Ndr2基因在肺癌中的表达和抑制肺腺癌细胞GLC-82增殖的实验研究
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摘要
目的意义：Ndr2基因是1999年从正常人全脑cDNA文库中克隆到的新基因[GenBank登录号AFl59092]染色体定位于14q12.1，基因组中由15个内含子，16个外显子构成。Ndr2基因的cDNA全长为2024bp，编码357个氨基酸的蛋白质，分子量约41kD。目前研究表明，Ndr2基因在多种肿瘤组织或细胞系如结肠癌、胶质瘤、白血病、淋巴瘤和腮腺癌中无表达或低表达，相反在上述肿瘤相应的正常组织细胞中有较高水平的表达。另外在中枢神经系统的大脑皮质、白质、神经核，唾液腺上皮细胞和骨骼肌细胞中高表达。同时基因转染实验表明，Ndr2可抑制胶质瘤BT325细胞由G1期向S期的过渡，因此，推测Ndr2可能是一种新的抑癌基因。本研究的目的意义是探讨Ndr2基因在肺癌发病机制中的作用，确定Ndr2基因的功能，为肺癌的防治提供理论依据。
方法：采用RT-PCR，Westem blot和免疫组织化学方法确定Ndr2在正常组织和肺癌组织的表达。利用蜕皮素诱导的哺乳动物真核表达载体，将Ndr2
第四车医人学博士lr2上
基因构建到I匕载体pmD中，同时将含NdlZ 基因的融合载体转染肺8＆癌GLC｛2
细胞，经过鉴定确定NdrZ基因的成功转染。MTT法观察转染肺腺癌GLC－82
细胞的生长情况。细胞集落实验观察细胞表型的改变。流式细胞仪测定转染
肺腺癌CLC－82细胞的细胞周期变化。通过V尼stem blot观察细胞周期素＊
在NdrZ基固转染肺腺癌 GLC－82细胞和空载体转染肺腺癌 GLC－82细胞的表
达差异。通过腺病毒p53基因转染肺腺癌 AX9细胞，观察p】基因对Ndl·2
基因表达的影响c
结果：经过RT－PCR方法提取正常肺组织的总RNA，反转录为CDNA，PCR
结果显示NdrZ在所检测的不同正常肺组织都有高表达。在正常肺组织中NdrZ
基因高表达；而其相应的肺癌组织呈现低表达或无表达，26例鳞癌中，有9
例无表达，8例4th达，9例高表达。14例腺癌中，4仔IJ无表达；3例低表达，
7例高表达。11例小细J腑癌有 4例无表达；3例4th达，4例高表达。正常
肺组织和肺癌的NdrZ表冰盯匕差异显著；P＜001。Western blot和免疫组织化
学方法进一步证实了这一结果。免疫组织化学结果显示NdrZ蛋白在正常气道
上皮细胞、平滑肌细胞、软骨细胞、浆液腺细胞、肺泡细胞胞浆中有高表达。
结果显示＊山2的表达与肺癌的分化相关，4例低分化鳞癌和二例低分化腺癌
冲瘤组织＊山二均无表达。3例高分化鳞癌和2例高分化腺癌与其正常肺组织
相比，NdrZ均高表达、19例中分化鳞癌中，有 5 ｛IJ无表达，8例低表达，6
例高表达。10例中分l匕腺癌，2例无表达；3伶低表达，5例高表达。11例 JJ、
细Ktw癌有4例无表达，3例fib达；4例高表达。另外，N山二的表达与肺癌
分期相关，在 40例 NSCLC中，6例 1期肺癌有 l伸J4th达。12例 11期肺癌
中 4例 NdrZ无表达，3例4ha达，5例高表达。22如1 Ill期肺癌中有 9伊J NdrZ
无表达，7例fto达，6例高表达。在门 例 SCLC中，l例 11期肺癌中 NdrZ
高表达。8 ｛Fd Ill期肺癌中 2 ｛II NdrZ无表达；3 ｛FJ｛Mi达，3 ｛FJ高表达，2 ｛FJ IV
期肺癌 NdrZ Jb无表达。
5
第四军医大学博士论文
利用蜕皮素诱导的哺乳动物真核表达载体转染NdrZ基因的肺腺癌GLC－82
细胞经过鉴定，NdrZ基因成功转染到肺腺癌GLC－82细胞内，蜕皮素诱导后
NdIZ基固得到高表达。M”IJ”法测定和细胞集落实验显示转染NdrZ基因的肺
腺癌＊＊G82细胞在蜕皮素诱导后，细Bbe殖受到抑制。流式细胞仪结果显示
NdrZ转染细胞存在GO／GI期细胞明显增多，NdrZ转染肺腺癌 GLC－82细胞
GO心1期细胞百分率为“．4O％，GZ－M期为6．刀％，S期为27．89％c而空载体
pmD季染肺腺癌 GLC－82 i田胞GO／GI期细胞百分率为 52．67O，GZ－A4期为
17．84地S期为29叩％。提示NdrZ能够通过细胞周期阻滞抑制肿瘤细胞增殖。
V乍stem Mot结果显示NdrZ转染肺腺癌GLC－82细胞的细胞周期素DI表达比
空载体转染肺腺癌hCE2 i邮胞的表达明显减弱。将腺病毒载体p53基因转染
肺腺癌 A刃9细胞，发现p53的表达能够上调NdrZ的表达。
结论：NdrZ在正常肺组织中高表达，而在肺癌组织中出现｛明达或无表
达。明确了NdrZ蛋白在正常气道上皮细胞、平滑肌细胞、软骨细胞、浆液腺
细胞、肺泡细胞胞浆中有高表达。NdrZ能够抑制肺腺癌 GLC七2细胞的增殖；
并能产生＊期阻滞，抑制细胞周期素＊的表达。p53的表达能够上调NdrZ
的表达。本研究的结果进一步支持NdrZ基因是一种新的抑癌基因；在肺癌中
INTRODUCTION: Ndr2 is a newly found member of Ndr gene family which consists of Ndrl/RTP/Drgl, Ndr2, Ndr3 and Ndr4. The precise molecular and cellular function of members of this family is still unknown. But they are known to be involved in cellular differentiation events. Ndrl was first identified, and present investigation suggests it might be related to differentiation and anti-oncogenesis. Human Ndr2 was found by subtractive hybridization of human glioma tissue with its normal counterpart. Our preliminary investigation showed that the mRNA expression patterns of Ndr2 is dominantly in salivary gland, brain, skeletal muscle and mammary gland, and low expression in bone marrow, testis, periperal blood, and placenta, but it did not expressed in leukocyte, colorectal and some tumor cell line such as, Hela S3, leukemia cell, Bukitt's lymphoma, adenocarcinoma SW480. The distinct expression patterns of the four family members suggest that Ndr2 might have relationship with
tumor.
AIM: To explore whether Ndr2 is related to tumor development, the expression of Ndr2 in lung cancer tissue and its role in lung cancer cell were observed.
METHODS: RT-PCR analysis of Ndr2 expression in lung cacinoma specimens was used. Lung carcinoma specimens were taken from liquid azote and homogenized soaked in Trizol, Total RNA was isolated and quantified. Total RNA was used for RT-PCR reaction to amplify Ndr2. Western blotting assay was used . The frozen tissue was homogenized soaked in lysis buffer, the total protein quantity was determined by quantitative kit, and then applied to SDS-PAGE. The separated protein on SDS-PAGE was electro-transfered onto NC membrane. Western blotting assay was carried out as routine method described as reference . The routine immunohistochemistry was carried out using anti-Ndr2 monoantibody. Stable transfection and inducible expression of Ndr2 were used in lung adenocarcinoma ceh1. Full length cDNA encoding human Ndr2 was inserted into ecdysone-inducible vector pIND, named as pIND-Ndr2. Recombinant vector containg Ndr2 and another helper vector pV were co-transfected into GLC-82 lung carcinoma cells. Single clone resistant to both zeocin and G418 was isolated and cultured for enlarging its number. Cells were induced by ponasterone A , and the expression of Ndr2 was assayed by RT-PCR and Western blotting as described above. Cell growth is assayed by MTT method. Row Cytometry was used to determine cell cycle. To observe the expression of Ndr2, recombinant vector adenovirus-p53 was transfected in A549 lung carcinoma cell.
RESULTS AND CONCLUSIONS: To explore whether Ndr2 is related to tumor development, its expression was evaluated firstly in 51 cases lung-carcinoma and equivalent number of normal tissue collected from clinical operation. RT-PCR
assay indicated that according to tumor-free lung tissue, displayed completely negative in 9 of 26 cases of squamous carcinoma , low expression in 8 of 26 cases of squamous carcinoma; displayed completely negative in 4 of 14 cases adenocarcinoma, low expression in 3 of 14 cases adenocarcinoma; and displayed completely negative in 4 of 11 cases small cell lung carcinoma, low expression in 4 of 1 leases small cell lung carcinoma. RT-PCR results were confirmed by Western blotting and imrnunohistochernistry by using monoclonal antibody to Ndr2. The data above demonstrated that Ndr2 displayed down-regulated expression in lung carcinoma tissue in both transcription and protein level. These data indicated that Ndr2 expression was down-regulated in lung carcinoma, and related to tumor grade and phase development. The lower the tumor grade is, the higher the negative rate of Ndr2 expression is. The later the tumor phase is, the higher the negative rate of Ndr2 expression is. Additionally, human lung carcinoma cell line GLC-82 stably transfected with Ndr2 was acquired and the induced over-expression of Ndr2 resulted into Gl phase inhibition, and the growth of the tumor cell was reduced, and the clone forming ability was also inhibited, the expression of cy
方法：采用RT-PCR，Westem blot和免疫组织化学方法确定Ndr2在正常组织和肺癌组织的表达。利用蜕皮素诱导的哺乳动物真核表达载体，将Ndr2
第四车医人学博士lr2上
基因构建到I匕载体pmD中，同时将含NdlZ 基因的融合载体转染肺8＆癌GLC｛2
细胞，经过鉴定确定NdrZ基因的成功转染。MTT法观察转染肺腺癌GLC－82
细胞的生长情况。细胞集落实验观察细胞表型的改变。流式细胞仪测定转染
肺腺癌CLC－82细胞的细胞周期变化。通过V尼stem blot观察细胞周期素＊
在NdrZ基固转染肺腺癌 GLC－82细胞和空载体转染肺腺癌 GLC－82细胞的表
达差异。通过腺病毒p53基因转染肺腺癌 AX9细胞，观察p】基因对Ndl·2
基因表达的影响c
结果：经过RT－PCR方法提取正常肺组织的总RNA，反转录为CDNA，PCR
结果显示NdrZ在所检测的不同正常肺组织都有高表达。在正常肺组织中NdrZ
基因高表达；而其相应的肺癌组织呈现低表达或无表达，26例鳞癌中，有9
例无表达，8例4th达，9例高表达。14例腺癌中，4仔IJ无表达；3例低表达，
7例高表达。11例小细J腑癌有 4例无表达；3例4th达，4例高表达。正常
肺组织和肺癌的NdrZ表冰盯匕差异显著；P＜001。Western blot和免疫组织化
学方法进一步证实了这一结果。免疫组织化学结果显示NdrZ蛋白在正常气道
上皮细胞、平滑肌细胞、软骨细胞、浆液腺细胞、肺泡细胞胞浆中有高表达。
结果显示＊山2的表达与肺癌的分化相关，4例低分化鳞癌和二例低分化腺癌
冲瘤组织＊山二均无表达。3例高分化鳞癌和2例高分化腺癌与其正常肺组织
相比，NdrZ均高表达、19例中分化鳞癌中，有 5 ｛IJ无表达，8例低表达，6
例高表达。10例中分l匕腺癌，2例无表达；3伶低表达，5例高表达。11例 JJ、
细Ktw癌有4例无表达，3例fib达；4例高表达。另外，N山二的表达与肺癌
分期相关，在 40例 NSCLC中，6例 1期肺癌有 l伸J4th达。12例 11期肺癌
中 4例 NdrZ无表达，3例4ha达，5例高表达。22如1 Ill期肺癌中有 9伊J NdrZ
无表达，7例fto达，6例高表达。在门 例 SCLC中，l例 11期肺癌中 NdrZ
高表达。8 ｛Fd Ill期肺癌中 2 ｛II NdrZ无表达；3 ｛FJ｛Mi达，3 ｛FJ高表达，2 ｛FJ IV
期肺癌 NdrZ Jb无表达。
5
第四军医大学博士论文
利用蜕皮素诱导的哺乳动物真核表达载体转染NdrZ基因的肺腺癌GLC－82
细胞经过鉴定，NdrZ基因成功转染到肺腺癌GLC－82细胞内，蜕皮素诱导后
NdIZ基固得到高表达。M”IJ”法测定和细胞集落实验显示转染NdrZ基因的肺
腺癌＊＊G82细胞在蜕皮素诱导后，细Bbe殖受到抑制。流式细胞仪结果显示
NdrZ转染细胞存在GO／GI期细胞明显增多，NdrZ转染肺腺癌 GLC－82细胞
GO心1期细胞百分率为“．4O％，GZ－M期为6．刀％，S期为27．89％c而空载体
pmD季染肺腺癌 GLC－82 i田胞GO／GI期细胞百分率为 52．67O，GZ－A4期为
17．84地S期为29叩％。提示NdrZ能够通过细胞周期阻滞抑制肿瘤细胞增殖。
V乍stem Mot结果显示NdrZ转染肺腺癌GLC－82细胞的细胞周期素DI表达比
空载体转染肺腺癌hCE2 i邮胞的表达明显减弱。将腺病毒载体p53基因转染
肺腺癌 A刃9细胞，发现p53的表达能够上调NdrZ的表达。
结论：NdrZ在正常肺组织中高表达，而在肺癌组织中出现｛明达或无表
达。明确了NdrZ蛋白在正常气道上皮细胞、平滑肌细胞、软骨细胞、浆液腺
细胞、肺泡细胞胞浆中有高表达。NdrZ能够抑制肺腺癌 GLC七2细胞的增殖；
并能产生＊期阻滞，抑制细胞周期素＊的表达。p53的表达能够上调NdrZ
的表达。本研究的结果进一步支持NdrZ基因是一种新的抑癌基因；在肺癌中
INTRODUCTION: Ndr2 is a newly found member of Ndr gene family which consists of Ndrl/RTP/Drgl, Ndr2, Ndr3 and Ndr4. The precise molecular and cellular function of members of this family is still unknown. But they are known to be involved in cellular differentiation events. Ndrl was first identified, and present investigation suggests it might be related to differentiation and anti-oncogenesis. Human Ndr2 was found by subtractive hybridization of human glioma tissue with its normal counterpart. Our preliminary investigation showed that the mRNA expression patterns of Ndr2 is dominantly in salivary gland, brain, skeletal muscle and mammary gland, and low expression in bone marrow, testis, periperal blood, and placenta, but it did not expressed in leukocyte, colorectal and some tumor cell line such as, Hela S3, leukemia cell, Bukitt's lymphoma, adenocarcinoma SW480. The distinct expression patterns of the four family members suggest that Ndr2 might have relationship with
tumor.
AIM: To explore whether Ndr2 is related to tumor development, the expression of Ndr2 in lung cancer tissue and its role in lung cancer cell were observed.
METHODS: RT-PCR analysis of Ndr2 expression in lung cacinoma specimens was used. Lung carcinoma specimens were taken from liquid azote and homogenized soaked in Trizol, Total RNA was isolated and quantified. Total RNA was used for RT-PCR reaction to amplify Ndr2. Western blotting assay was used . The frozen tissue was homogenized soaked in lysis buffer, the total protein quantity was determined by quantitative kit, and then applied to SDS-PAGE. The separated protein on SDS-PAGE was electro-transfered onto NC membrane. Western blotting assay was carried out as routine method described as reference . The routine immunohistochemistry was carried out using anti-Ndr2 monoantibody. Stable transfection and inducible expression of Ndr2 were used in lung adenocarcinoma ceh1. Full length cDNA encoding human Ndr2 was inserted into ecdysone-inducible vector pIND, named as pIND-Ndr2. Recombinant vector containg Ndr2 and another helper vector pV were co-transfected into GLC-82 lung carcinoma cells. Single clone resistant to both zeocin and G418 was isolated and cultured for enlarging its number. Cells were induced by ponasterone A , and the expression of Ndr2 was assayed by RT-PCR and Western blotting as described above. Cell growth is assayed by MTT method. Row Cytometry was used to determine cell cycle. To observe the expression of Ndr2, recombinant vector adenovirus-p53 was transfected in A549 lung carcinoma cell.
RESULTS AND CONCLUSIONS: To explore whether Ndr2 is related to tumor development, its expression was evaluated firstly in 51 cases lung-carcinoma and equivalent number of normal tissue collected from clinical operation. RT-PCR
assay indicated that according to tumor-free lung tissue, displayed completely negative in 9 of 26 cases of squamous carcinoma , low expression in 8 of 26 cases of squamous carcinoma; displayed completely negative in 4 of 14 cases adenocarcinoma, low expression in 3 of 14 cases adenocarcinoma; and displayed completely negative in 4 of 11 cases small cell lung carcinoma, low expression in 4 of 1 leases small cell lung carcinoma. RT-PCR results were confirmed by Western blotting and imrnunohistochernistry by using monoclonal antibody to Ndr2. The data above demonstrated that Ndr2 displayed down-regulated expression in lung carcinoma tissue in both transcription and protein level. These data indicated that Ndr2 expression was down-regulated in lung carcinoma, and related to tumor grade and phase development. The lower the tumor grade is, the higher the negative rate of Ndr2 expression is. The later the tumor phase is, the higher the negative rate of Ndr2 expression is. Additionally, human lung carcinoma cell line GLC-82 stably transfected with Ndr2 was acquired and the induced over-expression of Ndr2 resulted into Gl phase inhibition, and the growth of the tumor cell was reduced, and the clone forming ability was also inhibited, the expression of cy
引文
1． Rozengurt E. Autocrine loops, signal transduction, and cell cycle abnormalities in the molecular biology of lung cancer. Curr Opin Oncol, 1999; 1:116-122
2． Keohavong P, DeMichele MA, Melacrinos AC, Landreneau RJ, Weyant RJ, Siegfried JM. Detection of K-ras mutations in lung carcinoma relationship to prognosis. Clin Cancer Res, 1996; 2:411-418
3． Diez M, Pollan M, Maestro M, Torres A, Ortega D, Gomez A, Sanchez A, Hemando F, Balibrea JL. Prediction of recurrence by quantification of p!85neu protein in non-small cell lung cancer tissue. Br J Cancer, 1997;75(5) :684-689
4． Brambilla C & Brambilla E. Lung tumors, Fundamental biology and clinical management. New York:Marcel Dekker Inc. 1999
5． Asakura S, Kato H, Fujino S, Konishi T, Asada Y, Tezuka N, Mori A. Immunohistochemical study of transforming growth factor-beta and central fibrosis in Tl adenocarcinoma of the lung. Nippo Kyo Geka Gak Zas, 1995;43:1924-1928
6． Nagayama M, Sato A, Hayakawa H, Urano T, Takada Y, Takada A. Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumor dissemination. Cancer, 1994;73:1398-1405
7． Bolon I, Devouassoux M, Robert C, Moro D, Brambilla C, Brambilla E. Expression of urokinase-type plaminogen activator, stromelysin l,strolysin 3,and smatrilysin gene in lung carcinomas. Am J Pothol, 1997; 150: 1619-1629
8． Waltz DA, Natkin LR, Fujita RM, Wei Y, Chapman HA. Plasmin and plasminogen activator inhibitor type 1 promote cellar motility by regulating the
interaction between the urokinase receptor and vitronectin. J Clin Invest, 1997; 100:58-67
9． Ebert W, Knoch H, Werle B, Trefz G, Muley T, Spiess E. Pronostic value of increased lung tutor tissues cathepsin B. Anticancer Res, 1994;14:895-899
10． Gauthier LR, Granotier C, Soria JC, Faivre S, Boige V, Raymond E, Boussin FD. Detection of circulating carcinoma cells by telomerase activity. Br J Cancer, 2001 Mar 2;84(5) :631-635
11． Taga S, Osaki T, Ohgami A, Imoto H, Yasumoto K. Prognostic impact of telomerase activity in non-small cell lung cancers. Ann Surg, 1999 Nov;230(5) :715-720
12． Dejmek A, Yahata N, Ohyashiki K, Kakihana M, Hirano T, Kawate N, Kato H, Ebihara Y. Correlation between morphology and telomerase activity in cells from exfoliative lung cytologic specimens.Cancer, 2000 Apr 25;90(2) :117-125
13． Yahata N, Ohyashiki K, Ohyashiki JH, Iwama H, Hayashi S, Ando K, Hirano T, Tsuchida T, Kato H, Shay JW, Toyama K. Telomerase activity in lung cancer cells obtained from bronchial washings. J Natl Cancer Inst,1998 May 6;90(9) :684-690
14． Betticher DC, Heighway J, Hasleton PS, Altermatt HJ, Ryder WD, Cerny T, Thatcher N. Prognostic significance of CCND1 overexpression in primary resected non-small cell lung cancer. Br J Cancer, 1996;73:274-300
15． Sugjmura H, Wakai K, Genka K, Nagura K, Igarashi H, Nagayama K, Ohkawa A, Baba S, Morris BJ, Tsugane S, Ohno Y, Gao C, Li Z, Takezaki T, Tajima K, Iwamasa T. Association of Ile462Val(Exon 7) polymorphism of cytochrome p450IAl with lung cancer in Asian population: further evidence from a case-control study in Okinawa. Cancer Epidermiol biomarkers Prev, 1998;7(5) :413-
417
16． Canitrot Y, Bichat F, Cole SP, Deeley RG, Gerlach JH, Bastian G, Arvelo F, Poupon MF. Multidrug resistance genes (MRP) and MDR1 expression in small cell lung cancer xenografts: relationship with response to chemotherapy. Cancer Lett, 1998 Aug 14;130(1-2) :133-141
17． Gao Z, Gao Z, Fields JZ, Boman BM. Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells. Anticancer Res, 1998 Jul-Aug;18(4C):3073-3076
18． Hipfher DR, Deeley RG, Cole SP. Structural, mechanistic and clinical aspects of MRP1． Biochim Biophys Acta, 1999 Dec 6;1461(2) :359-376
19． Oguri T, Isobe T, Suzuki T, Nishio K, Fujiwara Y, Katoh O, Yamakido M. Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer. Int J Cancer, 2000 Apr 1;86(1) :95-100
20． Trussardi A, Poitevin G, Gorisse MC, Faroux MJ, Bobichon H, Delvincourt C, Jardillier JC. Sequential overexpression of LRP and MRP but not P-gp 170 in VP16-selected A549 adenocarcinoma cells. Int J Oncol, 1998 Sep;13(3) :543-548
21． Berger W, Elbling L, Micksche M. Expression of the major vault protein LRP in human non-small-cell lung cancer cells: activation by short-term exposure to antineoplastic drugs. Int J Cancer, 2000 Oct 15;88(2) :293-300
22． Oguri T, Fujiwara Y, Miyazaki M, Takahashi T, Kurata T, Yokozaki M, Ohashi N, Isobe T, Katoh O, Yamakido M. Induction of gamma-glutamylcysteine synthetase gene expression by platinum drugs in peripheral mononuclear cells of lung cancer patients. Ann Oncol, 1999 Apr; 10(4) :455-460
23． Minimo C, Bibbo M, Claudio PP. The role of pRb2/p130 protein in diagnosing
lung carcinoma on fine needle aspiration biopsies. Pathol Res Pract, 1999; 195:67-70
24． Rom WN, Hay JG, Lee TC, Jiang Y, Tchou-Wong KM. Molecular and genetic aspects of lung cancer. Am J Respir Crit Care Med, 2000;161:1355-1367
25． Geradts J, Fong KM, Zimmerman PV, Maynard R, Minna JD. Correlation abnormal RB, p16INK4 a and p53 expression with 3p loss of heterozygosiry, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res, 1999;5:791-800
26． Almog N, Rotter V. An insight into the life of p53 : a protein coping with many funtions! Review of the 9th p53 Workship, Crete, May 9-13, 1998． Biochim Biophys Ada, 1998; 1378(3) : R43-R54
27． Regele S, Kohlberger P, Vogl FD, Bohm W, Kreienberg R, Runnebaum IB. Serum p53 autoantibodies in patients with minimal lesions of ductal carcinoma in situ of the breast. Br J Cancer, 1999 Oct;81(4) : 702-704
28． Lenner P, Wiklund F, Emdin SO, Arnerlov C, Eklund C, Hallmans G, Zentgraf H, Dilhier J. Serum antibodies against p53 in relation to cancer risk and prognosis in breast cancer: a population-based epidemiological study. Br J Cancer, 1999 Feb;79(5-6) :927-932
29． Mitsudomi T, Suzuki S, Yatabe Y, Nishio M, Kuwabara M, Gotoh K, Hatooka S, Shinoda M, Suyama M, Ogawa M, Takahashi T, Ariyoshi Y, Takahashi T. Clinical implications of p53 autoantibodies in the sera of patients with non-small-cell lung cancer. J Natl Cancer Inst, 1998 Oct 21;90(20) :1563-1568
30． Laudanski J, Burzykowski T, Niklinska W, Chyczewski K, Furman M, Niklinski J. Prognostic value of serum p53 antibodies in patients with resected non-small cell lung cancer. Lung Cancer, 1998 Dec;22(3) : 191-200
31． Lai CL, Tsai CM, Tsai TT, Kuo BI, Chang KT, Fu HT, Pemg RP, Chen JY. Presence of serum anti-p53 antibodies is associated with pleural effusion and poor prognosis in lung cancer patients. Clin Cancer Res, 1998 Dec;4(12) :3025-3030
32． Zalcman G, Schlichtholz B, Tredaniel J, Urban T, Lubin R, Dubois I, Milleron B, Hirsch A, Soussi T. Monitoring of p53 autoantibodies in lung cancer during therapy: relationship to response to treatment. Clin Cancer Res, 1998 Jun;4(6) : 1359-1366
33． Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG gene transactivation and with transcriptional repression. EMBO J, 1998;17(16) :4668-4679
34． Lee KY, Yoo CG, Han SK, Shim YS, Kim YW. The effects of trasferring-tumor suppressor gene p16ENK4 a to p16ENK4 a-deleted cancer cells. Korean J Intern Med, 1999; 14(1) :53-58
35． Gazzeri S, Delia Valle V, Chaussade L, Brambilla C, Larsen CJ, Brambilla E. The human p19ARF protein enoded by the beta transcript of the p16INK4 a gene is frequently lost in small cell lung cancer. Cancer Res, 1998;58:3926-3931
36． 曾益新主编。肿瘤学，北京：人民卫生出版社.1999;186-187
37． Sulzer MA, Leers MP, van Noord JA, Bollen EC, Theunissen PH. Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med, 1998 Apr,157(4Pt 1) :1319-1323
38． Kimura K, Endo Y, Yonemura Y, Heizmann CW, Schafer BW, Watanabe Y, Sasaki T. Clinical significance of S100A4 and E-cadherin-related adhesion
molecules in non-small cell lung cancer, frit J Oncol, 2000 Jun;16(6) : 1125-1131
39． Shibanuma H, Hirano T, Tsuji K, Wu Q, Shrestha B, Konaka C, Ebihara Y, Kato H. Influence of E-cadherin dysfunction upon local invasion and metastasis in non-small cell lung cancer. Lung Cancer, 1998 Nov;22(2) : 85-95
40． Karayiannakis AJ, Syrigos KN, Chatzigianni E, Papanikolaou S, Alexiou D, Kalahanis N, Rosenberg T, Bastounis E. Aberrant E-cadherin expression associated with loss of differentiation and advanced stage in human pancreatic cancer. Anticancer Res, 1998 Nov-Dec;18(6A):4177-4180
41． Blok P, Craanen ME, Dekker W, Tytgat GN. Loss of E-cadherin expression in early gastric cancer. Histopathology, 1999 May;34(5) :410-415
42． Clemmons DR, Moses AC, McKay MJ, Sommer A, Rosen DM, Ruckle J. The combination of insulin-tike growth factor I and insulin-tike growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity. J Clin Endocrinol Metab, 2000 Apr;85(4) : 1518-24
43． Giovannucci E. Insulin-tike growth factor-I and binding protein-3 and risk of cancer. Horm Res, 1999;51 Suppl 3:34-41
44． Mazzoccoli G, Giuliani A, Bianco G, De Cata A, Bakanelli M, Carella AM, La Viola M, Tarquini R. Decreased serum levels of insulin-tike growth factor (IGF)-I in patients with lung cancer: temporal relationship with growth hormone (GH) levels. Anticancer Res, 1999 Mar-Apr,19(2B):1397-1399
45． Fujiwara Y, Ohata H, Kurold T, Koyama K, Tsuchiya E, Monden M, Nakamura Y. Isolation of a candidate tumor suppressor gene on chromosome 8p21． 3-p22 that is homologous to an extracellular domain of the PDGF receptor beta gene. Oncogene, 1995;10:891-895
46． Wistuba H, Behrens C, Virmani AK, Milchgrub S, Syed S, Lam S, Mackay B, Minna JD, Gazdar AF. Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res, 1999;59:1973-1979
47． Brambilla E, Negoescu A, Gazzeri S, Lantuejoul S, Moro D, Brambllla C, Coll JL. Apoptosis related factors p53-Bc12-Bax hi neuroendocrine lung tumor. Am J Pathol, 1996;149:1941-1952
48． Higashiyama M, Doi O, Kodama K, Yokouchi H, Nakamori S, Tateishi R. Bcl2 oncoprotein in surgically resected non-small cell lung cancer: possibly favorable prognostic factor in association with low incidence of distant metasis. J Surg Oncol, 1997;64:48-54
49． Shimono A, Okuda T, Kondoh H. N-myc-dependent repression of ndrl, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Mech Dev, 1999; 83(l-2) :39-52
50． Okuda T, Kondoh H . Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc. Biochem Biophys Res Commun, 1999; 266(1) :208-215
51． Yamauchi Y, Hongo S, Ohashi T, Shioda S, Zhou C, Nakai Y, Nishinaka N, Takahashi R, Takeda F, Takeda M. Molecular cloning and characterization of a novel developmentally regulated gene, Bdml, showing predominant expression in postnatal rat brain. Brain Res Mol Brain Res, 1999; 68(1-2) : 149-158
52． Nishinaka N, Hongo S, Zhou CJ, Shioda S, Takahashi R, Yamauchi Y, Ohashi T, Ohki T, Nakada N, Takeda F, Takeda M. Identification of the novel developmentally regulated gene, Bdm2, which is highly expressed in fetal rat brain. Brain Res Dev Brain Res, 2000; 120(1) :57-64
53． Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis.GRP78/BiP and novel genes. J Biol Chem, 1996; 271(47) :29659-29665
54． van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosnian FT. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms . Lab Invest, 1997; 77(l):85-92
55． Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res, 1998; 58(19) :4439-4444
56． Zhou D, Salnikow K, Costa M. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res, 1998; 58( 10) :2182-2189
57． Sahiikow K, Kluz T, Costa M. Role of Ca2+ in the regulation of nickel-inducible Cap43 gene expression. Toxicol Appl Pharmacol, 1999; 160(2) : 127-132
58． 邓艳春，药立波，刘新平et al人脑内一含有ACP样结构域新基因的发现， 生物化学与生物物理进展 2001;28(1) :72-76
59． Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T. Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics, 2001; 73(1) :86-97
60． Zhao W, Tang R, Huang Y, Wang W, Zhou Z, Gu S, Dai J, Ting K, Xie Y, Mao Y. Cloning and expression pattern of the human NDRG3 gene. Biochim Biophys Acta,2001; 1519(1-2) :134-138
61． Sahiikow K, Blagosklonny MV, Ryan H, Johnson R, Costa M. Carcinogenic nickel induces genes involed with hypoxia stress. Cancer Res, 2000; 60(1) :38-41
62． Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res, 2000; 60(3) :749-755
63． Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lorn. Am J Hum Genet, 2000; 67(l):47-58
64． No D, Yao TP, Evans RM. Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc Natl Acad Sci, 1996; 93:3346-3351
65． Harris AW, Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Adams JM. Cyclin Dl as the putative bcl-1 oncogene. Curr Top Microbiol Immunol, 1995;194:347-353
66． Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene, 1995 Jul 20; 11 (2) :211-219
67． Swisher SG, Roth JA, Nemunaitis J, Lawrence DD, Kemp BL, Carrasco CH, Connors DG, El-Naggar AK, Fossella F, Glisson BS, Hong WK, Khuri FR, Kurie JM, Lee JJ, Lee JS, Mack M, Merritt JA, Nguyen DM, Nesbitt JC, Perez-Soler R, Pisters KM, Putnam JB Jr, Richli WR, Savin M, Waugh MK. Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer hist, 1999; 91(9) : 763-771
68． Takayama K, nakanishi Y, Kara N. Gene therapy for lung cancer treatment. Nippon Rinsho, 2000; 5 8(5) : 1048-1052
69． Alemany R, Ruan S, Kataoka M, Koch PE, Mukhopadhyay T, Cristiano RJ, Roth JA, Zhang WW. Growth inhibitory effect of anti-k-ras adenovirus on lung
cancer cells. Cancer Gene Ther, 1996; 3(5) :296-301
70． Hoganson DK, Batra RK, Olsen JC, Boucher RC. Comparison of the effects three different toxin genes and their levels of expression on cell growth and bystander effect in lung adenocarcinoma. Cancer Res, 1996; 56(6) : 1315-1323
71． Esandi MC, van Someren GD, Bout A, Mulder AH, van Bekkum DW, Valerio D, Noteboom JL. IL-1/IL-3 gene therapy of non-small cell lung cancer in rats using cracked adenoproducer cells. Cancer Ther, 1998; 5(6) : 778-788
72． Krause K, Haugwitz U, Wasner M, Wiedmann M, Mossner J, Engeland K. Expression of the cell cycle phosphatase cdc25C is down-regulated by the tumor suppressor Protein p53 but not by p73． Biochem Biophys Res Commun, 2001; 284:743-750
2． Keohavong P, DeMichele MA, Melacrinos AC, Landreneau RJ, Weyant RJ, Siegfried JM. Detection of K-ras mutations in lung carcinoma relationship to prognosis. Clin Cancer Res, 1996; 2:411-418
3． Diez M, Pollan M, Maestro M, Torres A, Ortega D, Gomez A, Sanchez A, Hemando F, Balibrea JL. Prediction of recurrence by quantification of p!85neu protein in non-small cell lung cancer tissue. Br J Cancer, 1997;75(5) :684-689
4． Brambilla C & Brambilla E. Lung tumors, Fundamental biology and clinical management. New York:Marcel Dekker Inc. 1999
5． Asakura S, Kato H, Fujino S, Konishi T, Asada Y, Tezuka N, Mori A. Immunohistochemical study of transforming growth factor-beta and central fibrosis in Tl adenocarcinoma of the lung. Nippo Kyo Geka Gak Zas, 1995;43:1924-1928
6． Nagayama M, Sato A, Hayakawa H, Urano T, Takada Y, Takada A. Plasminogen activators and their inhibitors in non-small cell lung cancer. Low content of type 2 plasminogen activator inhibitor associated with tumor dissemination. Cancer, 1994;73:1398-1405
7． Bolon I, Devouassoux M, Robert C, Moro D, Brambilla C, Brambilla E. Expression of urokinase-type plaminogen activator, stromelysin l,strolysin 3,and smatrilysin gene in lung carcinomas. Am J Pothol, 1997; 150: 1619-1629
8． Waltz DA, Natkin LR, Fujita RM, Wei Y, Chapman HA. Plasmin and plasminogen activator inhibitor type 1 promote cellar motility by regulating the
interaction between the urokinase receptor and vitronectin. J Clin Invest, 1997; 100:58-67
9． Ebert W, Knoch H, Werle B, Trefz G, Muley T, Spiess E. Pronostic value of increased lung tutor tissues cathepsin B. Anticancer Res, 1994;14:895-899
10． Gauthier LR, Granotier C, Soria JC, Faivre S, Boige V, Raymond E, Boussin FD. Detection of circulating carcinoma cells by telomerase activity. Br J Cancer, 2001 Mar 2;84(5) :631-635
11． Taga S, Osaki T, Ohgami A, Imoto H, Yasumoto K. Prognostic impact of telomerase activity in non-small cell lung cancers. Ann Surg, 1999 Nov;230(5) :715-720
12． Dejmek A, Yahata N, Ohyashiki K, Kakihana M, Hirano T, Kawate N, Kato H, Ebihara Y. Correlation between morphology and telomerase activity in cells from exfoliative lung cytologic specimens.Cancer, 2000 Apr 25;90(2) :117-125
13． Yahata N, Ohyashiki K, Ohyashiki JH, Iwama H, Hayashi S, Ando K, Hirano T, Tsuchida T, Kato H, Shay JW, Toyama K. Telomerase activity in lung cancer cells obtained from bronchial washings. J Natl Cancer Inst,1998 May 6;90(9) :684-690
14． Betticher DC, Heighway J, Hasleton PS, Altermatt HJ, Ryder WD, Cerny T, Thatcher N. Prognostic significance of CCND1 overexpression in primary resected non-small cell lung cancer. Br J Cancer, 1996;73:274-300
15． Sugjmura H, Wakai K, Genka K, Nagura K, Igarashi H, Nagayama K, Ohkawa A, Baba S, Morris BJ, Tsugane S, Ohno Y, Gao C, Li Z, Takezaki T, Tajima K, Iwamasa T. Association of Ile462Val(Exon 7) polymorphism of cytochrome p450IAl with lung cancer in Asian population: further evidence from a case-control study in Okinawa. Cancer Epidermiol biomarkers Prev, 1998;7(5) :413-
417
16． Canitrot Y, Bichat F, Cole SP, Deeley RG, Gerlach JH, Bastian G, Arvelo F, Poupon MF. Multidrug resistance genes (MRP) and MDR1 expression in small cell lung cancer xenografts: relationship with response to chemotherapy. Cancer Lett, 1998 Aug 14;130(1-2) :133-141
17． Gao Z, Gao Z, Fields JZ, Boman BM. Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells. Anticancer Res, 1998 Jul-Aug;18(4C):3073-3076
18． Hipfher DR, Deeley RG, Cole SP. Structural, mechanistic and clinical aspects of MRP1． Biochim Biophys Acta, 1999 Dec 6;1461(2) :359-376
19． Oguri T, Isobe T, Suzuki T, Nishio K, Fujiwara Y, Katoh O, Yamakido M. Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer. Int J Cancer, 2000 Apr 1;86(1) :95-100
20． Trussardi A, Poitevin G, Gorisse MC, Faroux MJ, Bobichon H, Delvincourt C, Jardillier JC. Sequential overexpression of LRP and MRP but not P-gp 170 in VP16-selected A549 adenocarcinoma cells. Int J Oncol, 1998 Sep;13(3) :543-548
21． Berger W, Elbling L, Micksche M. Expression of the major vault protein LRP in human non-small-cell lung cancer cells: activation by short-term exposure to antineoplastic drugs. Int J Cancer, 2000 Oct 15;88(2) :293-300
22． Oguri T, Fujiwara Y, Miyazaki M, Takahashi T, Kurata T, Yokozaki M, Ohashi N, Isobe T, Katoh O, Yamakido M. Induction of gamma-glutamylcysteine synthetase gene expression by platinum drugs in peripheral mononuclear cells of lung cancer patients. Ann Oncol, 1999 Apr; 10(4) :455-460
23． Minimo C, Bibbo M, Claudio PP. The role of pRb2/p130 protein in diagnosing
lung carcinoma on fine needle aspiration biopsies. Pathol Res Pract, 1999; 195:67-70
24． Rom WN, Hay JG, Lee TC, Jiang Y, Tchou-Wong KM. Molecular and genetic aspects of lung cancer. Am J Respir Crit Care Med, 2000;161:1355-1367
25． Geradts J, Fong KM, Zimmerman PV, Maynard R, Minna JD. Correlation abnormal RB, p16INK4 a and p53 expression with 3p loss of heterozygosiry, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res, 1999;5:791-800
26． Almog N, Rotter V. An insight into the life of p53 : a protein coping with many funtions! Review of the 9th p53 Workship, Crete, May 9-13, 1998． Biochim Biophys Ada, 1998; 1378(3) : R43-R54
27． Regele S, Kohlberger P, Vogl FD, Bohm W, Kreienberg R, Runnebaum IB. Serum p53 autoantibodies in patients with minimal lesions of ductal carcinoma in situ of the breast. Br J Cancer, 1999 Oct;81(4) : 702-704
28． Lenner P, Wiklund F, Emdin SO, Arnerlov C, Eklund C, Hallmans G, Zentgraf H, Dilhier J. Serum antibodies against p53 in relation to cancer risk and prognosis in breast cancer: a population-based epidemiological study. Br J Cancer, 1999 Feb;79(5-6) :927-932
29． Mitsudomi T, Suzuki S, Yatabe Y, Nishio M, Kuwabara M, Gotoh K, Hatooka S, Shinoda M, Suyama M, Ogawa M, Takahashi T, Ariyoshi Y, Takahashi T. Clinical implications of p53 autoantibodies in the sera of patients with non-small-cell lung cancer. J Natl Cancer Inst, 1998 Oct 21;90(20) :1563-1568
30． Laudanski J, Burzykowski T, Niklinska W, Chyczewski K, Furman M, Niklinski J. Prognostic value of serum p53 antibodies in patients with resected non-small cell lung cancer. Lung Cancer, 1998 Dec;22(3) : 191-200
31． Lai CL, Tsai CM, Tsai TT, Kuo BI, Chang KT, Fu HT, Pemg RP, Chen JY. Presence of serum anti-p53 antibodies is associated with pleural effusion and poor prognosis in lung cancer patients. Clin Cancer Res, 1998 Dec;4(12) :3025-3030
32． Zalcman G, Schlichtholz B, Tredaniel J, Urban T, Lubin R, Dubois I, Milleron B, Hirsch A, Soussi T. Monitoring of p53 autoantibodies in lung cancer during therapy: relationship to response to treatment. Clin Cancer Res, 1998 Jun;4(6) : 1359-1366
33． Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG gene transactivation and with transcriptional repression. EMBO J, 1998;17(16) :4668-4679
34． Lee KY, Yoo CG, Han SK, Shim YS, Kim YW. The effects of trasferring-tumor suppressor gene p16ENK4 a to p16ENK4 a-deleted cancer cells. Korean J Intern Med, 1999; 14(1) :53-58
35． Gazzeri S, Delia Valle V, Chaussade L, Brambilla C, Larsen CJ, Brambilla E. The human p19ARF protein enoded by the beta transcript of the p16INK4 a gene is frequently lost in small cell lung cancer. Cancer Res, 1998;58:3926-3931
36． 曾益新主编。肿瘤学，北京：人民卫生出版社.1999;186-187
37． Sulzer MA, Leers MP, van Noord JA, Bollen EC, Theunissen PH. Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer. Am J Respir Crit Care Med, 1998 Apr,157(4Pt 1) :1319-1323
38． Kimura K, Endo Y, Yonemura Y, Heizmann CW, Schafer BW, Watanabe Y, Sasaki T. Clinical significance of S100A4 and E-cadherin-related adhesion
molecules in non-small cell lung cancer, frit J Oncol, 2000 Jun;16(6) : 1125-1131
39． Shibanuma H, Hirano T, Tsuji K, Wu Q, Shrestha B, Konaka C, Ebihara Y, Kato H. Influence of E-cadherin dysfunction upon local invasion and metastasis in non-small cell lung cancer. Lung Cancer, 1998 Nov;22(2) : 85-95
40． Karayiannakis AJ, Syrigos KN, Chatzigianni E, Papanikolaou S, Alexiou D, Kalahanis N, Rosenberg T, Bastounis E. Aberrant E-cadherin expression associated with loss of differentiation and advanced stage in human pancreatic cancer. Anticancer Res, 1998 Nov-Dec;18(6A):4177-4180
41． Blok P, Craanen ME, Dekker W, Tytgat GN. Loss of E-cadherin expression in early gastric cancer. Histopathology, 1999 May;34(5) :410-415
42． Clemmons DR, Moses AC, McKay MJ, Sommer A, Rosen DM, Ruckle J. The combination of insulin-tike growth factor I and insulin-tike growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity. J Clin Endocrinol Metab, 2000 Apr;85(4) : 1518-24
43． Giovannucci E. Insulin-tike growth factor-I and binding protein-3 and risk of cancer. Horm Res, 1999;51 Suppl 3:34-41
44． Mazzoccoli G, Giuliani A, Bianco G, De Cata A, Bakanelli M, Carella AM, La Viola M, Tarquini R. Decreased serum levels of insulin-tike growth factor (IGF)-I in patients with lung cancer: temporal relationship with growth hormone (GH) levels. Anticancer Res, 1999 Mar-Apr,19(2B):1397-1399
45． Fujiwara Y, Ohata H, Kurold T, Koyama K, Tsuchiya E, Monden M, Nakamura Y. Isolation of a candidate tumor suppressor gene on chromosome 8p21． 3-p22 that is homologous to an extracellular domain of the PDGF receptor beta gene. Oncogene, 1995;10:891-895
46． Wistuba H, Behrens C, Virmani AK, Milchgrub S, Syed S, Lam S, Mackay B, Minna JD, Gazdar AF. Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res, 1999;59:1973-1979
47． Brambilla E, Negoescu A, Gazzeri S, Lantuejoul S, Moro D, Brambllla C, Coll JL. Apoptosis related factors p53-Bc12-Bax hi neuroendocrine lung tumor. Am J Pathol, 1996;149:1941-1952
48． Higashiyama M, Doi O, Kodama K, Yokouchi H, Nakamori S, Tateishi R. Bcl2 oncoprotein in surgically resected non-small cell lung cancer: possibly favorable prognostic factor in association with low incidence of distant metasis. J Surg Oncol, 1997;64:48-54
49． Shimono A, Okuda T, Kondoh H. N-myc-dependent repression of ndrl, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Mech Dev, 1999; 83(l-2) :39-52
50． Okuda T, Kondoh H . Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc. Biochem Biophys Res Commun, 1999; 266(1) :208-215
51． Yamauchi Y, Hongo S, Ohashi T, Shioda S, Zhou C, Nakai Y, Nishinaka N, Takahashi R, Takeda F, Takeda M. Molecular cloning and characterization of a novel developmentally regulated gene, Bdml, showing predominant expression in postnatal rat brain. Brain Res Mol Brain Res, 1999; 68(1-2) : 149-158
52． Nishinaka N, Hongo S, Zhou CJ, Shioda S, Takahashi R, Yamauchi Y, Ohashi T, Ohki T, Nakada N, Takeda F, Takeda M. Identification of the novel developmentally regulated gene, Bdm2, which is highly expressed in fetal rat brain. Brain Res Dev Brain Res, 2000; 120(1) :57-64
53． Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis.GRP78/BiP and novel genes. J Biol Chem, 1996; 271(47) :29659-29665
54． van Belzen N, Dinjens WN, Diesveld MP, Groen NA, van der Made AC, Nozawa Y, Vlietstra R, Trapman J, Bosnian FT. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms . Lab Invest, 1997; 77(l):85-92
55． Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res, 1998; 58(19) :4439-4444
56． Zhou D, Salnikow K, Costa M. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res, 1998; 58( 10) :2182-2189
57． Sahiikow K, Kluz T, Costa M. Role of Ca2+ in the regulation of nickel-inducible Cap43 gene expression. Toxicol Appl Pharmacol, 1999; 160(2) : 127-132
58． 邓艳春，药立波，刘新平et al人脑内一含有ACP样结构域新基因的发现， 生物化学与生物物理进展 2001;28(1) :72-76
59． Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T. Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics, 2001; 73(1) :86-97
60． Zhao W, Tang R, Huang Y, Wang W, Zhou Z, Gu S, Dai J, Ting K, Xie Y, Mao Y. Cloning and expression pattern of the human NDRG3 gene. Biochim Biophys Acta,2001; 1519(1-2) :134-138
61． Sahiikow K, Blagosklonny MV, Ryan H, Johnson R, Costa M. Carcinogenic nickel induces genes involed with hypoxia stress. Cancer Res, 2000; 60(1) :38-41
62． Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res, 2000; 60(3) :749-755
63． Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lorn. Am J Hum Genet, 2000; 67(l):47-58
64． No D, Yao TP, Evans RM. Ecdysone-inducible gene expression in mammalian cells and transgenic mice. Proc Natl Acad Sci, 1996; 93:3346-3351
65． Harris AW, Bodrug SE, Warner BJ, Bath ML, Lindeman GJ, Adams JM. Cyclin Dl as the putative bcl-1 oncogene. Curr Top Microbiol Immunol, 1995;194:347-353
66． Grana X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene, 1995 Jul 20; 11 (2) :211-219
67． Swisher SG, Roth JA, Nemunaitis J, Lawrence DD, Kemp BL, Carrasco CH, Connors DG, El-Naggar AK, Fossella F, Glisson BS, Hong WK, Khuri FR, Kurie JM, Lee JJ, Lee JS, Mack M, Merritt JA, Nguyen DM, Nesbitt JC, Perez-Soler R, Pisters KM, Putnam JB Jr, Richli WR, Savin M, Waugh MK. Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer hist, 1999; 91(9) : 763-771
68． Takayama K, nakanishi Y, Kara N. Gene therapy for lung cancer treatment. Nippon Rinsho, 2000; 5 8(5) : 1048-1052
69． Alemany R, Ruan S, Kataoka M, Koch PE, Mukhopadhyay T, Cristiano RJ, Roth JA, Zhang WW. Growth inhibitory effect of anti-k-ras adenovirus on lung
cancer cells. Cancer Gene Ther, 1996; 3(5) :296-301
70． Hoganson DK, Batra RK, Olsen JC, Boucher RC. Comparison of the effects three different toxin genes and their levels of expression on cell growth and bystander effect in lung adenocarcinoma. Cancer Res, 1996; 56(6) : 1315-1323
71． Esandi MC, van Someren GD, Bout A, Mulder AH, van Bekkum DW, Valerio D, Noteboom JL. IL-1/IL-3 gene therapy of non-small cell lung cancer in rats using cracked adenoproducer cells. Cancer Ther, 1998; 5(6) : 778-788
72． Krause K, Haugwitz U, Wasner M, Wiedmann M, Mossner J, Engeland K. Expression of the cell cycle phosphatase cdc25C is down-regulated by the tumor suppressor Protein p53 but not by p73． Biochem Biophys Res Commun, 2001; 284:743-750