NGX6基因对结肠癌细胞的作用及机制研究
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摘要
结肠癌是最常见的消化道肿瘤之一，其发病机制涉及到多个抑瘤基因的失活和瘤基因的激活，尤其是抑瘤基因的失活。Vogelstein建立的结肠癌“APC→K-ras→DCC→p53→nm23”的多种瘤基因及抑瘤基因的突变和缺失的发病机制模式不能解释全部结肠癌的发生，且结肠癌细胞株发病机制的研究结果表明结肠癌的发病机制存在多样性，因此寻找新的抑瘤基因已成为揭示结肠癌发病机制的关键。我校肿瘤研究所细胞遗传室采用定位候选克隆的方法在9p11.1-12区域克隆了一个新基因NGX6，Genbank登录号：AF188239，其高表达可明显抑制鼻咽癌细胞系的生长，可能为抑瘤基因侯选者。并有研究初步证明NGX6在结肠癌，尤其是在有远处转移的结肠癌中表达下调或缺失。本研究通过脂质体介导NGX6转染结肠癌细胞系，进一步阐明NGX6在结肠癌发生发展中的作用及其分子机制。
我们通过脂质体转染方法将真核表达载体pcDNA3.1(+)/NGX6导入结肠癌细胞株HT-29细胞中，并用G418筛选，PCR、RT-PCR和点杂交鉴定，建立了稳定表达NGX6基因的HT-29细胞系。通过生长曲线、MTT、软琼脂集落形成、流式细胞术、裸鼠成瘤等方法探讨NGX6对HT-29结肠癌细胞系生物学行为的影响。借助免疫组化、免疫荧光、蛋白印迹等方法研究NGX6在体内、体外影响结肠癌细胞系生长的作用机制。
研究结果表明：转染了NGX6基因的HT-29细胞系的生长速度明显减慢，倍增时间由转染前的23.0小时延长至34.5小时；MTT显示NGX6转染组细胞在490nm处的吸光度较未转染组明显下降(p＜0.05)；软琼脂集落形成率降低(p＜0.05)；NGX6转染后HT-29细胞在裸鼠体内成瘤明显延缓，
博士学位论文 中文摘要
－－w＊”
移植瘤体积大小和重量较HT上9组和 PCDNA3．1（）空载体转染组有所减少，
将三组肿瘤进行病理切片，均为低分化腺癌，无组间差异，显示NGX6基因
对裸鼠移植瘤生长具有抑制作用。因此，推断NGX6基因重表达在体内及体
外均可逆转HT亿9结肠癌细胞系的恶性表型。
细胞周期调控机制的紊乱导致细胞失控性生长与分裂，显示出其恶性
特征，故肿瘤又是一种细胞周期病。研究中采用流式细胞仪分析了细胞周
期及细胞周期素的改变，结果显示稳定表达NGX6的HT七9细胞系 G／G；期
细胞分布较对照组明显增加，S期细胞数减少；细胞凋亡率在转染前后无明
显变化；cyclin E、cyclin B、cyclin DI的表达量下降，以 cyclin E和
cyclin DI的改变最为明显。Western blot验证 cyclin E、cyclin DI在
NGX6转染前后的变化，与流式细胞仪检测结果一致，以上结果说明在结肠
癌细胞系中NGX6可宜主要通过下调cyclin E、cyclin DI的表达，延缓细
胞周期的G；－S的进程，从而抑制HT七9细胞的过度增殖。
生物信息学预测NGX6具有－个EGF－like domain。研究表明转染NGX6
后的鼻咽癌细胞系的EGFR和酪氨酸激酶传导通路上的MAPK磷酸化程度均
较转染前明显降低，提示NGX6可能为EGFR的负性调控因子。为进一步探
讨其在结肠癌细胞系的作用机制，本研究采用免疫组化、免疫荧光、蛋白
印迹技术检测酪氨酸激酶传导通路上主要蛋白分子及细胞周期调控蛋白
cycl＊s、CKI在转染NGX6前后的变化。结果显示：转染NGX6后细胞信号
传导通路上的EGFR、K1as、p－JNK、c寸un均有不同程度的下调。细胞周
期蛋白依赖性激酶抑制物家族成员P27在转染NGX6后上调；P16在NGX6转
染前后HT《9结肠癌细胞系中均无表达，免疫组化结果与Wes朽＊ bio亡结
果一致。c寸un的免疫荧光结果提示cJun主要分布于胞核，部分位于胞
浆，且NGX6转染后核内cJun的分布较转染前减少。以上结果表明NG涨
可能抑制酪氨酸激酶传导通路的信号传导、下调细胞周期素eye＊n E、
cycl in DI和上调似 k27）的表达而阻滞细胞周期的进行，抑制细胞的
2
博士学位论文 中文摘要
增殖。
为了明确ATGX6蛋白在细胞中发挥作用的部位；我们进一步将NGX6MyC
融合蛋白的真核表达载体系统pCMV十yC通过瞬时转染将该重组体导入HT－
29结肠癌细胞系。采用兔疫荧光的方法检测NGX6－MyC融合蛋白的定位，荧
光显微镜观察结果，显示该融合蛋白位于细胞胞浆内，少部分存在于胞膜
上。根据生物信息学预测NGX6全长编码的蛋白具有两个跨膜区，去跨膜区
后NGX6定位于胞浆的结果，推测NGX6编码的蛋白可能在胞浆中合成后，
定位于膜上，分泌到胞外发挥其抑瘤作用。
为进一步研究了NGX6在体内作用的分子机制，实验中还采用免疫组化
的方法分析了 EGFR． K－ras、c－Jun和 p27在NGX6转染前后细胞株所致的
移植瘤中的表达变化。结果表明NGX6转染在移植瘤内亦可降低EGFR、K－
ras和cJ八n的表达，上调p27的表达，与体外NGX6的作用机制一致，结
果表明NGX6在体内也通过影响EGFR介导的酪氨酸激酶信号传导通路的激
活及CKI家族P27的表达抑制肿瘤的增殖。更为重要的是发现NGX6在移植
瘤中抑制血管内瘤栓形成，提示NGX6可能与结肠癌细胞的转移有关。借助
Colon carcinoma is one of the most common gastrointestinal tumor.Its pathogenesis include inactivation of tumor suppressor genes and activation of oncogenes, especially the inactivation of tumor suppressor genes is very important .The model of pathogenesis of colon carcinoma which was established by Vogelstein laboratory theory ,"APC - K-ras - DCC - p53 - nm23",can't elucidate the development of colon carcinoma completely, furthermore the pathogenesis of colon carcinoma is diverse .Therefore,it has become a critical subject to reveal the pathogenesis of colon carcinoma by identifying novel tumor suppressor genes.Cancer research institute has isolated a novel gene on the region of chromosome 9p by position- candidate cloning strategy, designated human NGX6, GenBank accession number : AF188239.NGX6 can suppress the proliferation of the nasopharyngea cell linel and maybe the important candidate of tumor suppressor genes. Some study states that NGX6 is down-regulated in colon carcinoma ,especially in that with distal metastasis.Our subject is to transfect mammalian expression vector pcDNA3.1(+)/NGX6 recombinant into colon cancer line HT-29 by lipofectin ,in order to further investigate the effect of NGX6 on colon carcinoma and elucidate its molecular mechanism.
NGX6 was transfected into colon carcinoma cell line (HT-29)by lipofectin and a stable cell line of pcDNA3.1(+)/NGX6/ HT-29 overexpressing NGX6 gene was established .The overexpression of NGX6 was identified by PCR, RT-PCR and Dot blot analysis. The effect of NGX6 on the malignant behavior of HT-29
was assessed by growth curves of cells , MTT, Clone formation in soft agar, FCM, tumor formation into nude mice.Its Molecular mechanism in vivo and in vitro was analyzed by immunohistochemical, Western Blot and immunofluorescence.
pcDNA3.1(+)/NGX6/HT-29 ceils had a significant inhibition in cell proliferation by the growth curves of cells and the ability of clonogenesis in soft agar compared with HT-29 and pcDNA3.1(+) /HT-29 cells. Its double proliferation time of HT-29 cells prolonged from 23.0 hours to 34.5 hours after transfected with NGX6. The result of MTT showed that NGX6 had a negative effect on the cell viability. There was a delay in tumorigenesis and a reduction in tumor size when pcDNA3.1(+)/NGX6/ HT-29 cells were transplanted into nude mice. HE stain showed that xenografts were poorly differentiated adenocarcinoma. Taken together, these results indicated that the overexpression of NGX6 can reverse the malignant phenotype of the HT-29 cell line.
The disorder of the cell cycle regulation can lead to the proliferation arid division of the cells out of control,Then the cells show its malignant characterization. So tumor is a kind of cell cycle disease .To investigate the possible effect of NGX6 gene on the distribution of cell cycle and apoptosis, FCM analysis were used to evaluate the cell cycle distribution and cyclins expression of cells. Flow cytometry analyses indicated that the overexpression of NGX6 could delay the progression of G1-S in cell cycle, while it had no effect on the apoptosis of cells. Flow cytometry analysis demonstrated that the expression of cyclin E, cyclin B, cyclin D1 decreased in NGX6-expressed HT-29 cells , especially the decrease of cyclin E and cyclin D1. All these studies provided evidence that NGX6 gene can repress the colon cancer cell's uncontrolled proliferation,which mechanism was that NGX6 mainly exerted at the G1/S boundary of the cell cycle by down-regulating the expression of cyclin E
and cyclin D1.
It was predicted that NGX6 gene possessed several structure including a EGF-like domain and two transmembrane regions. Study stated the phosphorylation degree of EGFR and MAPK , an important protein kinase on the EGFR relevant signal pathway, decreased in pcDNA3.1(+)/NGX6/HT-29 cells. Our study was designed to further investigate the alteration of critical molecular which included on the tyrsine kinase signal pathway , related cyclins and CKIs after transfected with NGX6 by of immunohistoc
我们通过脂质体转染方法将真核表达载体pcDNA3.1(+)/NGX6导入结肠癌细胞株HT-29细胞中，并用G418筛选，PCR、RT-PCR和点杂交鉴定，建立了稳定表达NGX6基因的HT-29细胞系。通过生长曲线、MTT、软琼脂集落形成、流式细胞术、裸鼠成瘤等方法探讨NGX6对HT-29结肠癌细胞系生物学行为的影响。借助免疫组化、免疫荧光、蛋白印迹等方法研究NGX6在体内、体外影响结肠癌细胞系生长的作用机制。
研究结果表明：转染了NGX6基因的HT-29细胞系的生长速度明显减慢，倍增时间由转染前的23.0小时延长至34.5小时；MTT显示NGX6转染组细胞在490nm处的吸光度较未转染组明显下降(p＜0.05)；软琼脂集落形成率降低(p＜0.05)；NGX6转染后HT-29细胞在裸鼠体内成瘤明显延缓，
博士学位论文 中文摘要
－－w＊”
移植瘤体积大小和重量较HT上9组和 PCDNA3．1（）空载体转染组有所减少，
将三组肿瘤进行病理切片，均为低分化腺癌，无组间差异，显示NGX6基因
对裸鼠移植瘤生长具有抑制作用。因此，推断NGX6基因重表达在体内及体
外均可逆转HT亿9结肠癌细胞系的恶性表型。
细胞周期调控机制的紊乱导致细胞失控性生长与分裂，显示出其恶性
特征，故肿瘤又是一种细胞周期病。研究中采用流式细胞仪分析了细胞周
期及细胞周期素的改变，结果显示稳定表达NGX6的HT七9细胞系 G／G；期
细胞分布较对照组明显增加，S期细胞数减少；细胞凋亡率在转染前后无明
显变化；cyclin E、cyclin B、cyclin DI的表达量下降，以 cyclin E和
cyclin DI的改变最为明显。Western blot验证 cyclin E、cyclin DI在
NGX6转染前后的变化，与流式细胞仪检测结果一致，以上结果说明在结肠
癌细胞系中NGX6可宜主要通过下调cyclin E、cyclin DI的表达，延缓细
胞周期的G；－S的进程，从而抑制HT七9细胞的过度增殖。
生物信息学预测NGX6具有－个EGF－like domain。研究表明转染NGX6
后的鼻咽癌细胞系的EGFR和酪氨酸激酶传导通路上的MAPK磷酸化程度均
较转染前明显降低，提示NGX6可能为EGFR的负性调控因子。为进一步探
讨其在结肠癌细胞系的作用机制，本研究采用免疫组化、免疫荧光、蛋白
印迹技术检测酪氨酸激酶传导通路上主要蛋白分子及细胞周期调控蛋白
cycl＊s、CKI在转染NGX6前后的变化。结果显示：转染NGX6后细胞信号
传导通路上的EGFR、K1as、p－JNK、c寸un均有不同程度的下调。细胞周
期蛋白依赖性激酶抑制物家族成员P27在转染NGX6后上调；P16在NGX6转
染前后HT《9结肠癌细胞系中均无表达，免疫组化结果与Wes朽＊ bio亡结
果一致。c寸un的免疫荧光结果提示cJun主要分布于胞核，部分位于胞
浆，且NGX6转染后核内cJun的分布较转染前减少。以上结果表明NG涨
可能抑制酪氨酸激酶传导通路的信号传导、下调细胞周期素eye＊n E、
cycl in DI和上调似 k27）的表达而阻滞细胞周期的进行，抑制细胞的
2
博士学位论文 中文摘要
增殖。
为了明确ATGX6蛋白在细胞中发挥作用的部位；我们进一步将NGX6MyC
融合蛋白的真核表达载体系统pCMV十yC通过瞬时转染将该重组体导入HT－
29结肠癌细胞系。采用兔疫荧光的方法检测NGX6－MyC融合蛋白的定位，荧
光显微镜观察结果，显示该融合蛋白位于细胞胞浆内，少部分存在于胞膜
上。根据生物信息学预测NGX6全长编码的蛋白具有两个跨膜区，去跨膜区
后NGX6定位于胞浆的结果，推测NGX6编码的蛋白可能在胞浆中合成后，
定位于膜上，分泌到胞外发挥其抑瘤作用。
为进一步研究了NGX6在体内作用的分子机制，实验中还采用免疫组化
的方法分析了 EGFR． K－ras、c－Jun和 p27在NGX6转染前后细胞株所致的
移植瘤中的表达变化。结果表明NGX6转染在移植瘤内亦可降低EGFR、K－
ras和cJ八n的表达，上调p27的表达，与体外NGX6的作用机制一致，结
果表明NGX6在体内也通过影响EGFR介导的酪氨酸激酶信号传导通路的激
活及CKI家族P27的表达抑制肿瘤的增殖。更为重要的是发现NGX6在移植
瘤中抑制血管内瘤栓形成，提示NGX6可能与结肠癌细胞的转移有关。借助
Colon carcinoma is one of the most common gastrointestinal tumor.Its pathogenesis include inactivation of tumor suppressor genes and activation of oncogenes, especially the inactivation of tumor suppressor genes is very important .The model of pathogenesis of colon carcinoma which was established by Vogelstein laboratory theory ,"APC - K-ras - DCC - p53 - nm23",can't elucidate the development of colon carcinoma completely, furthermore the pathogenesis of colon carcinoma is diverse .Therefore,it has become a critical subject to reveal the pathogenesis of colon carcinoma by identifying novel tumor suppressor genes.Cancer research institute has isolated a novel gene on the region of chromosome 9p by position- candidate cloning strategy, designated human NGX6, GenBank accession number : AF188239.NGX6 can suppress the proliferation of the nasopharyngea cell linel and maybe the important candidate of tumor suppressor genes. Some study states that NGX6 is down-regulated in colon carcinoma ,especially in that with distal metastasis.Our subject is to transfect mammalian expression vector pcDNA3.1(+)/NGX6 recombinant into colon cancer line HT-29 by lipofectin ,in order to further investigate the effect of NGX6 on colon carcinoma and elucidate its molecular mechanism.
NGX6 was transfected into colon carcinoma cell line (HT-29)by lipofectin and a stable cell line of pcDNA3.1(+)/NGX6/ HT-29 overexpressing NGX6 gene was established .The overexpression of NGX6 was identified by PCR, RT-PCR and Dot blot analysis. The effect of NGX6 on the malignant behavior of HT-29
was assessed by growth curves of cells , MTT, Clone formation in soft agar, FCM, tumor formation into nude mice.Its Molecular mechanism in vivo and in vitro was analyzed by immunohistochemical, Western Blot and immunofluorescence.
pcDNA3.1(+)/NGX6/HT-29 ceils had a significant inhibition in cell proliferation by the growth curves of cells and the ability of clonogenesis in soft agar compared with HT-29 and pcDNA3.1(+) /HT-29 cells. Its double proliferation time of HT-29 cells prolonged from 23.0 hours to 34.5 hours after transfected with NGX6. The result of MTT showed that NGX6 had a negative effect on the cell viability. There was a delay in tumorigenesis and a reduction in tumor size when pcDNA3.1(+)/NGX6/ HT-29 cells were transplanted into nude mice. HE stain showed that xenografts were poorly differentiated adenocarcinoma. Taken together, these results indicated that the overexpression of NGX6 can reverse the malignant phenotype of the HT-29 cell line.
The disorder of the cell cycle regulation can lead to the proliferation arid division of the cells out of control,Then the cells show its malignant characterization. So tumor is a kind of cell cycle disease .To investigate the possible effect of NGX6 gene on the distribution of cell cycle and apoptosis, FCM analysis were used to evaluate the cell cycle distribution and cyclins expression of cells. Flow cytometry analyses indicated that the overexpression of NGX6 could delay the progression of G1-S in cell cycle, while it had no effect on the apoptosis of cells. Flow cytometry analysis demonstrated that the expression of cyclin E, cyclin B, cyclin D1 decreased in NGX6-expressed HT-29 cells , especially the decrease of cyclin E and cyclin D1. All these studies provided evidence that NGX6 gene can repress the colon cancer cell's uncontrolled proliferation,which mechanism was that NGX6 mainly exerted at the G1/S boundary of the cell cycle by down-regulating the expression of cyclin E
and cyclin D1.
It was predicted that NGX6 gene possessed several structure including a EGF-like domain and two transmembrane regions. Study stated the phosphorylation degree of EGFR and MAPK , an important protein kinase on the EGFR relevant signal pathway, decreased in pcDNA3.1(+)/NGX6/HT-29 cells. Our study was designed to further investigate the alteration of critical molecular which included on the tyrsine kinase signal pathway , related cyclins and CKIs after transfected with NGX6 by of immunohistoc
引文
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19. Li J, Tan c, Xiang Q, et al. Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells. J Protein Chem. 2001 Apr;20(3):265-71.
20. Saedi MS, Zhu Z, Marker K, et al. Human kallikrein 2 (hK2), but not prostate-specific antigen (PSA), rapidly complexes with protease inhibitor 6 (PI-6) released from prostate carcinoma cells. Int J Cancer. 2001 Nov15;94(4):558-63.
21. Bahrenberg G, Brauers A, Joost HG, Jakse G. Reduced expression of
PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem Biophys Res Commun. 2000 Sep 7; 275 (3): 783-8.
22. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001 Aug 17;85(4):584-9.
23. Williams S J, McGuckin MA, Gotley DC, et al. Two novel mucin genes down-regulated in colorectal cancer identified by differential display. Cancer Res. 1999 Aug 15;59(16):4083-9.
24. Ma J, Li J, Zhou J, et al. Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal carcinoma cells by cDNA array. J Cancer Res Ctin Onto1. 2002 Dec; 128(12) :683-90.
25．覃吉超，陶德定，舒丹，等．对MOLT-4细胞用cyclin E+A／DNA流式细胞术分析．Chin Med J 2001；114(9)：967-971．
26．宋鑫，曹亚．癌变多阶段形成过程中的细胞稳态反馈机制及其通路．国外医学肿瘤学分册 2001．(28)．6：407-411．
27．邱健，姜馨，何文宪．CDKI p27Kipl及其在结(直)肠肿瘤中的研究世界华人消化杂志．2001；9(2)：209-211
28．曾益新 肿瘤学．北京：人民卫生出版社．1999年11月 第一版．
29．黎家庆，万远廉，才文彦．早期胃癌cyclin E表达的生物学意义．世界华人消化杂志 1999年1月15日；7(1)：31-33．
30．刘晓波，李里，庄宝珠，等．胃癌组织cyclin E表达的临床病理意义．世界华人消化杂志．1999；7(8)：656-658．
31. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol. 2002 Sep 15;20(18 Suppl):1S-13S.
32. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000 Oct 13;103(2):211-25.
33. Raymond E, Faivre S, Armand JP. et al. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60 Suppl 1:15-23
34. Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs. 2000 Apr;59(4):753-67.
35. Sorokin A, Lemmon MA, Ullrich A, et al. Stabilization of an active dimeric form of the epidermal growth factor receptor by introduction of an inter-receptor disulfide bond. J Biol Chem. 1994 Apr 1; 269(13):9752-9.
36. Albanell J, Rojo F, Baselga J. et al. Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839. Semin Oncol. 2001 0ct;28(5 Suppl 16):56-66.
37. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225).Curr Opin Oncol. 2001 Nov;13(6):506-13.
38. Heimberg M, Weinstein I, LeQuire VS, et al. The induction of fatty liver in neonatal animals by a purified protein (EGF) from mouse submaxillary gland. Life Sci. 1965 Sep; 4(17):1625-33.
39. Lee DC, Barlow KD, Gaido KW. The actions of 2,3,7,8tetrachlorodibenzo-p-dioxin on transforming growth factor-beta2 promoter activity are localized to the TATA box binding region and controlled through a tyrosine kinase-dependent pathway. Toxicol Appl Pharmacol. 1996 Mar;137(1):90-9.
40. Ma L, de Roquancourt A, Bertheau P, et al. Expression of amphiregulin and epidermal growth factor receptor in human breast cancer: analysis of autocriny and stromal-epithelial interactions. J Pathol. 2001 Aug;194(4):413-9
41. Sorensen BS, Torring N, Bor MV, et al. Quantitation of the mRNA
expression of the epidermal growth factor system: selective induction of beparin-binding epidermal growth factor-like growth factor and amphiregulin expression by growth factor stimulation of prostate stromal cells. J Lab Clin Med. 2000 Sep;136(3):209-17.
42. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225).Curr Opin Oncol. 2001 Nov;13(6):506-13.
43. Habib AA, Chun SJ, Neel BG, et al. Increased expression of epidermal growth factor receptor induces sequestration of extracellular signalrelated kinases and selective attenuation of specific epidermal growth factor-mediated signal transduction pathways. Mol Cancer Res. 2003 Jan;1(3):219-33.
44. Ishrath A, Kumar N, Dey CS. Differential activation of ERK and JNK by arsenite in mouse muscle cells. Comp Biochem Physiol C Toxicol Pharmacol. 2002 Jul;132(3):375-84.
45. Fischer PM, Lane DP. Inhibitors of cyclin-dependent kinases as anticancer therapeutics. Curr Med Chem. 2000 Dec;7(12):1213-45.
46. Baba Y, Tsukuda M, Mochimatsu I, et al. Reduced expression of p16 and p27 proteins in nasopharyngeal carcinoma. Cancer Detect Prey. 2001;25(5):414-9.
47. Salvesen HB, Akslen LA. Molecular pathogenesis and prognostic factors in endometrial carcinoma. APMIS. 2002 Oct;110(10):673-89. Review.
48. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 1999;50:401-23. Review.
49. Salvesen HB, Akslen LA. Molecular pathogenesis and prognostic factors in endometrial carcinoma. APMIS. 2002 0ct;110(10):673-89. Review.
50. Cavalla P, Piva R, Bortolotto S, et al. p27/kipl expression in oligodendrogliomas and its possible prognostic role. Acta Neuropathol
(Berl). 1999 Dec;98(6): 629-34.
51. Pan MH, Chen WJ, Lin-Shiau SY, et al. Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis. 2002 Oct;23(10): 1677-84.
52．刘勇，路名芝，潘伯荣．消化系肿瘤细胞增殖调控．新消化病学杂志．1997；5(8)：532-533．
53. Bull AD, BffinAH, Mella J. Colorectal cancer pathology reporting: a regional audit. J Clin Pathol.1997 Feb;50(2):138-42.
54. Thompson EW, Price JT. Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets. 2002 Apr;6 (2) :217-233.
55. McKerrow JH, Bhargava V, Hansell E, et al.A functional proteomics screen of proteases in colorectal carcinoma. Mol Med. 2000 May; 6(5): 450-60.
56．齐璇．基质金属蛋白酶及其抑制物与子宫内膜异位症．第四军医大学学报．
57. Bramhall SR, Neoptolemos JP, Stamp GW, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol. 1997 Jul; 182(3): 347-55.
58. Baker EA, Stephenson TJ, Reed MW, et al. Expression of proteinases and inhibitors in human breast cancer progression and survival. Mol Pathol. 2002 Oct; 55 (5): 300-4.
59．蒋泽生，高毅．基质金属蛋白酶的生物学特性及其在肝癌浸润转移中的作用．世界华人消化杂志 2000年12月15日；8(12)：1403-1404
60. Tickenbrock L, Kossmeier K, Rehmann H, et al. Differences Between the Interaction of beta-Catenin with Non-phosphorylated and Singlemimicked Phosphorylated 20-amino acid Residue Repeats of the APC
Protein. J Mol Biol. 2003 Mar 21;327(2):359-67.
61. Klingelhofer J, Troyanovsky RB, Laur OY, et al. Exchange of catenins in cadherin-catenin complex. Oncogene. 2003 Feb 27;22(8):1181-8.
62．方石岗，杨继震．肝细胞癌转移的研究进展．世界华人消化杂志．1999；7(9)：782-784．
63. Flug M, Kopf-Maier P. The basement membrane and its involvement in carcinoma cell invasion. Acta Anat (Basel). 1995;152(2):69-84. Review.
64. Mareel MM, Van Roy FM, Bracke ME. How and when do tumor cells metastasize?Crit Rev Oncog. 1993;4(5): 559-94. Review.
65. Herrmann M, Pape G, Herrmann W. Measurement of serum beta-crosslaps is influenced by proteolytic conditions. Clin Chem Lab Med. 2002 Aug; 40(8): 790-4.
66. Soell M, Elkaim R, Tenenbaum H. Cathepsin C, matrix metatloproteinases, and their tissue inhibitors in gingiva and gingival crevicular fluid from periodontitis-affected patients. J Dent Res. 2002 Mar; 81(3):174-8.
67. Chakrabarty S, Radjendirane V, Appelman H, et al. Extracellular Calcium and Calcium Sensing Receptor Function in Human Colon Carcinomas: Promotion of E-Cadherin Expression and Suppression of beta-Catenin/TCF Activation. Cancer Res. 2003 Jan 1;63(1): 67-71.
68. Kanazawa T, Watanabe T, Kazama S, et al. Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region. Int J Cancer. 2002 Nov 20;102(3):225-9.
69. Barshishat M, Levi I, Benharroch D, et al. Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line. Br J Cancer. 2002 Nov 18;87(11):1314-20.
70. Khoursheed M, Mathew TC, Makar RR, et al. Expression of CD44s in Human Colorectal Cancer. Pathol Oncol Res. 2002;8(3):170-4.
71. Visca P, Del Nonno F, Botti C. Role and prognostic significance of CD44s expression in colorectal cancer. Anticancer Res. 2002 Sep-Oct;22(5):2671-5.
72. Donato NJ, yan DH, Hung MC, et al. Epidermal growth factor receptor expression and function control cytotoxic responsiveness to tumor necrosis factor in ME-180 squamous carcinoma cells, cell Growth Differ. 1993 May;4(5):411-9.
73. Carragher NO, Frame MC. Calpain: a role in cell transformation and migration. Int J Biochem Cell Biol. 2002 Dec;34(12):1539-43.
74. Renhowe PA. Inhibitors of growth factor receptor kinase-dependent signaling pathways in anticancer chemotherapy-clinical progress. Curr Opin Drug Discov Devel. 2002 Mar;5(2):214-24.
75. Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 2001 Aug 15;61(16):6050-4.
76. Golijow C, Guerci A, Mouton S, Abba M, et al. Activation of K-ras and c-erbB-2 protooncogenes in human colonic adenocarcinomasActa Gastroenterol Latinoam. 2001 May;31(2):71-6.
77. Miyakura Y, Sugano K, Fukayama N, et al. Concurrent mutations of K-fas oncogene at codons 12 and 22 in colon cancer. Jpn J Clin Oncol. 2002 Jun;32(6):219-21.
78. Hsu, YH, Shaw, CK, Chuoug, CM, et. al. Immunohistochemical localization of deleted-in-colon-cancer (DCC) protein in human epithelial, neural, and neuro-endocrine tissues in paraffin sections with antigen retrieval. Kaohsiung J Med Sci. 2001 Jun;17(7):351-7.
79. Gryfe R, Swallow C, Bapat B, et al. Molecular biology of colorectal
cancer. Curr Probl Cancer. 1997 Sep-Oct;21(5):233-300.
80. Salovaara R, Roth S, Loukola A, et al. Frequent loss of SMAD4/DPC4 protein in colorectal cancers. Mol Pathol. 2002 Dec;55(6):385-388.
81. Forte A,D' Urso A, Gallinaro LS, et al. NM23 expression as prognostic factor in colorectal carcinoma. G Chir. 2002 Mar;23(3):61-3.
82. Ornstein DL, Cohn KH. Balance between activation and inhibition of matrix metalloproteinase-2 (MMP-2) is altered in colorectal tumors compared to normal colonic epithelium. Dig Dis Sci. 2002 Aug;47(8):1821-30.
83. Ogata Y, Miura K, Ohkita A, et al. Imbalance between matrix metalloproteinase 9 and tissue inhibitor metalloproteinase 1 expression by tumor cells implicated in liver metastasis from colorectal carcinoma. Kurume Med J. 2001; 48(3): 211-8.
2．顾公望，周汉高．肝癌病因的新概念华人消化杂志1998；6(3)：185-187．
3. Huerta S, Srivatsan ES, Venkatasan N, et al. Human colon cancer cells deficient in DCC produce abnormal transcripts in progression of carcinogenesis, ig Dis Sci. 2001 Sep; 46(9):1884-91.
4. Faviana P, Boldrini L, Spisni R, et al. Neoangiogenesis in colon cancer: correlation between vascular density, vascular endothelial growth factor (VEGF) and p53 protein expression. Oncol Rep. 2002 MayJun;9(3):617-20.
5．宋大健．大肠息肉研究进展 中国肛肠病杂志 2002年第2期第22卷。
6. Vecsey-Semjen, Becker KF, et al. Novel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers. Oncogene 2002 Jul 11;21(30):4646-62
7. Li J, Tan c, Xiang Q, et al. Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells. J Protein Chem. 2001 Apr;20(3):265-71.
8．魏启幼，范松青，张利群．甲状腺乳头腺癌中EGFR、nm23-H_1和P53蛋白的表达。临床与实验病理学杂志。1999年第4期第15卷。
9. Ma D, Niederkorn JY. Role of epidermal growth factor receptor in the metastasis of intraocular melanomas. Invest Ophthalmol Vis Sci. 1998 Jun;39(7):1067-75.
10．张晓梅，沈守荣，王晓艳，等．胃癌和大肠癌中肿瘤相关基因NGX6的表达．世界华人消化杂志2002；10(8)：873-876．
11. larke LE, Leitzel K, Smith J, et al Epidermal growth factor receptor mRNA in peripheral blood of patients with pancreatic, lung, and colon
carcinomas detected by RT-PCR. Int J Oncol. 2003 Feb;22(2):425-30.
12. Zajac V, Tomka M, Ilencikova D, et al.A double germline mutations in the APC and p53 genes. Neoplasma. 2000;47(6):335-41.
13．梅文燕，丁小燕．Wnt信号途径及其作用机制生命的化学 2000年第5期．
14. Hsu, YH, Shaw, CK, Chuoug, CM, et. al. Immunohistochemical localization of deleted-in-colon-cancer (DCC) protein in human epithelial, neural, and neuro-endocrine tissues in paraffin sections with antigen retrieval. Kaohsiung J Med Sci. 2001 Jun;17(7):351-7.
15. Jang KT, Chae SW, Sohn JH, et al. Coexpression of MUC1 with p53 or MUC2 correlates with lymph node metastasis in colorectal carcinomas. Korean Med Sci. 2002 Feb;17(1):29-33.
16. Sanz-Ortega J, Sanz-Esponera J, Caldes T, et al. LOH at the APC/MCC gene (5Q21) in gastric cancer and preneoplastic lesions. Prognostic implications. Pathol Res Pract. 1996 Dec;192(12):1206-10.
17. Vecsey-Semjen B, Becker KF, Sinski A, et al. Novel colon cancer cell lines leading to better understanding of the diversity of respective primary cancers. Oncogene. 2002 Jul 11; 21(30): 4646-62.
18．李江，谭琛，向秋，等．用双向电泳和质谱技术检测NGX6转染后人鼻咽癌细胞表达差异的蛋白质．生物化学与生物物理进展。2001年第28卷第4期．573-578
19. Li J, Tan c, Xiang Q, et al. Proteomic detection of changes in protein synthesis induced by NGX6 transfected in human nasopharyngeal carcinoma cells. J Protein Chem. 2001 Apr;20(3):265-71.
20. Saedi MS, Zhu Z, Marker K, et al. Human kallikrein 2 (hK2), but not prostate-specific antigen (PSA), rapidly complexes with protease inhibitor 6 (PI-6) released from prostate carcinoma cells. Int J Cancer. 2001 Nov15;94(4):558-63.
21. Bahrenberg G, Brauers A, Joost HG, Jakse G. Reduced expression of
PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem Biophys Res Commun. 2000 Sep 7; 275 (3): 783-8.
22. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer. 2001 Aug 17;85(4):584-9.
23. Williams S J, McGuckin MA, Gotley DC, et al. Two novel mucin genes down-regulated in colorectal cancer identified by differential display. Cancer Res. 1999 Aug 15;59(16):4083-9.
24. Ma J, Li J, Zhou J, et al. Profiling genes differentially expressed in NGX6 overexpressed nasopharyngeal carcinoma cells by cDNA array. J Cancer Res Ctin Onto1. 2002 Dec; 128(12) :683-90.
25．覃吉超，陶德定，舒丹，等．对MOLT-4细胞用cyclin E+A／DNA流式细胞术分析．Chin Med J 2001；114(9)：967-971．
26．宋鑫，曹亚．癌变多阶段形成过程中的细胞稳态反馈机制及其通路．国外医学肿瘤学分册 2001．(28)．6：407-411．
27．邱健，姜馨，何文宪．CDKI p27Kipl及其在结(直)肠肿瘤中的研究世界华人消化杂志．2001；9(2)：209-211
28．曾益新 肿瘤学．北京：人民卫生出版社．1999年11月 第一版．
29．黎家庆，万远廉，才文彦．早期胃癌cyclin E表达的生物学意义．世界华人消化杂志 1999年1月15日；7(1)：31-33．
30．刘晓波，李里，庄宝珠，等．胃癌组织cyclin E表达的临床病理意义．世界华人消化杂志．1999；7(8)：656-658．
31. Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol. 2002 Sep 15;20(18 Suppl):1S-13S.
32. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000 Oct 13;103(2):211-25.
33. Raymond E, Faivre S, Armand JP. et al. Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60 Suppl 1:15-23
34. Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs. 2000 Apr;59(4):753-67.
35. Sorokin A, Lemmon MA, Ullrich A, et al. Stabilization of an active dimeric form of the epidermal growth factor receptor by introduction of an inter-receptor disulfide bond. J Biol Chem. 1994 Apr 1; 269(13):9752-9.
36. Albanell J, Rojo F, Baselga J. et al. Pharmacodynamic studies with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839. Semin Oncol. 2001 0ct;28(5 Suppl 16):56-66.
37. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225).Curr Opin Oncol. 2001 Nov;13(6):506-13.
38. Heimberg M, Weinstein I, LeQuire VS, et al. The induction of fatty liver in neonatal animals by a purified protein (EGF) from mouse submaxillary gland. Life Sci. 1965 Sep; 4(17):1625-33.
39. Lee DC, Barlow KD, Gaido KW. The actions of 2,3,7,8tetrachlorodibenzo-p-dioxin on transforming growth factor-beta2 promoter activity are localized to the TATA box binding region and controlled through a tyrosine kinase-dependent pathway. Toxicol Appl Pharmacol. 1996 Mar;137(1):90-9.
40. Ma L, de Roquancourt A, Bertheau P, et al. Expression of amphiregulin and epidermal growth factor receptor in human breast cancer: analysis of autocriny and stromal-epithelial interactions. J Pathol. 2001 Aug;194(4):413-9
41. Sorensen BS, Torring N, Bor MV, et al. Quantitation of the mRNA
expression of the epidermal growth factor system: selective induction of beparin-binding epidermal growth factor-like growth factor and amphiregulin expression by growth factor stimulation of prostate stromal cells. J Lab Clin Med. 2000 Sep;136(3):209-17.
42. Kim ES, Khuri FR, Herbst RS. Epidermal growth factor receptor biology (IMC-C225).Curr Opin Oncol. 2001 Nov;13(6):506-13.
43. Habib AA, Chun SJ, Neel BG, et al. Increased expression of epidermal growth factor receptor induces sequestration of extracellular signalrelated kinases and selective attenuation of specific epidermal growth factor-mediated signal transduction pathways. Mol Cancer Res. 2003 Jan;1(3):219-33.
44. Ishrath A, Kumar N, Dey CS. Differential activation of ERK and JNK by arsenite in mouse muscle cells. Comp Biochem Physiol C Toxicol Pharmacol. 2002 Jul;132(3):375-84.
45. Fischer PM, Lane DP. Inhibitors of cyclin-dependent kinases as anticancer therapeutics. Curr Med Chem. 2000 Dec;7(12):1213-45.
46. Baba Y, Tsukuda M, Mochimatsu I, et al. Reduced expression of p16 and p27 proteins in nasopharyngeal carcinoma. Cancer Detect Prey. 2001;25(5):414-9.
47. Salvesen HB, Akslen LA. Molecular pathogenesis and prognostic factors in endometrial carcinoma. APMIS. 2002 Oct;110(10):673-89. Review.
48. Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu Rev Med. 1999;50:401-23. Review.
49. Salvesen HB, Akslen LA. Molecular pathogenesis and prognostic factors in endometrial carcinoma. APMIS. 2002 0ct;110(10):673-89. Review.
50. Cavalla P, Piva R, Bortolotto S, et al. p27/kipl expression in oligodendrogliomas and its possible prognostic role. Acta Neuropathol
(Berl). 1999 Dec;98(6): 629-34.
51. Pan MH, Chen WJ, Lin-Shiau SY, et al. Tangeretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis. 2002 Oct;23(10): 1677-84.
52．刘勇，路名芝，潘伯荣．消化系肿瘤细胞增殖调控．新消化病学杂志．1997；5(8)：532-533．
53. Bull AD, BffinAH, Mella J. Colorectal cancer pathology reporting: a regional audit. J Clin Pathol.1997 Feb;50(2):138-42.
54. Thompson EW, Price JT. Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets. 2002 Apr;6 (2) :217-233.
55. McKerrow JH, Bhargava V, Hansell E, et al.A functional proteomics screen of proteases in colorectal carcinoma. Mol Med. 2000 May; 6(5): 450-60.
56．齐璇．基质金属蛋白酶及其抑制物与子宫内膜异位症．第四军医大学学报．
57. Bramhall SR, Neoptolemos JP, Stamp GW, et al. Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol. 1997 Jul; 182(3): 347-55.
58. Baker EA, Stephenson TJ, Reed MW, et al. Expression of proteinases and inhibitors in human breast cancer progression and survival. Mol Pathol. 2002 Oct; 55 (5): 300-4.
59．蒋泽生，高毅．基质金属蛋白酶的生物学特性及其在肝癌浸润转移中的作用．世界华人消化杂志 2000年12月15日；8(12)：1403-1404
60. Tickenbrock L, Kossmeier K, Rehmann H, et al. Differences Between the Interaction of beta-Catenin with Non-phosphorylated and Singlemimicked Phosphorylated 20-amino acid Residue Repeats of the APC
Protein. J Mol Biol. 2003 Mar 21;327(2):359-67.
61. Klingelhofer J, Troyanovsky RB, Laur OY, et al. Exchange of catenins in cadherin-catenin complex. Oncogene. 2003 Feb 27;22(8):1181-8.
62．方石岗，杨继震．肝细胞癌转移的研究进展．世界华人消化杂志．1999；7(9)：782-784．
63. Flug M, Kopf-Maier P. The basement membrane and its involvement in carcinoma cell invasion. Acta Anat (Basel). 1995;152(2):69-84. Review.
64. Mareel MM, Van Roy FM, Bracke ME. How and when do tumor cells metastasize?Crit Rev Oncog. 1993;4(5): 559-94. Review.
65. Herrmann M, Pape G, Herrmann W. Measurement of serum beta-crosslaps is influenced by proteolytic conditions. Clin Chem Lab Med. 2002 Aug; 40(8): 790-4.
66. Soell M, Elkaim R, Tenenbaum H. Cathepsin C, matrix metatloproteinases, and their tissue inhibitors in gingiva and gingival crevicular fluid from periodontitis-affected patients. J Dent Res. 2002 Mar; 81(3):174-8.
67. Chakrabarty S, Radjendirane V, Appelman H, et al. Extracellular Calcium and Calcium Sensing Receptor Function in Human Colon Carcinomas: Promotion of E-Cadherin Expression and Suppression of beta-Catenin/TCF Activation. Cancer Res. 2003 Jan 1;63(1): 67-71.
68. Kanazawa T, Watanabe T, Kazama S, et al. Poorly differentiated adenocarcinoma and mucinous carcinoma of the colon and rectum show higher rates of loss of heterozygosity and loss of E-cadherin expression due to methylation of promoter region. Int J Cancer. 2002 Nov 20;102(3):225-9.
69. Barshishat M, Levi I, Benharroch D, et al. Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line. Br J Cancer. 2002 Nov 18;87(11):1314-20.
70. Khoursheed M, Mathew TC, Makar RR, et al. Expression of CD44s in Human Colorectal Cancer. Pathol Oncol Res. 2002;8(3):170-4.
71. Visca P, Del Nonno F, Botti C. Role and prognostic significance of CD44s expression in colorectal cancer. Anticancer Res. 2002 Sep-Oct;22(5):2671-5.
72. Donato NJ, yan DH, Hung MC, et al. Epidermal growth factor receptor expression and function control cytotoxic responsiveness to tumor necrosis factor in ME-180 squamous carcinoma cells, cell Growth Differ. 1993 May;4(5):411-9.
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