差500倍。并且食管癌预后很差，中晚期患者5年生存率仅为10％左右。中国是世界上食管癌发病率和死亡率最高的国家，每年全世界新增加的30万食管癌患者中，有一半发生在中国。在中国，河南省，特别是豫北地区的林州市(原林县)及其毗邻的辉县、安阳等地，是我国也是世界上食管癌发病率和死亡率最高的地区。过去几十年，老一代科学家对该地区人群进行了多学科、系统性、综合研究，在食管癌的发病因素，发病机制和防治方面做出了卓越的贡献。明确提出，食管癌变是一个多阶段进行性发展过程，确立了癌前病变的概念，提出亚硝胺及霉菌毒素等可能是该地区重要的致癌因素。但是，目前该地区人群食管癌发病率和死亡率仍未得到根本控制，甚至无明显改善。其主要原因是，对食管癌确切的发病因素和多阶段演进的分子学机制尚不十分清楚，缺乏有效的Ⅰ级预防措施和手段，缺乏早期诊断的生物学指标和方法。这也正是该研究领域所面临的重大研究课题。
目前普遍的观点认同食管癌变是多种基因变化综合作用(先后累积或叠加)的结果，食管癌变的不同阶段，分子变化可能不同，并是导致食管轻度癌前病变持续向癌的方向发展、决定食管癌前病变双向发展的不稳定特性的主要机制。纠正这些变化，或增强这些基因的正常功能，将有助于阻止或延缓癌变的发生。高发区人群普查和随访研究发现，食管癌前病变呈现明显的双向发展的不稳定特性，即这些病变可向癌的方向发展，也可退回到较轻度
河南林州地区同一个体食管癌前病变和癌组织分子变化的特征
的病变，或维持同一状态多年不变;很显然，单纯从形态学角度难以阐明这
种现象。90年代开始，对食管癌变的分子变化有了较深入的了解。本实验室
及其他学者的研究提示:食管癌变早期已发生许多重要的分子变化，主要包
括某些肿瘤抑制基因的失活，如P53突变，Rb杂合缺失，P14和P15纯合缺
失，以及某些癌基因的活化或过度表达，例如eyclin DI，C一myc，C一erbBZ等。
这些分子变化可能是导致轻度癌前病变持续向癌的方向发展的重要机制。多
数学者的研究是针对癌组织进行研究，对癌旁组织的研究较少，对同一个体
癌组织及癌旁组织的研究报道更少。为了深入了解分子变化在食管癌变多阶
段演进中的生物学意义，本研究利用Rl乍PCR、免疫组化及碘染色技术，系统
分析同一个体手术切除组织的不同部位、不同组织类型的分子事件变化特征
及规律，加深了对这些变化规律性及生物学意义的认识。
1.材料与方法
1.1食管癌前病变组织、癌组织及无症状居民活检组织的收集及处理
45例癌和癌旁食管癌组织均来自河南食管癌高发区林州手术切除标本(男
30例，女巧例，平均年龄57.37士8.34岁，年龄范围36一75岁)，所有患者术
前均未接受放疗和化疗。手术切除标本病理学检查均为食管鳞状细胞癌。新
鲜手术标本沿纵线切开分成两部分，一部分在癌肿组织和癌旁目测无病变部
位(手术切端)分别取一对样品，做好标记，连同大体标本放入液氮中冷藏。
另一部分在新鲜状态下进行卢戈氏(Lugol’s)液染色处理。
1.2色素镜(lugo一，s液染色)检查
在常规胃镜观察后，用洗涤喷雾管在食管表面均匀喷洒体积分数为2%的
Lugofs液，1 05后立即温水冲洗，观察，对染色阳性及阴性区取活检粘膜。
观察和记录染色结果，将碘染色区分为“染色区”，即碘染后食管粘膜呈棕褐
色反应和“不染区”，即碘染后食管粘膜无呈色反应。将“不染区”细分为“点
状不染区”。“花斑状不染区”，“条状不染区”和“片状不染区”等四种类型。
每例碘染后，均认真冲洗并吸出冲洗液，尽量减少碘溶液的刺激作用。在上
郑州大学博士论文2003届
述碘“不染区”和“染色区”分别取活检组织(所有不染区均取活检l一2块)，
并常规在食管中段(距门齿30一32cm)和下段(食管赏门交界线上2一3cm)各
取l一2块活检组织。
1.3食管癌手术切除大体标本粘膜碘染色
新鲜手术标本用生理盐水冲洗去粘液后，将粘膜面喷洒体积分数为1.2%
Lugo，s碘液染色，105后立即在生理盐水冲洗，记录染色结果，并在所有片状
不染区和染色区分别取材。共取样品43对，其中男30例，女13例，平均年
龄5632士7.56岁，年龄范围36一75岁。
L4免疫组织化学
组织经85%乙醇固定、石蜡包埋、连续切片，用于组织病理学检查和免疫
组化检查。免疫组化采用卵白素一生物素一辣根过氧化氢酶复合物(ABC)或过
氧化物酶标志的链霉卵白素(SP)染色法。
1 .5 RT-PCR
选取16对癌和癌旁样品(其中男10例，女6例，平均年龄为56名7士6.48
岁，年龄范围36一75岁)以及10例来自食管癌高发区无症状人群普查活检样
品(其中男6例，女4例，平均年龄为41.2士3.34岁，年龄范围33一53岁)用
于mRNA表达研究。新鲜组织经液氮冷藏后转入一70oC冰箱，RNA提取使
用Promega公司sv Total RNA Isolation System试剂盒提取，反转录使用
Esophageal carcinoma (EC) is one of the six most common malignant diseases worldwide. The dramatic geographic distribution is the striking characteristic for EC, the ratios for EC incidence between the high- and low-risk areas could be as great as 500:1. Moreover, EC has a very poor prognosis; the five-year survival rate for the middle and advanced EC is only 10%. Linzhou (formerly Linxian) and Huixian of Henan Province, northern China, have been well recognized as the highest incidence areas for EC in the world. EC remains a leading cause of cancer-related deaths in these area. The reason for this stable incidence pattern are because of that: the exact etiological factors for EC have not been identified; the mechanism of esophageal carcinogenesis is not very clear; and there are lack of useful reagents for chemoprevention, sensitive biomarkers for early detection and high-risk subject screening.
Studies by us and other laboratories indicate that an early indicator for the subjects predisposed to EC is the abnormal hyperproliferation of esophageal epithelial cells, morphologically manifested as basal cell hyperplasia (BCH), especially at the papilla region, dysplasia and cacinoma in situ, all these lesions could be considered as preacancerous lesions for EC. Our field work has showed that these lesions appear unstable, i.e., of the lesions with the similar morphology, some may progress to more severe type, or remain at that stage for long time, or return to less severe lesion, even to normal. These phenomena raise some important questions. For example, what are the key factors to address the mild lesions to more severe lesions? What is the mechanism to determine the
reversibility of these lesions? Apparently, these questions could not be answered only by morphological analysis. To further characterize the molecular changes and their correlations with morphological alterations at the different stages of carcinogenesis may provide important clues to elucidate these questions: mass survey and follow-up studies to the population at high-incidence area for EC with linear interval biopsies could not be overemphasized in elucidating the natural history for EC, accumulating important biological material bank for molecular analysis and evaluating the effects of chemoprevention.
The knowledge about the molecular alterations of esophageal carcinogenesis has been greatly improved in 1990s. The studies finished by ours and the other research groups showed that many important molecular alterations have occurred in the early stage of esophageal carcinogenesis, mainly including some tumor inhibition genes inactive, such as p53 mutation, Rb LOH, p14 and p15 loss, and some oncogene, such as Cyclin D1, C-myc, C-erbB2 active or overexpression. The molecular alterations may be the key mechanism to address the mild precancerous lesions into cancer. Most of the studies has focused on the cancer tissues but not the adjacent tissues, and there are few reports on molecular changes in both cancer tissue and adjacent tissue from the same EC patient. To further characterize the molecular changes in the multistage progress in esophageal carcinogenesis from the same patient, we designed this multi-profile and multi-molecular study focusing on the molecular events in cancer and adjacent tissue from the same EC patient.
1 Materials and Methods
1.1 Surgical and biopsy tissue collection and processing
All the surgically resected primary EC specimens were collected from 45 EC patients in Linzhou, Henan, the high incidence area for EC (30 men and 15 women, 36 to 75 years of age, with a mean ±SD of 57 37 ±8.34 years,) . All the patients had not received either chemotherapy or radiotherapy before surgery. All the specimens were confirmed by pathology as esophageal squamous cell carcinoma. Within one hour after excision, each specimen was cut into two segments, the
cancer tissue and its adjacent tissue were collected as one case in one segment and stored in liquid nitrogen for further study The other segment was stain
目前普遍的观点认同食管癌变是多种基因变化综合作用(先后累积或叠加)的结果，食管癌变的不同阶段，分子变化可能不同，并是导致食管轻度癌前病变持续向癌的方向发展、决定食管癌前病变双向发展的不稳定特性的主要机制。纠正这些变化，或增强这些基因的正常功能，将有助于阻止或延缓癌变的发生。高发区人群普查和随访研究发现，食管癌前病变呈现明显的双向发展的不稳定特性，即这些病变可向癌的方向发展，也可退回到较轻度
河南林州地区同一个体食管癌前病变和癌组织分子变化的特征
的病变，或维持同一状态多年不变;很显然，单纯从形态学角度难以阐明这
种现象。90年代开始，对食管癌变的分子变化有了较深入的了解。本实验室
及其他学者的研究提示:食管癌变早期已发生许多重要的分子变化，主要包
括某些肿瘤抑制基因的失活，如P53突变，Rb杂合缺失，P14和P15纯合缺
失，以及某些癌基因的活化或过度表达，例如eyclin DI，C一myc，C一erbBZ等。
这些分子变化可能是导致轻度癌前病变持续向癌的方向发展的重要机制。多
数学者的研究是针对癌组织进行研究，对癌旁组织的研究较少，对同一个体
癌组织及癌旁组织的研究报道更少。为了深入了解分子变化在食管癌变多阶
段演进中的生物学意义，本研究利用Rl乍PCR、免疫组化及碘染色技术，系统
分析同一个体手术切除组织的不同部位、不同组织类型的分子事件变化特征
及规律，加深了对这些变化规律性及生物学意义的认识。
1.材料与方法
1.1食管癌前病变组织、癌组织及无症状居民活检组织的收集及处理
45例癌和癌旁食管癌组织均来自河南食管癌高发区林州手术切除标本(男
30例，女巧例，平均年龄57.37士8.34岁，年龄范围36一75岁)，所有患者术
前均未接受放疗和化疗。手术切除标本病理学检查均为食管鳞状细胞癌。新
鲜手术标本沿纵线切开分成两部分，一部分在癌肿组织和癌旁目测无病变部
位(手术切端)分别取一对样品，做好标记，连同大体标本放入液氮中冷藏。
另一部分在新鲜状态下进行卢戈氏(Lugol’s)液染色处理。
1.2色素镜(lugo一，s液染色)检查
在常规胃镜观察后，用洗涤喷雾管在食管表面均匀喷洒体积分数为2%的
Lugofs液，1 05后立即温水冲洗，观察，对染色阳性及阴性区取活检粘膜。
观察和记录染色结果，将碘染色区分为“染色区”，即碘染后食管粘膜呈棕褐
色反应和“不染区”，即碘染后食管粘膜无呈色反应。将“不染区”细分为“点
状不染区”。“花斑状不染区”，“条状不染区”和“片状不染区”等四种类型。
每例碘染后，均认真冲洗并吸出冲洗液，尽量减少碘溶液的刺激作用。在上
郑州大学博士论文2003届
述碘“不染区”和“染色区”分别取活检组织(所有不染区均取活检l一2块)，
并常规在食管中段(距门齿30一32cm)和下段(食管赏门交界线上2一3cm)各
取l一2块活检组织。
1.3食管癌手术切除大体标本粘膜碘染色
新鲜手术标本用生理盐水冲洗去粘液后，将粘膜面喷洒体积分数为1.2%
Lugo，s碘液染色，105后立即在生理盐水冲洗，记录染色结果，并在所有片状
不染区和染色区分别取材。共取样品43对，其中男30例，女13例，平均年
龄5632士7.56岁，年龄范围36一75岁。
L4免疫组织化学
组织经85%乙醇固定、石蜡包埋、连续切片，用于组织病理学检查和免疫
组化检查。免疫组化采用卵白素一生物素一辣根过氧化氢酶复合物(ABC)或过
氧化物酶标志的链霉卵白素(SP)染色法。
1 .5 RT-PCR
选取16对癌和癌旁样品(其中男10例，女6例，平均年龄为56名7士6.48
岁，年龄范围36一75岁)以及10例来自食管癌高发区无症状人群普查活检样
品(其中男6例，女4例，平均年龄为41.2士3.34岁，年龄范围33一53岁)用
于mRNA表达研究。新鲜组织经液氮冷藏后转入一70oC冰箱，RNA提取使
用Promega公司sv Total RNA Isolation System试剂盒提取，反转录使用
Esophageal carcinoma (EC) is one of the six most common malignant diseases worldwide. The dramatic geographic distribution is the striking characteristic for EC, the ratios for EC incidence between the high- and low-risk areas could be as great as 500:1. Moreover, EC has a very poor prognosis; the five-year survival rate for the middle and advanced EC is only 10%. Linzhou (formerly Linxian) and Huixian of Henan Province, northern China, have been well recognized as the highest incidence areas for EC in the world. EC remains a leading cause of cancer-related deaths in these area. The reason for this stable incidence pattern are because of that: the exact etiological factors for EC have not been identified; the mechanism of esophageal carcinogenesis is not very clear; and there are lack of useful reagents for chemoprevention, sensitive biomarkers for early detection and high-risk subject screening.
Studies by us and other laboratories indicate that an early indicator for the subjects predisposed to EC is the abnormal hyperproliferation of esophageal epithelial cells, morphologically manifested as basal cell hyperplasia (BCH), especially at the papilla region, dysplasia and cacinoma in situ, all these lesions could be considered as preacancerous lesions for EC. Our field work has showed that these lesions appear unstable, i.e., of the lesions with the similar morphology, some may progress to more severe type, or remain at that stage for long time, or return to less severe lesion, even to normal. These phenomena raise some important questions. For example, what are the key factors to address the mild lesions to more severe lesions? What is the mechanism to determine the
reversibility of these lesions? Apparently, these questions could not be answered only by morphological analysis. To further characterize the molecular changes and their correlations with morphological alterations at the different stages of carcinogenesis may provide important clues to elucidate these questions: mass survey and follow-up studies to the population at high-incidence area for EC with linear interval biopsies could not be overemphasized in elucidating the natural history for EC, accumulating important biological material bank for molecular analysis and evaluating the effects of chemoprevention.
The knowledge about the molecular alterations of esophageal carcinogenesis has been greatly improved in 1990s. The studies finished by ours and the other research groups showed that many important molecular alterations have occurred in the early stage of esophageal carcinogenesis, mainly including some tumor inhibition genes inactive, such as p53 mutation, Rb LOH, p14 and p15 loss, and some oncogene, such as Cyclin D1, C-myc, C-erbB2 active or overexpression. The molecular alterations may be the key mechanism to address the mild precancerous lesions into cancer. Most of the studies has focused on the cancer tissues but not the adjacent tissues, and there are few reports on molecular changes in both cancer tissue and adjacent tissue from the same EC patient. To further characterize the molecular changes in the multistage progress in esophageal carcinogenesis from the same patient, we designed this multi-profile and multi-molecular study focusing on the molecular events in cancer and adjacent tissue from the same EC patient.
1 Materials and Methods
1.1 Surgical and biopsy tissue collection and processing
All the surgically resected primary EC specimens were collected from 45 EC patients in Linzhou, Henan, the high incidence area for EC (30 men and 15 women, 36 to 75 years of age, with a mean ±SD of 57 37 ±8.34 years,) . All the patients had not received either chemotherapy or radiotherapy before surgery. All the specimens were confirmed by pathology as esophageal squamous cell carcinoma. Within one hour after excision, each specimen was cut into two segments, the
cancer tissue and its adjacent tissue were collected as one case in one segment and stored in liquid nitrogen for further study The other segment was stain
引文
1 Estimates of the worldwide mortality from eighteen major cancers in 1985． Implications for prevention and projections of future burden, (eng; includes abstract) By Pisani P, Int J Cancer, 1993 Dec 2; Vol. 55 (6) , pp. 891-903; PMID 8253525
2 杜百廉 主编 食管癌 中国科学技术出版社，1994
3 A randomized double-blind intervention study on the effect of calcium supplementation on esophageal precancerous lesions in a high-risk population in China, (eng; includes abstract) By Wang LD, Cancer Epidemiol Biomarkers Prev, 1993 Jan-Feb; Vol. 2 (1) , pp. 71-8; PMID. 8420615
4 曾益新 主编 肿瘤学 人民卫生出版社，1999
5 Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1) . (eng; includes abstract) By Ekstrom G, Biochem Pharmacol, 1989 Apr 15; Vol. 38 (8) , pp. 1313-9; PMID: 2495801
6 [CYP2D6 and GSTM1 genetic polymorphism and lung cancer susceptibility] (chi; includes abstract) By Gao J, Zhonghua Zhong Liu Za Zhi, 1998 May; Vol. 20 (3) , pp. 185-6; PMID 10921002
7 Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma, (eng; includes abstract) By Yu MW, Gastroenterology, 1995 Oct; Vol. 109 (4) , pp. 1266-73; PMID: 7557094
8 Lin et al. Cancer Epidemiol Biomarkers Prev, 7: 1013-1018, 1998
9 Inherited polymorphism in the N-acetyltransferase 1 (NAT1) and 2 (NAT2) genes and susceptibility to gastric and colorectal adenocarcinoma. (eng; includes abstract) By Katoh T, Int J Cancer, 2000 Jan 1; Vol. 85 (1) , pp. 46-9; PMID 10585581
10 RA Woutersen, LM Appelman, A Van Garderen Hoetmer, etal. In halation toxicity of acetal dehydeinrats. III. Carcinogeni-citystudy [J] Toxicology, 1986, 41:213-231．
11 Role of oxidative DNA damage in cancer initiation and promotion. (eng; includes abstract) By Poulsen HE, Eur J Cancer Prev, 1998 Feb; Vol. 7 (1) , pp. 9-16; PMID 9511847
12 邢德印，谭文，宋南，林东昕。DNA修复基因hOGG1多态与食管癌遗传易感性。中华医学遗传学杂志，2000，17(6) ：377-381
13 Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals, (eng; includes abstract) By Clerici M, J Clin Invest, 1993 Mar; Vol. 91 (3) , pp. 759-65, PMID: 8450057
14 Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency, (eng; includes abstract) By Waldrop SL, J Clin Invest, 1997 Apr 1, Vol. 99 (7) , pp. 1739-50; PMID 9120019
15 舒青，马群风，刘素英，张宁。Rb基因多态性与食管癌遗传易感性的研究。中华外科杂志，2000，38(5) ：375-378
16 邓琳，曹亚。cyclinD1的多态性与肿瘤。国外医学肿瘤学分册，2001， 28(3) ：163-164
17 Microsatellite instability. Shifting concepts in tumorigenesis. (eng) By Brentnall TA, Am J Pathol, 1995 Sep; Vol. 147 (3) , pp. 561-3; PMID 7677169
18 Human fetal G gamma-and A gamma-globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes, (eng; includes abstract) By Slightom JL, Cell, 1980 Oct; Vol. 21 (3) , pp. 627-38; PMID 7438203
19 Molecular biology. CACA sequences-the ends and the means? (eng)
By Rogers J, Nature, 1983 Sep 8-14; Vol. 305 (5930) , pp. 101-2; PMID: 6888554
20 Simple sequences are ubiquitous repetitive components of eukaryotic genomes, (eng; includes abstract) By Tautz D, Nucleic Acids Res, 1984 May 25, Vol. 12 (10) , pp. 4127-38; PMID: 6328411
21 Microsatellites for linkage analysis of genetic traits, (eng; includes abstract) By Hearne CM, Trends Genet, 1992 Aug; Vol. 8 (8) , pp. 288-94; PMID: 1509520
22 Occurrence of microsatellite instability in gastric carcinoma is associated with enhanced expression of erbB-2 oncoprotein. (eng; includes abstract) By Lin JT, Cancer Res, 1995 Apr 1; Vol. 55 (7) , pp. 1428-30; PMID 7882346
23 李卫东，王亮，王秀琴。食管癌组织染色体位点特异性的杂合性丢失和微卫星DNA序列不稳定。中华医学遗传学杂志，1996，13(4) ：194-197
24 A genetic model for colorectal tumorigenesis. (eng) By Fearon ER, Cell, 1990 Jun 1; Vol. 61 (5) , pp. 759-67; PMID 2188735
25 Mutation analysis of the CHK2 gene in breast carcinoma and other cancers, (eng; includes abstract) By Ingvarsson S, Breast Cancer Res, 2002; Vof. 4 (3) , pp. R4; PMID 12052256
26 Labeling index and labeling distribution of cells in esophageal epithelium of individuals at increased risk for esophageal cancer in Huixian, China, (eng; includes abstract) By Wang LD, Cancer Res, 1990 May 1; Vol. 50 (9) , pp. 2651-3; PMID: 2328490
27 Surfing the p53 network, (eng) By Vogelstein B, Nature, 2000 Nov 16; Vol. 408 (6810) , pp. 307-10; PMID 11099028
28 The p53 family: same response, different signals? (eng; includes abstract) By Chen X, Mol Med Today, 1999 Sep; Vol. 5 (9) , pp. 387-92; PMID: 10462750
29 p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities, (eng; includes abstract) By Yang A, Mol Cell, 1998 Sep; Vol. 2 (3) , pp. 305-16; PMID. 9774969
30 The p53 gene family, (eng; includes abstract) By Kaelin WG Jr, Oncogene, 1999 Dec 13; Vol. 18 (53) , pp. 7701-5; PMID. 10618710
31 p63． (eng; includes abstract) By Little NA, Int J Biochem Cell Biol, 2002 Jan; Vol. 34 (1) , pp. 6-9; PMID 11733180
32 p51A (TAp63gamma), a p53 homolog, accumulates in response to DNA damage for cell regulation, (eng; includes abstract) By Katoh I, Oncogene, 2000 Jun 22; Vol. 19 (27) , pp. 3126-30; PMID. 10871867
33 Down-regulation of p63 is required for epidermal UV-B-induced apoptosis. (eng; includes abstract) By Liefer KM, Cancer Res, 2000 Aug 1; Vol. 60 (15) , pp. 4016-20; PMID 10945600
34 P63 and P73: P53 mimics, menaces and more, (eng; includes abstract) By Yang A, Nat Rev Mol Cell Biol, 2000 Dec; Vol. 1 (3) , pp. 199-207; PMID 11252895
35 AIS is an oncogene amplified in squamous cell carcinoama. (eng;includes abstract) By Hibi K,Proc Natl acad Sci U S A.2000 May 9;Vol 97(10) ,pp 5462-7; PMID 10805802
36 Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions, (eng; includes abstract) By Nylander K, Int J Cancer, 2000 Aug 1; Vol. 87 (3) , pp. 368-72; PMID. 10897041
37 High level expression of deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? (eng; includes abstract) By Crook T, Oncogene, 2000 Jul 13; Vol. 19 (30) , pp. 3439-44; PMID 10918601
38 Elevated expression of p63 protein in human esophageal squamous
cell carcinomas, (eng; includes abstract) By Hu H, Int J Cancer, 2002 Dec 20; Vol. 102 (6) , pp. 580-3; PMID: 12447998
39 TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe, (eng; includes abstract) By Tanie P, Br J Cancer, 2001 Sep 1; Vol. 85 (5) , pp. 721-6; PMID 11531258
40 The p53 tumour suppressor gene, (eng; includes abstract) By Levine AJ, Nature, 1991 Jun 6; Vol. 351 (6326) , pp. 453-6; PMID 2046748
41 王立东，陈虹。肿瘤抑制基因P53-Rb系统变化与食管癌变关系研究及展望。世界华人消化杂志，2001，9(4) ：367-371
42 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. (eng; includes abstract) By Harper JW, Cell, 1993 Nov 19; Vol. 75 (4) , pp. 805-16; PMID 8242751
43 p21 is a universal inhibitor of cyclin kinases. (eng; includes abstract) By Xiong Y, Nature, 1993 Dec 16; Vol. 366 (6456) , pp. 701-4; PMID 8259214
44 Overexpression of p21WAF1/CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines, (eng; includes abstract) By Sheikh MS, Oncogene, 1995 Nov 2; Vol. 11 (9) , pp. 1899-905; PMID 7478620
45 王文亮，黄高。肝细胞肝癌组织中p21WAF1的表达及其意义。中华医学杂志，1998，78(1) ：74-75
46 王立东，周琦，高珊珊，杨光育。人贲门癌WAF-1基因和P53肿瘤抑制基因表达的初步研究。河南医科大学学报，1995，30(2) ：148-153
47 The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis, (eng, includes abstract) By Bremnes RM, Lung Cancer, 2002 May; Vol. 36 (2) , pp. 115-24; PMID. 11955645
48 E-cadherin expression in primary and metastatic thoracic neoplasms and in Barrett's oesophagus, (eng; includes abstract) By Bongiomo PF,
Br J Cancer, 1995 Jan; Vol. 71 (1) , pp. 166-72; PMID 7819034
49 E-cadherin expression in renal cell cancer and its significance in metastasis and survival, (eng; includes abstract) By Katagiri A, Br J Cancer, 1995 Feb; Vol. 71 (2) , pp. 376-9; PMID 7841055
50 E-cadherin but not N-cadherin expression is correlated with the intracellular distribution of catenins in human hepatocellular carcinomas, (eng; includes abstract) By Nuruki K, Oncol Rep, 1998 Sep-Oct; Vol. 5 (5) , pp. 1109-14; PMID 9683818
51 Characterization of DNA polymorphisms in the E-cadherin gene (CDH1) promoter region, (eng; includes abstract) By Nakamura A, Mutat Res, 2002 May 22; Vol. 502 (1-2) , pp. 19-24; PMID 11996968
52 Prognostic significance of CyclinDI and E-Cadherin in patients with esophageal squamous cell carcinoma: multiinstitutional retrospective analysis. Research Committee on Malignancy of Esophageal Cancer, Japanese Society for Esophageal Diseases, (eng; includes abstract), J Am Coll Surg, 2001 Jun; Vol. 192 (6) , pp. 708-18; PMID 11400964
53 A novel cyclin encoded by a bch-linked candidate oncogene. (eng; includes abstract) By Motokura T, Nature, 1991 Apr 11; Vol. 350 (6318) , pp. 512-5; PMID 1826542
54 Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining, (eng; includes abstract) By Gillett C, Cancer Res, 1994 Apr 1; Vol. 54 (7) , pp. 1812-7; PMID 8137296
55 Amplification and expression of the human cyclin D gene in esophageal cancer, (eng; includes abstract) By Jiang W, Cancer Res, 1992 May 15; Vol. 52 (10) , pp. 2980-3; PMID 1533816
56 The PRAD-1/cyclin D1 oncogene product accumulates aberrantly in a subset of colorectal carcinomas, (eng; includes abstract) By Bartkova J, Int J Cancer, 1994 Aug 15; Vol. 58 (4) , pp. 568-73; PMID 8056453
57 Frequent alterations of cell cycle regulators in early-stage breast lesions as detected by immunohistochemistry. (eng; includes abstract) By Marsh KL, Br J Cancer, 1998 May; Vol. 77 (9) , pp. 1460-8; PMID: 9652762
58 Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. (eng; includes abstract) By Quelle DE, Genes Dev, 1993Aug; Vol. 7 (8) , pp. 1559-71; PMID 8339933
59 Altered p16/MTS1/CDKN2 and cyclin D1/PRAD-1 gene expression is associated with the prognosis of squamous cell carcinoma of the esophagus, (eng; includes abstract) By Takeuchi H, Clin Cancer Res, 1997 Dec; Vol. 3 (12 Pt 1) , pp. 2229-36; PMID: 9815619
60 Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis. (eng; includes abstract) By Wang LD, Int J Cancer, 1994 Nov 15; Vol. 59 (4) , pp. 514-9; PMID: 7960222
61 王立东，郑树，刘宾，郭瑞锋，王启鸣，范宗民，陈虹，庄则豪，秦艳茹，安继业，孙超，高社干，李吉林，宋子博，贺新伟，李吉学，李燕杰，高珊珊。郭花芹。河南食管癌高发区居民食管色素镜检查及手术标本碘染色结果分析。郑州大学学报(医学板)，2002，37(6) ：720-732。
62 Fragile X genotype characterized by an unstable region of DNA. (eng; includes abstract) By Yu S, Science, 1991 May 24, Vol. 252 (5010) , pp. 1179-81 ,PMID. 2031189
63 Precise localization of aphidicolin-induced breakpoints on the short arm of human chromosome 3． (eng; includes abstract) By Paradee W, Genomics, 1995 May 20; Vol. 27 (2) , pp. 358-61; PMID 7558007
64 The FHIT gene, spanning the chromosome 3p14． 2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers, (eng; includes abstract) By Ohta M, Cell, 1996 Feb 23; Vol. 84 (4) , pp. 587-97; PMID 8598045
65 The neu oncogene encodes an epidermal growth factor receptor-related protein, (eng; includes abstract) By Bargmann Cl, Nature, 1986 Jan 16-22; Vol. 319 (6050) , pp. 226-30; PMID. 3945311
66 Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line, (eng; includes abstract) By Fukushige S, Mol Cell Biol, 1986 Mar; Vol. 6 (3) , pp. 955-8; PMID 2430175
67 Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer, (eng; includes abstract) By Wright C, Cancer Res, 1989 Apr 15; Vol. 49 (8) , pp. 2087-90; PMID 2564806
68 Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression, (eng; includes abstract) By Reis CA, Cancer Res, 1999 Mar 1; Vol. 59 (5) , pp. 1003-7; PMID 10070955
69 Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini, (eng; includes abstract) By Ligtenberg MJ, J Biol Chem, 1990 Apr 5; Vol. 265 (10) , pp. 5573-8; PMID 2318825
70 MUC1 and cancer, (eng; includes abstract) By Taylor-Papadimitriou J, Biochim Biophys Acta, 1999 Oct 8; Vol. 1455 (2-3) , pp. 301-13; PMID 10571020
71 Phosphorylation of the cytoplasmic domain of the MUC1 mucin correlates with changes in cell-cell adhesion, (eng; includes abstract) By Quin RJ, Int J Cancer, 2000 Aug 15; Vol. 87 (4) , pp. 499-506; PMID 10918188
72 Mucin gene expression in ovarian cancers, (eng; includes abstract) By Giuntoli RL 2nd, Cancer Res, 1998 Dec 1; Vol. 58 (23) , pp. 5546-50; PMID 9850092
73 Mucin gene transcripts in benign and borderline mucinous tumours of
the ovary: an in situ hybridization study, (eng; includes abstract) By Boman F, J Pathol, 2001 Mar; Vol. 193 (3) , pp. 339-44; PMID 11241413
74 Mucins (MUC1 and MUC3) of gastrointestinal and breast epithelia reveal different and heterogeneous tumor-associated aberrations in glycosylation. (eng; includes abstract) By Cao Y, J Histochem Cytochem, 1997 Nov; Vol. 45 (11) , pp. 1547-57; PMID 9358856
75 Decreased MUC1 expression induces E-cadherin-mediated cell adhesion of breast cancer cell lines, (eng; includes abstract) By Kondo K, Cancer Res, 1998 May 1; Vol. 58 (9) , pp. 2014-9; PMID 9581847
76 庄则豪，王立东，高珊珊，范宗民，宋子博，齐义军，李燕杰，李吉学。河南食管癌高发区食管和贲门癌组织中粘蛋白1的表达。郑州大学学报医学版，2002，37(6) ：774-777
77 Expression of MUC1 in esophageal squamous-cell carcinoma and its relationship with prognosis of patients from Linzhou city, a high incidence area of northern China, (eng; includes abstract) By Song ZB, World J Gastroenterol, 2003 Mar; Vol. 9 (3) , pp. 404-7; PMID: 12632485
78 A novel transforming gene in a human malignant melanoma cell line (eng; includes abstract) By Padua RA, Nature, 1984 Oct 18-24; Vol. 311 (5987) , pp. 671-3; PMID 6090953
79 Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. (eng; includes abstract) By Naldini L, Oncogene, 1991 Apr; Vol. 6 (4) , pp. 501-4; PMID: 1827664
80 Expression of the Met/HGF receptor in normal and neoplastic human tissues, (eng; includes abstract) By Di Renzo MF, Oncogene, 1991 Nov; Vol. 6 (11) , pp. 1997-2003; PMID 1719465
81 Properties and functions of scatter factor/hepatocyte growth factor and
its receptor c-Met. (eng; includes abstract) By Weidner KM, Am J Respir Cell Mol Biol, 1993 Mar; Vol. 8 (3) , pp. 229-37; PMID 8383506
82 Hepatocyte growth factor/scatter factor induces not only scattering but also cohort migration of human colorectal-adenocarcinoma cells, (eng; includes abstract) By Nabeshima K, Int J Cancer, 1998 Dec 9; Vol. 78 (6) , pp. 750-9; PMID 9833769
83 HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice, (eng; includes abstract) By Kuba K, Cancer Res, 2000 Dec 1; Vol. 60 (23) , pp. 6737-43; PMID 11118060
84 A heparan sulfate-degrading endoglycosidase from rat liver tissue, (eng) By Hok M, Biochem Biophys Res Commun, 1975 Dec 15; Vol. 67 (4) , pp. 1422-8; PMID 1035
85 Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor, (eng; includes abstract) By Vlodavsky I, Cancer Metastasis Rev, 1996 Jun; Vol. 15 (2) , pp. 177-86; PMID 8842489
86 Heparanase as mediator of angiogenesis: mode of action, (eng) By Elkin M, FASEB J, 2001 Jul; Vol. 15 (9) , pp. 1661-3; PMID 11427519
87 Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis, (eng; includes abstract) By Vlodavsky I, Nat Med, 1999 Jul; Vol. 5 (7) , pp. 793-802; PMID 10395325
88 Quantitative analysis of heparanase gene expression in esophageal squamous cell carcinoma, (eng; includes abstract) By Ikeguchi M, Ann Surg Oncol, 2003 Apr-May; Vol. 10 (3) , pp. 297-304; PMID: 12679316
89 Heparanase gene expression and its correlation with spontaneous apoptosis in hepatocytes of cirrhotic liver and carcinoma, (eng; includes abstract) By Ikeguchi M, Eur J Cancer, 2003 Jan; Vol. 39 (1) ,
pp. 86-90; PMID: 12504663
90 王立东，刘宾，郭瑞锋，白永敏，孙超。河南食管癌高发区居民食管和贲门上皮癌变过程中c-erbB-2和c-myc的表达变化。郑州大学学报医学版，2002，37(6) ：739-742
91 Cloning and characterization of the human heparanase-1 (HPR1) gene promoter: role of GA-binding protein and Sp1 in regulating HPR1 basal promoter activity, (eng; includes abstract) By Jiang P, J Biol Chem, 2002 Mar 15; Vol. 277 (11) , pp. 8989-98; PMID 11779847
92 安继业，李吉学，王立东。食管癌的早期检测及对治疗效果的影响。肿瘤研究与临床，2003，15(1) ：65-68
93 L. D. Wang, Q. Zhou, R.Y Guo, B. C. Zhang, Y. Xing, Q. J. Li and C. S. Yang. Reproducibility of esophageal biopsy sampling procedure in a high esophageal cancer incidence are in northern China. Cancer Epidemiology, Biomarkers & Prevention. 1996, 5: 405-406
94 Zhou Q, Wang LD, Guo RY, Xing Y, Zhang BC and Li QJ. Reproducibility of esophageal biopsy sampling procedure. Chin J Cancer Res., 1995, 7: 298-304
95 Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China, (eng; includes abstract) By Dawsey SM, Cancer, 1998 Jul 15; Vol. 83 (2) , pp. 220-31; PMID 9669803
96 Iodine staining for early endoscopic detection of esophageal cancer in alcoholics, (eng; includes abstract) By Ban S, Endoscopy, 1998 Mar; Vol. 30 (3) , pp. 253-7; PMID 9615873
97 Ligresti R, Lightdale CJ. Diagnosis of esophgogastric tumors. Edoscopy, 1998, 30:73-75
98 Early detection of esophageal cancer by chromoendoscopy. (eng) By Steinbach G, Cancer, 1995 Sep 15; Vol. 76 (6) , pp. 919-21; PMID 8625215
99 Successful screening for early esophageal cancer in alcoholics using endoscopy and mucosa iodine staining, (eng; includes abstract) By Yokoyama A, Cancer, 1995 Sep 15; Vol. 76 (6) , pp. 928-34; PMID 8625217
2 杜百廉 主编 食管癌 中国科学技术出版社，1994
3 A randomized double-blind intervention study on the effect of calcium supplementation on esophageal precancerous lesions in a high-risk population in China, (eng; includes abstract) By Wang LD, Cancer Epidemiol Biomarkers Prev, 1993 Jan-Feb; Vol. 2 (1) , pp. 71-8; PMID. 8420615
4 曾益新 主编 肿瘤学 人民卫生出版社，1999
5 Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1) . (eng; includes abstract) By Ekstrom G, Biochem Pharmacol, 1989 Apr 15; Vol. 38 (8) , pp. 1313-9; PMID: 2495801
6 [CYP2D6 and GSTM1 genetic polymorphism and lung cancer susceptibility] (chi; includes abstract) By Gao J, Zhonghua Zhong Liu Za Zhi, 1998 May; Vol. 20 (3) , pp. 185-6; PMID 10921002
7 Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma, (eng; includes abstract) By Yu MW, Gastroenterology, 1995 Oct; Vol. 109 (4) , pp. 1266-73; PMID: 7557094
8 Lin et al. Cancer Epidemiol Biomarkers Prev, 7: 1013-1018, 1998
9 Inherited polymorphism in the N-acetyltransferase 1 (NAT1) and 2 (NAT2) genes and susceptibility to gastric and colorectal adenocarcinoma. (eng; includes abstract) By Katoh T, Int J Cancer, 2000 Jan 1; Vol. 85 (1) , pp. 46-9; PMID 10585581
10 RA Woutersen, LM Appelman, A Van Garderen Hoetmer, etal. In halation toxicity of acetal dehydeinrats. III. Carcinogeni-citystudy [J] Toxicology, 1986, 41:213-231．
11 Role of oxidative DNA damage in cancer initiation and promotion. (eng; includes abstract) By Poulsen HE, Eur J Cancer Prev, 1998 Feb; Vol. 7 (1) , pp. 9-16; PMID 9511847
12 邢德印，谭文，宋南，林东昕。DNA修复基因hOGG1多态与食管癌遗传易感性。中华医学遗传学杂志，2000，17(6) ：377-381
13 Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals, (eng; includes abstract) By Clerici M, J Clin Invest, 1993 Mar; Vol. 91 (3) , pp. 759-65, PMID: 8450057
14 Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency, (eng; includes abstract) By Waldrop SL, J Clin Invest, 1997 Apr 1, Vol. 99 (7) , pp. 1739-50; PMID 9120019
15 舒青，马群风，刘素英，张宁。Rb基因多态性与食管癌遗传易感性的研究。中华外科杂志，2000，38(5) ：375-378
16 邓琳，曹亚。cyclinD1的多态性与肿瘤。国外医学肿瘤学分册，2001， 28(3) ：163-164
17 Microsatellite instability. Shifting concepts in tumorigenesis. (eng) By Brentnall TA, Am J Pathol, 1995 Sep; Vol. 147 (3) , pp. 561-3; PMID 7677169
18 Human fetal G gamma-and A gamma-globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes, (eng; includes abstract) By Slightom JL, Cell, 1980 Oct; Vol. 21 (3) , pp. 627-38; PMID 7438203
19 Molecular biology. CACA sequences-the ends and the means? (eng)
By Rogers J, Nature, 1983 Sep 8-14; Vol. 305 (5930) , pp. 101-2; PMID: 6888554
20 Simple sequences are ubiquitous repetitive components of eukaryotic genomes, (eng; includes abstract) By Tautz D, Nucleic Acids Res, 1984 May 25, Vol. 12 (10) , pp. 4127-38; PMID: 6328411
21 Microsatellites for linkage analysis of genetic traits, (eng; includes abstract) By Hearne CM, Trends Genet, 1992 Aug; Vol. 8 (8) , pp. 288-94; PMID: 1509520
22 Occurrence of microsatellite instability in gastric carcinoma is associated with enhanced expression of erbB-2 oncoprotein. (eng; includes abstract) By Lin JT, Cancer Res, 1995 Apr 1; Vol. 55 (7) , pp. 1428-30; PMID 7882346
23 李卫东，王亮，王秀琴。食管癌组织染色体位点特异性的杂合性丢失和微卫星DNA序列不稳定。中华医学遗传学杂志，1996，13(4) ：194-197
24 A genetic model for colorectal tumorigenesis. (eng) By Fearon ER, Cell, 1990 Jun 1; Vol. 61 (5) , pp. 759-67; PMID 2188735
25 Mutation analysis of the CHK2 gene in breast carcinoma and other cancers, (eng; includes abstract) By Ingvarsson S, Breast Cancer Res, 2002; Vof. 4 (3) , pp. R4; PMID 12052256
26 Labeling index and labeling distribution of cells in esophageal epithelium of individuals at increased risk for esophageal cancer in Huixian, China, (eng; includes abstract) By Wang LD, Cancer Res, 1990 May 1; Vol. 50 (9) , pp. 2651-3; PMID: 2328490
27 Surfing the p53 network, (eng) By Vogelstein B, Nature, 2000 Nov 16; Vol. 408 (6810) , pp. 307-10; PMID 11099028
28 The p53 family: same response, different signals? (eng; includes abstract) By Chen X, Mol Med Today, 1999 Sep; Vol. 5 (9) , pp. 387-92; PMID: 10462750
29 p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities, (eng; includes abstract) By Yang A, Mol Cell, 1998 Sep; Vol. 2 (3) , pp. 305-16; PMID. 9774969
30 The p53 gene family, (eng; includes abstract) By Kaelin WG Jr, Oncogene, 1999 Dec 13; Vol. 18 (53) , pp. 7701-5; PMID. 10618710
31 p63． (eng; includes abstract) By Little NA, Int J Biochem Cell Biol, 2002 Jan; Vol. 34 (1) , pp. 6-9; PMID 11733180
32 p51A (TAp63gamma), a p53 homolog, accumulates in response to DNA damage for cell regulation, (eng; includes abstract) By Katoh I, Oncogene, 2000 Jun 22; Vol. 19 (27) , pp. 3126-30; PMID. 10871867
33 Down-regulation of p63 is required for epidermal UV-B-induced apoptosis. (eng; includes abstract) By Liefer KM, Cancer Res, 2000 Aug 1; Vol. 60 (15) , pp. 4016-20; PMID 10945600
34 P63 and P73: P53 mimics, menaces and more, (eng; includes abstract) By Yang A, Nat Rev Mol Cell Biol, 2000 Dec; Vol. 1 (3) , pp. 199-207; PMID 11252895
35 AIS is an oncogene amplified in squamous cell carcinoama. (eng;includes abstract) By Hibi K,Proc Natl acad Sci U S A.2000 May 9;Vol 97(10) ,pp 5462-7; PMID 10805802
36 Characterization of the expression pattern of p63 alpha and delta Np63 alpha in benign and malignant oral epithelial lesions, (eng; includes abstract) By Nylander K, Int J Cancer, 2000 Aug 1; Vol. 87 (3) , pp. 368-72; PMID. 10897041
37 High level expression of deltaN-p63: a mechanism for the inactivation of p53 in undifferentiated nasopharyngeal carcinoma (NPC)? (eng; includes abstract) By Crook T, Oncogene, 2000 Jul 13; Vol. 19 (30) , pp. 3439-44; PMID 10918601
38 Elevated expression of p63 protein in human esophageal squamous
cell carcinomas, (eng; includes abstract) By Hu H, Int J Cancer, 2002 Dec 20; Vol. 102 (6) , pp. 580-3; PMID: 12447998
39 TP53 mutations, amplification of P63 and expression of cell cycle proteins in squamous cell carcinoma of the oesophagus from a low incidence area in Western Europe, (eng; includes abstract) By Tanie P, Br J Cancer, 2001 Sep 1; Vol. 85 (5) , pp. 721-6; PMID 11531258
40 The p53 tumour suppressor gene, (eng; includes abstract) By Levine AJ, Nature, 1991 Jun 6; Vol. 351 (6326) , pp. 453-6; PMID 2046748
41 王立东，陈虹。肿瘤抑制基因P53-Rb系统变化与食管癌变关系研究及展望。世界华人消化杂志，2001，9(4) ：367-371
42 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. (eng; includes abstract) By Harper JW, Cell, 1993 Nov 19; Vol. 75 (4) , pp. 805-16; PMID 8242751
43 p21 is a universal inhibitor of cyclin kinases. (eng; includes abstract) By Xiong Y, Nature, 1993 Dec 16; Vol. 366 (6456) , pp. 701-4; PMID 8259214
44 Overexpression of p21WAF1/CIP1 induces growth arrest, giant cell formation and apoptosis in human breast carcinoma cell lines, (eng; includes abstract) By Sheikh MS, Oncogene, 1995 Nov 2; Vol. 11 (9) , pp. 1899-905; PMID 7478620
45 王文亮，黄高。肝细胞肝癌组织中p21WAF1的表达及其意义。中华医学杂志，1998，78(1) ：74-75
46 王立东，周琦，高珊珊，杨光育。人贲门癌WAF-1基因和P53肿瘤抑制基因表达的初步研究。河南医科大学学报，1995，30(2) ：148-153
47 The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis, (eng, includes abstract) By Bremnes RM, Lung Cancer, 2002 May; Vol. 36 (2) , pp. 115-24; PMID. 11955645
48 E-cadherin expression in primary and metastatic thoracic neoplasms and in Barrett's oesophagus, (eng; includes abstract) By Bongiomo PF,
Br J Cancer, 1995 Jan; Vol. 71 (1) , pp. 166-72; PMID 7819034
49 E-cadherin expression in renal cell cancer and its significance in metastasis and survival, (eng; includes abstract) By Katagiri A, Br J Cancer, 1995 Feb; Vol. 71 (2) , pp. 376-9; PMID 7841055
50 E-cadherin but not N-cadherin expression is correlated with the intracellular distribution of catenins in human hepatocellular carcinomas, (eng; includes abstract) By Nuruki K, Oncol Rep, 1998 Sep-Oct; Vol. 5 (5) , pp. 1109-14; PMID 9683818
51 Characterization of DNA polymorphisms in the E-cadherin gene (CDH1) promoter region, (eng; includes abstract) By Nakamura A, Mutat Res, 2002 May 22; Vol. 502 (1-2) , pp. 19-24; PMID 11996968
52 Prognostic significance of CyclinDI and E-Cadherin in patients with esophageal squamous cell carcinoma: multiinstitutional retrospective analysis. Research Committee on Malignancy of Esophageal Cancer, Japanese Society for Esophageal Diseases, (eng; includes abstract), J Am Coll Surg, 2001 Jun; Vol. 192 (6) , pp. 708-18; PMID 11400964
53 A novel cyclin encoded by a bch-linked candidate oncogene. (eng; includes abstract) By Motokura T, Nature, 1991 Apr 11; Vol. 350 (6318) , pp. 512-5; PMID 1826542
54 Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining, (eng; includes abstract) By Gillett C, Cancer Res, 1994 Apr 1; Vol. 54 (7) , pp. 1812-7; PMID 8137296
55 Amplification and expression of the human cyclin D gene in esophageal cancer, (eng; includes abstract) By Jiang W, Cancer Res, 1992 May 15; Vol. 52 (10) , pp. 2980-3; PMID 1533816
56 The PRAD-1/cyclin D1 oncogene product accumulates aberrantly in a subset of colorectal carcinomas, (eng; includes abstract) By Bartkova J, Int J Cancer, 1994 Aug 15; Vol. 58 (4) , pp. 568-73; PMID 8056453
57 Frequent alterations of cell cycle regulators in early-stage breast lesions as detected by immunohistochemistry. (eng; includes abstract) By Marsh KL, Br J Cancer, 1998 May; Vol. 77 (9) , pp. 1460-8; PMID: 9652762
58 Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. (eng; includes abstract) By Quelle DE, Genes Dev, 1993Aug; Vol. 7 (8) , pp. 1559-71; PMID 8339933
59 Altered p16/MTS1/CDKN2 and cyclin D1/PRAD-1 gene expression is associated with the prognosis of squamous cell carcinoma of the esophagus, (eng; includes abstract) By Takeuchi H, Clin Cancer Res, 1997 Dec; Vol. 3 (12 Pt 1) , pp. 2229-36; PMID: 9815619
60 Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis. (eng; includes abstract) By Wang LD, Int J Cancer, 1994 Nov 15; Vol. 59 (4) , pp. 514-9; PMID: 7960222
61 王立东，郑树，刘宾，郭瑞锋，王启鸣，范宗民，陈虹，庄则豪，秦艳茹，安继业，孙超，高社干，李吉林，宋子博，贺新伟，李吉学，李燕杰，高珊珊。郭花芹。河南食管癌高发区居民食管色素镜检查及手术标本碘染色结果分析。郑州大学学报(医学板)，2002，37(6) ：720-732。
62 Fragile X genotype characterized by an unstable region of DNA. (eng; includes abstract) By Yu S, Science, 1991 May 24, Vol. 252 (5010) , pp. 1179-81 ,PMID. 2031189
63 Precise localization of aphidicolin-induced breakpoints on the short arm of human chromosome 3． (eng; includes abstract) By Paradee W, Genomics, 1995 May 20; Vol. 27 (2) , pp. 358-61; PMID 7558007
64 The FHIT gene, spanning the chromosome 3p14． 2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers, (eng; includes abstract) By Ohta M, Cell, 1996 Feb 23; Vol. 84 (4) , pp. 587-97; PMID 8598045
65 The neu oncogene encodes an epidermal growth factor receptor-related protein, (eng; includes abstract) By Bargmann Cl, Nature, 1986 Jan 16-22; Vol. 319 (6050) , pp. 226-30; PMID. 3945311
66 Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line, (eng; includes abstract) By Fukushige S, Mol Cell Biol, 1986 Mar; Vol. 6 (3) , pp. 955-8; PMID 2430175
67 Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer, (eng; includes abstract) By Wright C, Cancer Res, 1989 Apr 15; Vol. 49 (8) , pp. 2087-90; PMID 2564806
68 Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression, (eng; includes abstract) By Reis CA, Cancer Res, 1999 Mar 1; Vol. 59 (5) , pp. 1003-7; PMID 10070955
69 Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini, (eng; includes abstract) By Ligtenberg MJ, J Biol Chem, 1990 Apr 5; Vol. 265 (10) , pp. 5573-8; PMID 2318825
70 MUC1 and cancer, (eng; includes abstract) By Taylor-Papadimitriou J, Biochim Biophys Acta, 1999 Oct 8; Vol. 1455 (2-3) , pp. 301-13; PMID 10571020
71 Phosphorylation of the cytoplasmic domain of the MUC1 mucin correlates with changes in cell-cell adhesion, (eng; includes abstract) By Quin RJ, Int J Cancer, 2000 Aug 15; Vol. 87 (4) , pp. 499-506; PMID 10918188
72 Mucin gene expression in ovarian cancers, (eng; includes abstract) By Giuntoli RL 2nd, Cancer Res, 1998 Dec 1; Vol. 58 (23) , pp. 5546-50; PMID 9850092
73 Mucin gene transcripts in benign and borderline mucinous tumours of
the ovary: an in situ hybridization study, (eng; includes abstract) By Boman F, J Pathol, 2001 Mar; Vol. 193 (3) , pp. 339-44; PMID 11241413
74 Mucins (MUC1 and MUC3) of gastrointestinal and breast epithelia reveal different and heterogeneous tumor-associated aberrations in glycosylation. (eng; includes abstract) By Cao Y, J Histochem Cytochem, 1997 Nov; Vol. 45 (11) , pp. 1547-57; PMID 9358856
75 Decreased MUC1 expression induces E-cadherin-mediated cell adhesion of breast cancer cell lines, (eng; includes abstract) By Kondo K, Cancer Res, 1998 May 1; Vol. 58 (9) , pp. 2014-9; PMID 9581847
76 庄则豪，王立东，高珊珊，范宗民，宋子博，齐义军，李燕杰，李吉学。河南食管癌高发区食管和贲门癌组织中粘蛋白1的表达。郑州大学学报医学版，2002，37(6) ：774-777
77 Expression of MUC1 in esophageal squamous-cell carcinoma and its relationship with prognosis of patients from Linzhou city, a high incidence area of northern China, (eng; includes abstract) By Song ZB, World J Gastroenterol, 2003 Mar; Vol. 9 (3) , pp. 404-7; PMID: 12632485
78 A novel transforming gene in a human malignant melanoma cell line (eng; includes abstract) By Padua RA, Nature, 1984 Oct 18-24; Vol. 311 (5987) , pp. 671-3; PMID 6090953
79 Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. (eng; includes abstract) By Naldini L, Oncogene, 1991 Apr; Vol. 6 (4) , pp. 501-4; PMID: 1827664
80 Expression of the Met/HGF receptor in normal and neoplastic human tissues, (eng; includes abstract) By Di Renzo MF, Oncogene, 1991 Nov; Vol. 6 (11) , pp. 1997-2003; PMID 1719465
81 Properties and functions of scatter factor/hepatocyte growth factor and
its receptor c-Met. (eng; includes abstract) By Weidner KM, Am J Respir Cell Mol Biol, 1993 Mar; Vol. 8 (3) , pp. 229-37; PMID 8383506
82 Hepatocyte growth factor/scatter factor induces not only scattering but also cohort migration of human colorectal-adenocarcinoma cells, (eng; includes abstract) By Nabeshima K, Int J Cancer, 1998 Dec 9; Vol. 78 (6) , pp. 750-9; PMID 9833769
83 HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice, (eng; includes abstract) By Kuba K, Cancer Res, 2000 Dec 1; Vol. 60 (23) , pp. 6737-43; PMID 11118060
84 A heparan sulfate-degrading endoglycosidase from rat liver tissue, (eng) By Hok M, Biochem Biophys Res Commun, 1975 Dec 15; Vol. 67 (4) , pp. 1422-8; PMID 1035
85 Involvement of heparan sulfate and related molecules in sequestration and growth promoting activity of fibroblast growth factor, (eng; includes abstract) By Vlodavsky I, Cancer Metastasis Rev, 1996 Jun; Vol. 15 (2) , pp. 177-86; PMID 8842489
86 Heparanase as mediator of angiogenesis: mode of action, (eng) By Elkin M, FASEB J, 2001 Jul; Vol. 15 (9) , pp. 1661-3; PMID 11427519
87 Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis, (eng; includes abstract) By Vlodavsky I, Nat Med, 1999 Jul; Vol. 5 (7) , pp. 793-802; PMID 10395325
88 Quantitative analysis of heparanase gene expression in esophageal squamous cell carcinoma, (eng; includes abstract) By Ikeguchi M, Ann Surg Oncol, 2003 Apr-May; Vol. 10 (3) , pp. 297-304; PMID: 12679316
89 Heparanase gene expression and its correlation with spontaneous apoptosis in hepatocytes of cirrhotic liver and carcinoma, (eng; includes abstract) By Ikeguchi M, Eur J Cancer, 2003 Jan; Vol. 39 (1) ,
pp. 86-90; PMID: 12504663
90 王立东，刘宾，郭瑞锋，白永敏，孙超。河南食管癌高发区居民食管和贲门上皮癌变过程中c-erbB-2和c-myc的表达变化。郑州大学学报医学版，2002，37(6) ：739-742
91 Cloning and characterization of the human heparanase-1 (HPR1) gene promoter: role of GA-binding protein and Sp1 in regulating HPR1 basal promoter activity, (eng; includes abstract) By Jiang P, J Biol Chem, 2002 Mar 15; Vol. 277 (11) , pp. 8989-98; PMID 11779847
92 安继业，李吉学，王立东。食管癌的早期检测及对治疗效果的影响。肿瘤研究与临床，2003，15(1) ：65-68
93 L. D. Wang, Q. Zhou, R.Y Guo, B. C. Zhang, Y. Xing, Q. J. Li and C. S. Yang. Reproducibility of esophageal biopsy sampling procedure in a high esophageal cancer incidence are in northern China. Cancer Epidemiology, Biomarkers & Prevention. 1996, 5: 405-406
94 Zhou Q, Wang LD, Guo RY, Xing Y, Zhang BC and Li QJ. Reproducibility of esophageal biopsy sampling procedure. Chin J Cancer Res., 1995, 7: 298-304
95 Mucosal iodine staining improves endoscopic visualization of squamous dysplasia and squamous cell carcinoma of the esophagus in Linxian, China, (eng; includes abstract) By Dawsey SM, Cancer, 1998 Jul 15; Vol. 83 (2) , pp. 220-31; PMID 9669803
96 Iodine staining for early endoscopic detection of esophageal cancer in alcoholics, (eng; includes abstract) By Ban S, Endoscopy, 1998 Mar; Vol. 30 (3) , pp. 253-7; PMID 9615873
97 Ligresti R, Lightdale CJ. Diagnosis of esophgogastric tumors. Edoscopy, 1998, 30:73-75
98 Early detection of esophageal cancer by chromoendoscopy. (eng) By Steinbach G, Cancer, 1995 Sep 15; Vol. 76 (6) , pp. 919-21; PMID 8625215
99 Successful screening for early esophageal cancer in alcoholics using endoscopy and mucosa iodine staining, (eng; includes abstract) By Yokoyama A, Cancer, 1995 Sep 15; Vol. 76 (6) , pp. 928-34; PMID 8625217
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