CagA+幽门螺杆菌胃癌前及癌变中NF-κB的表达增强

摘要

目的: 探讨核因子-κB(nuclear factor-Kappa B, NF-κB)在癌前病变及胃癌组织中的表达及其与细胞毒素相关抗原A幽门螺杆菌(CagA⁺H. pylori)感染之间的关系.

方法: 慢性浅表性胃炎34例, 肠腺化生31例, 不典型增生34例, 胃癌55例, 应用免疫组化方法(SABC法)检测NF-κB p65的表达, 以¹⁴C-呼气试验、快速尿素酶试验和Warthin-Starry银染色检测H. pylori, 采用斑点金免疫渗滤法检测患者血清抗H. pylori CagA IgG抗体, 分析NF-κB p65表达与CagA⁺H. pylori感染之间、以及与胃癌组织学分型、临床病理分期、淋巴结转移的关系.

结果: 在慢性浅表性胃炎、肠腺化生、不典型增生和胃癌组中, NF-κB p65阳性表达率分别为15.0%, 41.9%, 64.7%和78.2%, 呈逐渐增高趋势, 各组间有显著性差异(χ² = 43.98, P<0.01); H. pylori感染率分别为70.0%, 67.7%, 73.5%和54.5%, 各组间无显著性差异(P>0.05). CagA⁺H. pylori构成比分别为53.6%, 61.9%, 68.0%和73.3%, 各组间无显著性差异(P>0.05). 在肠化组中, H. pylori 阳性和CagA⁺H. pylori感染的患者NF-κB p65阳性表达率分别为57.1%和76.9%, 显著高于同组无H. pylori感染的10.0%(χ² = 6.18, P<0.05)和CagA- H. pylori感染者的25.0%(χ² = 5.45, P<0.05). 在胃癌组中, NF-κB p65阳性表达与T分期(χ² = 5.91, P<0.05)及淋巴结转移有关(χ² = 7.47, P<0.05), 但与胃癌组织学分型无关(P>0.05).

结论: NF-κB的异常活化在胃癌前病变及癌变过程中起作用, 早期的活化与CagA⁺H. pylori感染有关.

关键词: 核因子-κB; CagA⁺H. pylori; 胃癌; 癌前病变

Increased expression of NF-κB p65 in CagA+ H. pylori-related gastric precancerous lesions and carcinoma

Guo-Ping Li, Ling-Fei Wu, Ze-Jin Pu, Jia-Lin Feng, Zong-Mao Zheng, Bing-Zhou Wang

Guo-Ping Li, Ling-Fei Wu, Ze-Jin Pu, Zong-Mao Zheng, Bing-Zhou Wang, Department of Gastroenterology, the Second Affiliated Hospital, Medical College of Shantou University, Shantou 515041, Guangdong Province, China

Jia-Lin Feng, Department of Information, the Second Affiliated Hospital, Medical College of Shantou University, Shantou 515041, Guangdong Province, China

Supported by: Science and Technology Department of Guangdong Province, No. 2003C30307.

Correspondence to: Ling-Fei Wu, Department of Gastroenterology, the Second Affiliated Hospital, Medical College of Shantou University, Shantou 515041, Guangdong Province, China. lingfeiwu@21cn.com

Received: June 28, 2005
Revised: July 10, 2005
Accepted: July 15, 2005
Published online: September 15, 2005

Abstract

AIM: To determine the expression of nuclear factor kappa B (NF-κB) in human gastric precancerous lesions and carcinoma and its correlation with CagA⁺H. pylori infection.

METHODS: The expression of NF-κB p65 was detected by immunohistochemistry (SABC assay), and H. pylori were examined using 14C-breath test, rapid urease test and Warthin-Starry staining in patients with chronic superficial gastritis (CSG: n = 34), intestinal metaplasia (IM: n = 31), atypical dysplasia (AD: n = 34) and gastric cancer (GC: n = 55). Serum CagA IgG antibody was detected by dot immunogold filtration assay. The correlations of NF-κB p65 expression with CagA⁺H. pylori infection as well as the histological types, clinicopathological stages and lymph node metastasis were analyzed.

RESULTS: The expression of NF-κB p65 in CSG, IM, AD, GC was 15.0%, 41.9%, 64.7%, and 78.2%, respectively, and there were significant differences between them (χ² = 43.98, P <0.01). The rates of H. pylori infection were 70.0%, 67.7%, 73.5%, and 54.5%, respectively, and there were no significant differences between them (P > 0.05). The percentage of CagA⁺H. pylori infection were 53.6%, 61.9%, 68.0%, and 73.3%, respectively, and there were no significantdifferences (P > 0.05). In IM, the positive rate of NF-κB p65 expression in H. pylori or CagA⁺H. pylori positive patients were significantly higher than that in patients without H. pylori infection or with CagA- H. pylori infection (57.1%, 76.9% vs 10%, 25.0%, P <0.05). In GC patients, the positive expression of NF-κB p65 was correlation with the T stages(χ² = 5.91, P <0.05)and lymph node metastasis (χ² = 7.47, P <0.01), but not with the pathohistological types (P > 0.05).

CONCLUSION: NF-κB is constitutively activated in human gastric precancerous lesions and carcinoma tissue and correlates with tumor progression. The early activation may be related to CagA⁺H. pylori infection.

Key Words: Nuclear factor kappa B; CagA⁺H. pylori; Gastric cancer; Precancerous lesions

0 引言

幽门螺杆菌(H. pylori)感染是慢性活动性胃炎的主要病因, 是萎缩性胃炎肠上皮化生和不典型增生等癌前病变的促进因素[1-5].流行病学调查资料表明,H. pylori感染者发生胃癌的危险性较非感染者6倍[6],但确切机制仍不清楚. 核因子-κB(nuclear factor kappa B, NF-κB)作为一种多向转录调节因子[7], 广泛参与多种生理和病理过程的基因调控[8-11], 最近发现它在肿瘤发生发展中亦起重要作用[12-15], 但有关在胃癌发病中的作用报道尚少. 有文献报道, 表达细胞毒素相关抗原A的H. pylori(CagA⁺H. pylori) 可上调NF-κB的表达[16]. 我们研究胃癌及癌前病变中NF-κB的表达以及H. pylori, 尤其是CagA⁺H. pylori的感染状态,旨在探讨二者之间的相互作用关系及其对胃癌发生发展的影响.

1 材料和方法

1.1 材料

2002-5/2004-12我院胃癌患者55例, 男30例, 女25例, 年龄32-77(平均62.4)岁. 高分化癌25例, 中分化癌13例, 低分化癌11例, 黏液腺癌6例.T1期2例, T2期11例, T3期29例, T4期13例.淋巴结转移40例, 无淋巴结转移15例.所有患者术前均未行化疗或放疗.胃镜取材活检标本中慢性浅表性胃炎40例,慢性萎缩性胃炎伴肠化31例, 不典型增生34例,患者均经病理组织学诊断证实.胃黏膜活检标本取自胃窦或病变区, 手术标本均取癌灶及癌旁2 cm组织, 采用40 g/L多聚甲醛固定, 常规脱水、石蜡包埋, 备测.取胃窦部黏膜作快速尿素酶试验、Warthin-starry 银染色结合¹⁴C-呼气试验, 其中2项阳性定为H. pylori感染.微量胶囊法¹⁴C-呼气试验所需试剂由深圳养和生物科技公司提供, 按说明书检测样品每分钟衰变数(dmp), ≥200 dmp为(+), ≤150 dmp为(-); Warthin-Starry银染色按常规组织病理学技术进行, 深棕色细长弯曲为H. pylori染色.CagA⁺H. pylori 检测 采用斑点金免疫渗滤法.试剂盒购自西安联尔生物技术公司, 仅对H. pylori阳性者检测,反应完成后有1个红色斑点为阴性, 有2个红色斑点为阳性, 无红色斑点为无效.阳性者被视为CagA⁺H. pylori感染.

1.2 方法

采用链霉亲和素-生物素-过氧化物酶复合物(SABC)法 兔抗人NF-κB p65及SP试剂盒购自北京中山生物公司.4μm厚连续切片, 二甲苯脱蜡、酒精水化后, 浸入30 mL/L的双氧水中30 min以阻断内源性过氧化物酶的活性, 微波抗原修复, 山羊血清封闭, 分别依次滴加抗NF-κB p65抗体(工作浓度1: 100), 4℃过夜, PBS液洗涤3次.生物素化二抗, 加辣根过氧化物酶标记的链霉卵白素工作液, 室温﹑湿盒中作用30 min, PBS液洗涤3次, DAB液显色, 苏木精轻度复染后脱水、透明、封片.以PBS代替一抗作阴性对照, 用已知胃癌阳性切片作阳性对照.在组织切片中显示胞质或胞核染为淡黄至棕黄色者为阳性细胞.先在低倍镜下选择阳性细胞最集中的5个视野,每个视野观察100个细胞,最后取5个视野中阳性细胞平均百分数作为每张切片的观察结果.根据Handel et al[17]的分级标准采用双盲法记分, 根据阳性细胞所占比例判断结果: <5%为阴性(-),5%-24%为弱阳性(+),25%-50%为中度阳性(++), >50%为强阳性(+++).根据染色强度将阳性信号分为3类: 染色强度弱(+)-淡黄色或仅个别细胞呈黄至棕黄色染色, 染色强度强(+++)-呈棕黄至棕褐色染色, 中等染色强度(++)-染色强度介于弱阳性与强阳性之间. 染色强度×阳性细胞百分数为每例组织染色的综合记分.综合记分≥1判为表达阳性, <1则为阴性.

统计学处理 采用χ²检验和Spearman等级相关分析, 应用SPSS10.0软件包, 检验水准α = 0.05.

2 结果

2.1 胃部疾病中H. pylori 及CagA⁺H. pylori感染和NF-κB p65表达

慢性浅表性胃炎40例中,H. pylori 阳性28例(CagA⁺H. pylori 15例,占53.6%),H. pylori阴性12例, H. pylori感染率为70.0%.慢性萎缩性胃炎伴肠化31例中, H. pylori 阳性21例(CagA⁺H. pylori 13例, 占61.9%), H. pylori 阴性10 例, H. pylori感染率为 67.7%.不典型增生34例中, H. pylori阳性25例(CagA⁺H. pylori 17 例,占68.0%), H. pylori 阴性 9 例, H. pylori感染率为73.5%.55例胃癌组织中, H. pylori 阳性30例(CagA⁺H. pylori22例, 占73.3%), H. pylori 阴性25例, H. pylori 感染率为 54.5%.各组H. pylori感染率无显著性差异(χ² = 4.32, P>0.05).CagA⁺H. pylori感染的比例在胃炎、胃癌前病变至胃癌组中有逐渐增高趋势, 但无统计学意义(χ² = 2.69,P>0.05).NF-κB p65蛋白表达呈棕黄色颗粒, 定位于细胞质, 部分亦可见于细胞核.慢性浅表性胃炎组织中胞质、胞核中很少呈现表达.癌前病变组织中其表达信号逐渐增强, 在不典型增生中炎性细胞浸润明显, 腺体结构破坏, 异型细胞胞质中可见其表达, 为棕黄颗粒(图1A).胃癌细胞中则常见其表达,呈粗细不等的棕黄或棕褐色颗粒, 胞质、胞核同时着色,表达强度为中等或强阳性(图1B-C).慢性浅表性胃炎﹑慢性萎缩性胃炎伴肠化﹑不典型增生和胃癌组织中NF-κB p65的表达率分别为15.0%, 41.9%, 64.7%和78.2%, 呈递增趋势, 经统计学处理, 差异有显著性(χ² = 43.98, P<0.005).

图1 NF-κB p65的表达(SP法,×400). A: 不典型增生; B: 高分化胃腺癌; C: 中分化胃腺癌.

2.2 H. pylori与NF-κB p65表达的关系

按照H. pylori感染情况分组, 浅表性胃炎中H. pylori (+)组NF-κB p65表达率高于H. pylori(-)组, 但无显著性差异(P>0.05). 肠化患者中H. pylori(+)组NF-κB p65表达率显著高于H. pylori(-)组, 差异有统计学意义(χ² = 6.18, P<0.05).不典型增生和胃癌组中H.pylori(+)与H. pylori(-)患者NF-κB p65表达阳性率相近, 经统计学处理, 均无显著性差异(P>0.05)(表1).按照CagA情况分组, 慢性萎缩性胃炎伴肠化组中CagA⁺H. pylori患者NF-κB p65阳性率为76.9%, CagA- H. pylori患者的阳性率为25.0%,二者相比, 差异有统计学意义(χ² = 5.45,P<0.05).其余各组组内比较均无显著性差异(P>0.05)(表2).

表1 NF-κB p65表达与H. pylori感染的关系n(%).

分组	H. pylori(+)	NF-κB p65	H. pylori(-)	NF-κB p65
浅表性胃炎	28	5 (17.9)	12	1(8.3)
肠化	21	12 (57.1)	10	1(10.0)a
不典型增生	25	16 (64.0)	9	6(66.7)
胃癌	30	24(80.0)	25	19(76.0)

^aP<0.05 vs H. pylori (+).

表2 NF-κB p65表达与CagA⁺H. pylori 感染的关系n(%).

分组	CagA+H. pylori	NF-κB p65	CagA-H. pylori	NF-κB p65
浅表性胃炎	15	4(26.7)	13	1(7.7)
肠化	13	10(76.9)	8	2(25.0)a
不典型增生	17	13(76.5)	8	3(37.5)
胃癌	22	18(81.8)	8	6(75.0)

^aP<0.05 vs CagA⁺H. pylori.

2.3 NF-κB p65与胃癌临床病理特征的关系

NF-κB p65表达阳性率与胃癌病理学类型无关, 与胃癌的临床分期、浸润深度及淋巴结转移有关(表3).

表3 NF-κB p65表达与胃癌临床病理特征的关系n(%).

临床病理因素	n	NF-κB p65
高分化腺癌	25	22(88.0)
中分化腺癌	13	10(76.9)
未分化/黏液癌	17	11(64.7)
Ｔ1+Ｔ2	13	7(53.8)
Ｔ3+Ｔ4	42	36(85.7)a
无淋巴结转移	15	8(53.3)
有淋巴结转移	40	35(87.5)b

^aP<0.05 vs T₁+T₂,

^bP<0.01无淋巴结转移.

3 讨论

流行病学调查资料表明, 胃癌发生率与当地H. pylori感染率呈正相关, 然而, H. pylori如何引起胃癌的机制并不清楚.一般认为, 胃癌的发生是一个有多因素参与的复杂而漫长的过程.大多从慢性浅表性胃炎至萎缩性胃炎, 逐渐出现肠上皮化生和不典型增生等癌前病变, 最终才转化成癌.本结果表明, 在有胃病症状的人群中H. pylori的感染率为54.5%-73.5%, 与文献报道相同[18,19].胃癌组患者的感染率较低(54.5%), 我们认为可能与研究方法有关.通过血清学方法, 我们发现在胃炎、胃癌前病变至胃癌组中CagA⁺H. pylori感染比例有逐渐增高趋势, 显示检测抗体的方法可能比实时检测细菌更能反映H. pylori对胃部疾病的长期影响, 新近Storskrubb et al在H. pylori对胃癌前病变的一组流行病学调查报告中亦支持此观点[20].慢性萎缩性胃炎伴肠化H. pylori阳性或CagA⁺H. pylori患者NF-κB p65的阳性表达率显著高于H. pylori阴性或CagA^-H. pylori 患者, 慢性浅表性胃炎组中H. pylori阳性NF-κB p65表达虽高于H. pylori阴性患者, 但未显出差异且均在较低的水平, 提示H. pylori感染引起NF-κB p65表达上调需要一定的时间.不典型增生及胃癌组NF-κB p65的表达均明显增高, 且与H. pylori或CagA⁺H. pylori感染无关, 说明一旦进入病变严重或不可逆阶段, 由于涉及多种遗传物质的改变, H. pylori的作用已不再易于显示出来, NF-κB p65的激活是多因素作用长期累积的结果[21,22].CagA⁺H. pylori感染的胃炎向胃癌转变过程中NF-κB p65可能是重要的分子生物学环节.H. pylori, 特别是CagA⁺H. pylori引起NF-κB p65活化, 并与其它因素一起启动靶基因c-myc,Cyclin D 和bcl-2 的转录[23-27],破坏正常细胞的分化过程, 最终导致胃上皮细胞向恶性方向转化[28], 可能是其参与胃癌发生的机制之一. 最近研究发现, NF-κB在肿瘤的发生、发展中起重要作用, 可调控细胞的增殖﹑分化、凋亡及恶性转化, 其活性失控常与哺乳动物肿瘤发生有关[29-31].有证据表明, NF-κB的持续活化可作为结肠癌、胰腺癌、乳腺癌、前列腺癌等多种实体肿瘤的标志[7-11,22,29]. Wang et al[32]检测胰腺组织中NF-κB p65的表达, 结果胰腺癌的表达阳性率为67%, 而正常胰腺组织表达罕见.在前列腺癌的研究中, Huang et al[33]报道NF-κB活化后可抑制细胞凋亡, 促进其增殖. Sasaki et al[15]应用免疫组织化学方法检测 NF-κB p65 在胃癌细胞胞质和胞核中的表达情况, 结果肿瘤组织中NF-κB p65的表达明显高于癌旁正常上皮细胞; 电泳迁移率改变分析显示胃癌组织中 NF-κB的 DNA 结合活性与核转位的活性均增加. 本研究中NF-κB p65在慢性浅表性胃炎、慢性萎缩性胃炎伴肠化、不典型增生及胃癌组织中的表达阳性率呈递增趋势, 各组之间差异有统计学意义,且随着组织学病变程度的加重, 阳性细胞数量逐渐增多,分布范围也逐渐扩大, 与Sasaki et al[15]结果一致.NF-κB p65在癌前病变中有较高的阳性率,表明NF-κB p65蛋白表达参与了胃癌前病变的进展, 为胃癌癌变的早期事件, 有可能成为检测早期癌变的标志物.本组55例胃癌中, NF-κB p65表达阳性率在高分化腺癌中较高, 但与中分化腺癌、低分化或黏液癌无显著性差异, 提示NF-κB的表达与肿瘤发生的组织学类型无关.比较不同肿瘤分期中NF-κB p65的表达, T3, T4期的胃癌此蛋白的表达显著高于T1, T2期, 而且伴淋巴结转移者显著高于无淋巴结转移者, 显示NF-κB p65表达与胃癌的分期、浸润深度及淋巴结转移等病理学特性关系密切, 越近晚期的癌肿表达阳性率相对也越高, 与史朝晖et al[34]、王维et al[35]的报道相似, 提示NF-κB p65的异常活化与胃癌的发病密切相关外, 还可能对胃癌侵袭生长施加影响, 并可增加其转移潜能[13,14].从另一角度分析, 此蛋白表达与胃癌侵润及转移有关, 则有可能作为判断胃癌预后的指标[36].

备注

编辑: 潘伯荣 审读: 张海宁

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