NF-kB上调VEGF表达影响胃癌预后
陈贵, 谢岳林, 嘉定南翔医院外科 上海市 201802
于颖彦, 尹浩然, 朱正纲, 上海第二医科大学附属瑞金医院消化外科研究所 上海市 200025
陈贵, 男, 1955-03-13生, 外科主任, 副主任医师.
上海市重点学科基金资助, No. SZD04002
通讯作者: 于颖彦, 200025, 上海市, 上海第二医科大学附属瑞金医院消化外科研究所. yingyan3y@yahoo.com.cn
电话: 021-59122482
收稿日期: 2005-04-04 接受日期: 2005-04-09
, http://www.100md.com
Effect of VEGF expression up-regulated by nuclear factor-kB prognosis of gastric carcinoma
Gui Chen, Ying-Yan Yu, Yue-Lin Xie, Hao-Ran Yin, Zheng-Gang Zhu
Gui Chen, Yue-Lin Xie, Department of Surgery, Jiading Nanxiang Hospital, Shanghai 201802, China
Ying-Yan Yu, Hao-Ran Yin, Zheng-Gang Zhu, Affiliated Ruijin Hospital, the Second Medical University, Shanghai 200025, China
, http://www.100md.com
Supported by the Key Discipline Foundation of Shanghai, No.SZD04002
Correspondence to: Ying-Yan Yu, Institute of Digestive Surgery, Affiliated Ruijin Hospital, the Second Medical University, Shanghai 200025, China. yingyan3y@yahoo.com.cn
Received: 2005-04-04 Accepted: 2005-04-09
Abstract
, http://www.100md.com
AIM: To investigate the up-regulation of vascular endothelial growth factor (VEGF) induced by the activation of nuclear factor-kB (NF-kB) and its effect on the prognosis of gastric carcinoma.
METHODS: Forty-one gastric carcinoma specimens were obtained by surgery and the expression of NF-kB, VEGF and CD34 were detected in paraffin-embedded tissue sections by immunohistochemical method.
RESULTS: NF-kB was activated and expressed in 68.3% (28/41) gastric carcinoma and VEGF was expressed in 70.7% (29/41). A significant correlation was found between NF-kB activation and VEGF expression(k = 0.393, P = 0.012). The microvessel Density in co-expression of NF-kB and VEGF group was significantly higher than that in non-expression group (P = 0.000). The co-expression of NF-kB and VEGF group showed markedly poorer prognosis than that did in non-expression group (P = 0.035).
, 百拇医药
CONCLUSION: The activation of NF-kB contributes to tumor angiogenesis in gastric carcinoma by up-regulation of VEGF, which results in a poorer prognosis.
Key Words: Gastric carcinoma; NF-kB; Vascular endothelial growth factor; Microvessel density; Prognosis
Chen G, Yu YY, Xie YL, Yin HR, Zhu ZG. Effect of VEGF expression up-regulated by nuclear factor-kB prognosis of gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2005;13(11):1275-1277
, 百拇医药
摘要
目的: 探讨胃癌内核转录因子kB(nuclear factor-kB，NF-kB)活化对血管内皮生长因子(vascular endothelial growth factor, VEGF)表达的影响及对预后的影响.
方法: 选择胃癌根治术切除标本41例，应用免疫组织化学方法测定NK-kB，VEGF及CD34的表达, 检测结果与胃癌临床病理学多参数进行经统计分析.
结果: NF-kB呈活化型型表达者占受检病例的68.3%，VEGF呈强阳性表达者占受检病例的70.73%.NF-kB活化型表达组与VEGF高表达组有较高一致性(k = 0.393，P = 0.012).NF-kB与VEGF同时表达组微血管密度明显较NF-kB与VEGF同时阴性组高(P = 0.000)，NF-kB与VEGF同时表达组生存期明显短于NF-kB与VEGF同时阴性组(P = 0.035).
, 百拇医药
结论: 胃癌细胞通过活化NF-kB信号通道促进VEGF高表达，从而影响肿瘤内微血管密度及预后.
关键词: 胃癌; NF-kB; VEGF; 微血管密度; 预后
陈贵, 于颖彦, 谢岳林, 尹浩然, 朱正纲. NF-kB上调VEGF表达影响胃癌预后. 世界华人消化杂志 2005;13(11):1275-1277
肠型胃癌NF-kB呈活化型表达(Envision X200).
图2 肠型胃癌VEGF呈强阳性表达(Envision X200).
, 百拇医药
2.2 NF-kB调控VEGF表达对胃癌预后的影响 NF-kB活化型表达同时伴有VEGF表达组胃癌平均生存期明显短于NF-kB及VEGF阴性表达组(37.7±5.8%vs 75.9±10.9%，P = 0.035)，经生存期分析显示两组之间具有显著性差异(图3).
图3 (PDF) Kaplan-Meier法及Log Rank检验示NF-kB及VEGF共表达组预后明显较NF-kB及VEGF阴性组差(P = 0.035).
3 讨论
NF-kB平时以同源或异源性二聚体的非活性形式存在于几乎所有类型细胞的胞质中，只在各种刺激因素作用下才被激活.NF-kB除与机体的免疫应答、炎症反应密切相关外，还参与调控细胞增殖和凋亡相关基因，在肿瘤的发生过程中起重要作用.我们曾报道胃癌细胞存在NF-kB的活化形式，呈NF-kB活化表达的胃癌其临床生存期明显较NF-kB阴性组短，其确切机制除癌周淋巴细胞NF-kB活化后机体抗肿瘤免疫增强参与其中外，可能还涉及肿瘤细胞自身特性的改变[5-6].为此，现就NF-kB活化对其下游基因产物VEGF的调控从而导致肿瘤微血管密度增加对胃癌预后的研究进行了研究.VEGF是实体瘤内新生血管形成的主要调节系统，参与肿瘤的发生、发展及转移过程，该基因的转录受NF-kB信号通道活化的调控.越来越多的实验显示，抑制NF-kB信号通道活化可以明显抑制VEGF表达及微血管形成[7-9].肿瘤细胞合成的VEGF分布于肿瘤血管周围，VEGF与血管内皮细胞膜的KDR受体结合，诱导血管生成[10].肿瘤的生长可分为无血管期和有血管期.在无血管期，肿瘤主要依靠与周围组织的弥散来获取营养和排泄代谢产物.当肿瘤发展到1-2mm直径大小时进入有血管期，肿瘤内出现新生毛细血管并获得进一步的生长能力，肿瘤迅速生长并可发生转移[11].本结果表明NF-kB呈活化型表达组胃癌VEGF表达呈显著增强，且NF-kB与VEGF共表达组胃癌生存期明显短于NF-kB与VEGF阴性组，统计学处理显示NF-kB活化型表达与VEGF表达之间存在相关性.NF-kB与VEGF均表达组肿瘤内微血管密度明显增加，提示NF-kB活化型表达造成胃癌预后差的原因之一是通过上调VEGF表达促进微血管形成从而加速肿瘤生长与转移所致.然而，上调VEGF表达只是NF-kB活化的表现之一.鉴于NF-kB作为细胞内重要转录因子参与多种与细胞增殖、凋亡相关基因的调控，不能排除NF-kB呈活化型表达组预后差可能与胃癌细胞增殖能力及抗凋亡能力等其他生物学指标改变有关，故胃癌中NF-kB活化与其他生物学指标等的关系均值得深入探讨.
, 百拇医药
4 参考文献
1 Wulczyn FG, Krappmann D, Scheidereit C. The NF-kB/Rel and IkB gene families: Mediators of immune response
and inflammation. J Mol Med 1996;74:749-769
2 Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ. Blockade of Nuclear Factor-kB Signaling Inhibats
Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular
, 百拇医药
Endothelial Growth Factor and Interleukin 8. Cancer Res 2000;60:5334-5339
3 钟霞, 于皆平, 冉宗学. 大肠癌中NF-kBP65、VEGF表达相关性研究. 肿瘤学杂志 2001;7:346-348
4 於亮亮, 于皆平, 冉宗学, 于红刚. 核因子kB与大肠肿瘤细胞凋亡及增生的关系. 世界华人消化杂志 2002;10:309-312
5 叶正宝, 陈贵, 于颖彦, 计骏, 马韬, 尹浩然, 朱正纲. 核转录因子/白介素-8与胃癌血管生成中及预后关系研究.
中华消化杂志 2003;23:668-670
6 于颖彦, 朱正纲, 陈贵, 计骏, 马韬, 刘炳亚, 尹浩然. 胃癌及癌周淋巴细胞NF-kB激活的临床意义. 中华胃肠外科
, http://www.100md.com
杂志 2005;8:85-86
7 Xiong HQ,Abbruzzese JL, Lin E, Wang L, Zheng L, Xie K. NF-kappaB activity blockadeimpairs the angiogenic potential
of human pancreatic cancer cells. Int JCancer 2004;108:181-188
8 Fujioka S,Sclabas GM, Schmidt C, Niu J, Frederick WA, Dong QG, Abbruzzese JL, EvansDB, Baker C, Chiao PJ. Inhibition
of constitutive NF-kappa B activity by Ikappa B alpha M suppresses tumorigenesis. Oncogene 2003;22:1365-1370
, 百拇医药
9 Shibata A,Nagaya T, Imai T, Funahashi H, Nakao A, Seo H. Inhibition of NF-kappaBactivity decreases the VEGF
mRNA expression in MDA-MB-231 breast cancercells. Breast Cancer Res Treat 2002;73:237-243
10 Maeda K, ChungYS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M. PrognosticValue of
Vascular endothelial growth factorexpression in gastric carcinoma. Cancer 1996;77:858-863
11 Woodhouse EC,Chuaqui RF, Liotta LA. General mechanisms of metastasis. Cancer 1997;80(8 Suppl):1529-1537
编辑 潘伯荣 审读 张海宁, http://www.100md.com( 陈 贵, 于颖彦, 谢岳林, 尹浩然, 朱正纲)
于颖彦, 尹浩然, 朱正纲, 上海第二医科大学附属瑞金医院消化外科研究所 上海市 200025
陈贵, 男, 1955-03-13生, 外科主任, 副主任医师.
上海市重点学科基金资助, No. SZD04002
通讯作者: 于颖彦, 200025, 上海市, 上海第二医科大学附属瑞金医院消化外科研究所. yingyan3y@yahoo.com.cn
电话: 021-59122482
收稿日期: 2005-04-04 接受日期: 2005-04-09
, http://www.100md.com
Effect of VEGF expression up-regulated by nuclear factor-kB prognosis of gastric carcinoma
Gui Chen, Ying-Yan Yu, Yue-Lin Xie, Hao-Ran Yin, Zheng-Gang Zhu
Gui Chen, Yue-Lin Xie, Department of Surgery, Jiading Nanxiang Hospital, Shanghai 201802, China
Ying-Yan Yu, Hao-Ran Yin, Zheng-Gang Zhu, Affiliated Ruijin Hospital, the Second Medical University, Shanghai 200025, China
, http://www.100md.com
Supported by the Key Discipline Foundation of Shanghai, No.SZD04002
Correspondence to: Ying-Yan Yu, Institute of Digestive Surgery, Affiliated Ruijin Hospital, the Second Medical University, Shanghai 200025, China. yingyan3y@yahoo.com.cn
Received: 2005-04-04 Accepted: 2005-04-09
Abstract
, http://www.100md.com
AIM: To investigate the up-regulation of vascular endothelial growth factor (VEGF) induced by the activation of nuclear factor-kB (NF-kB) and its effect on the prognosis of gastric carcinoma.
METHODS: Forty-one gastric carcinoma specimens were obtained by surgery and the expression of NF-kB, VEGF and CD34 were detected in paraffin-embedded tissue sections by immunohistochemical method.
RESULTS: NF-kB was activated and expressed in 68.3% (28/41) gastric carcinoma and VEGF was expressed in 70.7% (29/41). A significant correlation was found between NF-kB activation and VEGF expression(k = 0.393, P = 0.012). The microvessel Density in co-expression of NF-kB and VEGF group was significantly higher than that in non-expression group (P = 0.000). The co-expression of NF-kB and VEGF group showed markedly poorer prognosis than that did in non-expression group (P = 0.035).
, 百拇医药
CONCLUSION: The activation of NF-kB contributes to tumor angiogenesis in gastric carcinoma by up-regulation of VEGF, which results in a poorer prognosis.
Key Words: Gastric carcinoma; NF-kB; Vascular endothelial growth factor; Microvessel density; Prognosis
Chen G, Yu YY, Xie YL, Yin HR, Zhu ZG. Effect of VEGF expression up-regulated by nuclear factor-kB prognosis of gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2005;13(11):1275-1277
, 百拇医药
摘要
目的: 探讨胃癌内核转录因子kB(nuclear factor-kB，NF-kB)活化对血管内皮生长因子(vascular endothelial growth factor, VEGF)表达的影响及对预后的影响.
方法: 选择胃癌根治术切除标本41例，应用免疫组织化学方法测定NK-kB，VEGF及CD34的表达, 检测结果与胃癌临床病理学多参数进行经统计分析.
结果: NF-kB呈活化型型表达者占受检病例的68.3%，VEGF呈强阳性表达者占受检病例的70.73%.NF-kB活化型表达组与VEGF高表达组有较高一致性(k = 0.393，P = 0.012).NF-kB与VEGF同时表达组微血管密度明显较NF-kB与VEGF同时阴性组高(P = 0.000)，NF-kB与VEGF同时表达组生存期明显短于NF-kB与VEGF同时阴性组(P = 0.035).
, 百拇医药
结论: 胃癌细胞通过活化NF-kB信号通道促进VEGF高表达，从而影响肿瘤内微血管密度及预后.
关键词: 胃癌; NF-kB; VEGF; 微血管密度; 预后
陈贵, 于颖彦, 谢岳林, 尹浩然, 朱正纲. NF-kB上调VEGF表达影响胃癌预后. 世界华人消化杂志 2005;13(11):1275-1277
肠型胃癌NF-kB呈活化型表达(Envision X200).
图2 肠型胃癌VEGF呈强阳性表达(Envision X200).
, 百拇医药
2.2 NF-kB调控VEGF表达对胃癌预后的影响 NF-kB活化型表达同时伴有VEGF表达组胃癌平均生存期明显短于NF-kB及VEGF阴性表达组(37.7±5.8%vs 75.9±10.9%，P = 0.035)，经生存期分析显示两组之间具有显著性差异(图3).
图3 (PDF) Kaplan-Meier法及Log Rank检验示NF-kB及VEGF共表达组预后明显较NF-kB及VEGF阴性组差(P = 0.035).
3 讨论
NF-kB平时以同源或异源性二聚体的非活性形式存在于几乎所有类型细胞的胞质中，只在各种刺激因素作用下才被激活.NF-kB除与机体的免疫应答、炎症反应密切相关外，还参与调控细胞增殖和凋亡相关基因，在肿瘤的发生过程中起重要作用.我们曾报道胃癌细胞存在NF-kB的活化形式，呈NF-kB活化表达的胃癌其临床生存期明显较NF-kB阴性组短，其确切机制除癌周淋巴细胞NF-kB活化后机体抗肿瘤免疫增强参与其中外，可能还涉及肿瘤细胞自身特性的改变[5-6].为此，现就NF-kB活化对其下游基因产物VEGF的调控从而导致肿瘤微血管密度增加对胃癌预后的研究进行了研究.VEGF是实体瘤内新生血管形成的主要调节系统，参与肿瘤的发生、发展及转移过程，该基因的转录受NF-kB信号通道活化的调控.越来越多的实验显示，抑制NF-kB信号通道活化可以明显抑制VEGF表达及微血管形成[7-9].肿瘤细胞合成的VEGF分布于肿瘤血管周围，VEGF与血管内皮细胞膜的KDR受体结合，诱导血管生成[10].肿瘤的生长可分为无血管期和有血管期.在无血管期，肿瘤主要依靠与周围组织的弥散来获取营养和排泄代谢产物.当肿瘤发展到1-2mm直径大小时进入有血管期，肿瘤内出现新生毛细血管并获得进一步的生长能力，肿瘤迅速生长并可发生转移[11].本结果表明NF-kB呈活化型表达组胃癌VEGF表达呈显著增强，且NF-kB与VEGF共表达组胃癌生存期明显短于NF-kB与VEGF阴性组，统计学处理显示NF-kB活化型表达与VEGF表达之间存在相关性.NF-kB与VEGF均表达组肿瘤内微血管密度明显增加，提示NF-kB活化型表达造成胃癌预后差的原因之一是通过上调VEGF表达促进微血管形成从而加速肿瘤生长与转移所致.然而，上调VEGF表达只是NF-kB活化的表现之一.鉴于NF-kB作为细胞内重要转录因子参与多种与细胞增殖、凋亡相关基因的调控，不能排除NF-kB呈活化型表达组预后差可能与胃癌细胞增殖能力及抗凋亡能力等其他生物学指标改变有关，故胃癌中NF-kB活化与其他生物学指标等的关系均值得深入探讨.
, 百拇医药
4 参考文献
1 Wulczyn FG, Krappmann D, Scheidereit C. The NF-kB/Rel and IkB gene families: Mediators of immune response
and inflammation. J Mol Med 1996;74:749-769
2 Huang S, Robinson JB, Deguzman A, Bucana CD, Fidler IJ. Blockade of Nuclear Factor-kB Signaling Inhibats
Angiogenesis and Tumorigenicity of Human Ovarian Cancer Cells by Suppressing Expression of Vascular
, 百拇医药
Endothelial Growth Factor and Interleukin 8. Cancer Res 2000;60:5334-5339
3 钟霞, 于皆平, 冉宗学. 大肠癌中NF-kBP65、VEGF表达相关性研究. 肿瘤学杂志 2001;7:346-348
4 於亮亮, 于皆平, 冉宗学, 于红刚. 核因子kB与大肠肿瘤细胞凋亡及增生的关系. 世界华人消化杂志 2002;10:309-312
5 叶正宝, 陈贵, 于颖彦, 计骏, 马韬, 尹浩然, 朱正纲. 核转录因子/白介素-8与胃癌血管生成中及预后关系研究.
中华消化杂志 2003;23:668-670
6 于颖彦, 朱正纲, 陈贵, 计骏, 马韬, 刘炳亚, 尹浩然. 胃癌及癌周淋巴细胞NF-kB激活的临床意义. 中华胃肠外科
, http://www.100md.com
杂志 2005;8:85-86
7 Xiong HQ,Abbruzzese JL, Lin E, Wang L, Zheng L, Xie K. NF-kappaB activity blockadeimpairs the angiogenic potential
of human pancreatic cancer cells. Int JCancer 2004;108:181-188
8 Fujioka S,Sclabas GM, Schmidt C, Niu J, Frederick WA, Dong QG, Abbruzzese JL, EvansDB, Baker C, Chiao PJ. Inhibition
of constitutive NF-kappa B activity by Ikappa B alpha M suppresses tumorigenesis. Oncogene 2003;22:1365-1370
, 百拇医药
9 Shibata A,Nagaya T, Imai T, Funahashi H, Nakao A, Seo H. Inhibition of NF-kappaBactivity decreases the VEGF
mRNA expression in MDA-MB-231 breast cancercells. Breast Cancer Res Treat 2002;73:237-243
10 Maeda K, ChungYS, Ogawa Y, Takatsuka S, Kang SM, Ogawa M, Sawada T, Sowa M. PrognosticValue of
Vascular endothelial growth factorexpression in gastric carcinoma. Cancer 1996;77:858-863
11 Woodhouse EC,Chuaqui RF, Liotta LA. General mechanisms of metastasis. Cancer 1997;80(8 Suppl):1529-1537
编辑 潘伯荣 审读 张海宁, http://www.100md.com( 陈 贵, 于颖彦, 谢岳林, 尹浩然, 朱正纲)
