P-gp和Topo-Ⅱ在原发性肝癌中的表达及临床意义

目的研究多药耐药相关蛋白P-糖蛋白（gp）和拓扑异构酶Ⅱ（Topo-Ⅱ）在原发性肝癌组织中的表达及临床意义。方法采用免疫组化S-P法检测49例原发性肝癌组织V-gp和Topo-Ⅱ的表达。结果V-gp和Topo-Ⅱ在原发性肝癌中阳性表达率分别为61．22％（30／49）和32．65％（16／49），V-gp主要在细胞膜和细胞浆中表达，Topo-Ⅱ在细胞核内表达，V-gp和Topo-Ⅱ表达与Edmonson分级有关，Topo-Ⅱ还与转移有关。V-gp、Topo-Ⅱ在原发性肝癌中表达呈负相关（P〈0．05）。结论肝癌组织V-gp和Topo-Ⅱ表达可能是肝癌对化疗不敏感的原因之一。     

P-gp、GST-π和P53在胆囊癌中的表达及意义

目的:探讨P-gp、GST-π和P53的表达与胆囊癌临床病理因素及预后的相关性.方法:应用免疫组织化学SP法对术前未经化疗的49例胆囊癌术后标本P-gp、GST-π和P53的表达进行检测,分析P-gp、GST-π和P53的表达与胆囊癌临床病理因素及预后的相关性.结果:P-gp、GST-π和P53在胆囊癌组织中的阳性表达率分别为75.5%(37/49)、65.3%(32/49)和69.4%(34/49).P-gp、P53的表达与淋巴结转移情况呈正相关(P<0.05).临床分期S4、S5期和有淋巴结转移的胆囊癌P53表达率显著高于S1-S3期和淋巴结未转移者(80.0% vs 52.6%,P<0.05).中低分化胆囊癌的GST-π表达率显著高于高分化及乳头状腺癌(均P<0.05).P-gp和P53的表达之间具有正相关性(r=0.343,P<0.05).P-gp和GST-π表达阳性者累积生存率显著低于阴性者.结论:P-gp,GST-π和P53是反映胆囊癌生物学行为的重要指标.联合检测P-gp和GST-π的表达对胆囊癌预后的判定具有重要的参考价值.     

原发性肝癌组织中骨桥蛋白与MMP-2的表达及临床意义

检测原发性肝癌组织中骨桥蛋白(OPN)及基质金属蛋白酶-2(MMP-2)的表达。对原发性肝癌与正常肝脏组织标本,应用免疫组织化学技术检测OPN和MMP-2蛋白的表达。42例肝癌组织中OPN及MMP-2蛋白的表达阳性率分别为71．4%和66．7%,两者表达呈正相关(P＜0．01)。并且两者在肝癌不同分期和分级之间差异有统计学意义(P＜0．05)。4例正常肝脏组织中均未见阳性表达。OPN阳性表达可能与肿瘤的浸润转移有关,OPN与MMP-2可能在肝癌的进展中起协同作用。     

P-糖蛋白在贲门癌原发灶及其淋巴结转移灶的表达及意义

目的探讨P-糖蛋白(P-gp)在贲门癌原发灶及其淋巴结转移灶的表达差异,并分析与临床病理学因素的关系。方法收集30例经病理确诊的贲门癌原发灶、淋巴结转移灶及对应癌旁正常组织,采用免疫组织化学二步法检测3组标本的P-gp表达。结果 (1)P-gp在淋巴结转移灶、原发灶及癌旁正常组织的阳性表达率分别为66.7%、40%和16.7%,P-gp在淋巴结转移灶中的表达高于原发灶,原发灶高于正常组织(P<0.05)。(2)P-gp在贲门癌原发灶的表达与性别、年龄、浸润深度及分化程度均无关(P<0.05);在淋巴结转移灶的表达与性别、年龄、浸润深度无关,与分化程度有关(P<0.05)。结论 P-gp参与贲门癌肿瘤细胞的原发性多药耐药;淋巴结转移灶与原发灶的肿瘤细胞间存在多药耐药异质性。     

骨桥蛋白和P21在原发性肝癌中的表达及其临床意义

目的　探讨骨桥蛋白(OPN)和P2 1在原发性肝癌组织中的表达及它们在肝癌转移中的作用。方法　采用免疫组化S P法检测69例原发性肝癌组织中OPN和P2 1的表达情况。结果　①OPN和P2 1的阳性表达主要定位于癌细胞的细胞浆;OPN、P2 1在69例肝癌组织中阳性表达率分别为72 .5 % (5 0 / 69)和62 .3 % (4 3 / 69)。②在发生转移的肝癌组织中OPN和P2 1阳性表达率分别为84.2 % (3 2 / 3 8)和76.3 % (2 9/ 3 8) ,高于无转移的肝癌组织中OPN(5 8.1% ,18/ 3 1)和P2 1(4 5 .2 % ,14 / 3 1)阳性表达率,差异具有显著性,P <0 .0 5。③两者均阳性表达的3 5例肝癌中有2 4例(74.3 % )已发生转移,与两者均阴性表达的11例肝癌中仅有1例(9.1% )发生转移比较差异有显著性,P <0 .0 5 ,提示OPN和P2 1均阳性表达与肿瘤转移的发生密切相关。④OPN和P2 1的表达与肿瘤的大小、AFP水平、有无HBV感染、肿瘤分化、性别、年龄等因素无关,但与肿瘤侵袭转移的发生有关,P <0 .0 5。⑤OPN和P2 1的表达呈显著正相关(r =0 .2 5 7,P <0 .0 5 )。结论　OPN和P2 1的表达与肝癌侵袭转移的发生有密切关系,两者均阳性表达时对预测肝癌已发生转移具有指导意义。     

环氧合酶-2与P-糖蛋白在人肝癌细胞中的表达及其意义

目的 探讨环氧合酶(COX)-2在肝细胞癌发生、发展中的作用及其对P-糖蛋白(P-gp)表达的影响. 方法 收集2003年10月-2005年6月因肝癌切除术切取的肝癌组织标本,用RTPCR、免疫组织化学方法分别检测COX-2 mRNA和COX-2蛋白在肝癌组织和腹部手术取得的正常肝组织中的表达.同时检测多药耐药基因1 mRNA和P-gp在肝癌组织中的表达情况,并分析COX-2与P-gp在肝癌组织中表达的相关性.各样本率间比较采用x2检验、用精确概率法分析组间差异,样本间均数的比较用t检验,用Spearman' s等级相关公式分析COX-2和P-gp的相关性.结果 共收集肝癌组织52例,正常肝组织20例.正常肝组织中未见COX-2表达,COX-2表达在中、低分化肝癌组织的阳性率(94.1％)高于高分化肝癌组织(38.9％,x2= 6.80,P＜0.01);在HBsAg阳性的肝癌组织中的表达(91.7％)高于HBsAg阴性的肝癌组织(62.5％,x2= 4.70,P＜0.05);在合并肝硬化的肝癌组织中的表达(96.7％)高于无肝硬化的肝癌组织(63.6％,x2= 7.51,P＜0.01);P-gp在癌组织中的表达(86.6％)高于相应的癌旁组织(30.7％,x2= 64.42,P＜0.01).RT-PCR检测结果显示COX-2 mRNA在正常肝组织中无表达,而多药耐药基因l mRNA在肝癌组织和正常肝组织中均有表达.同时表达COX-2和多药耐药基因1为42例,两者呈正相关(r=0.563,P＜0.01).结论 本研究结果提示COX-2参与了以P-gp介导的肝癌的多药耐药机制.     

Stathmin蛋白在人原发性肝癌中的表达与原发性肝癌生物学行为的关系

目的 探讨Stathmin蛋白在人原发性肝癌中的表达及其与原发性肝癌生物学行为的关系.方法 分别采用免疫组化法和Western blot法检测20例正常肝组织和36例原发性肝癌组织中Stathmin蛋白的表达.结果免疫组化法检测Stathmin蛋白在正常肝组织、低级别原发性肝癌 (Ⅱ级-Ⅲ级)及高级别原发性肝癌(Ⅳ级)组织中阳性表达率分别为20%、65%、100%.Ⅱ级-Ⅲ级组、Ⅳ级组分别与正常肝组织比较,差异均有统计学意义(P<0.05);Ⅱ级-Ⅲ级组与Ⅳ级组比较,差异有统计学意义(P<0.05).Western blot法检测显示,Stathmin蛋白在正常肝组织、Ⅱ级-Ⅲ级组、Ⅳ级组表达相对值分别为0.35±0.16、0.69±0.22、0.91±0.18.Ⅱ级-Ⅲ级组、Ⅳ级组分别与正常肝组织比较,差异均有统计学意义(P<0.01),Ⅱ级-Ⅲ级组与Ⅳ级组比较,差异有统计学意义(P<0.01).结论 Stathmin在原发性肝癌中过表达,与原发性肝癌的发生及发展可能有关.     

肝癌组织中maspin mRNA和蛋白的表达及意义

目的探讨肝癌组织中maspin基因在mRNA和蛋白水平的表达及意义。方法应用逆转录聚合酶链反应(RT-PCR)和免疫组织化学(IHC)法检测maspin在人正常肝脏、肝硬化和肝癌组织中的表达。结果maspin在人正常肝脏、肝硬化和肝癌组织中mRNA阳性表达率分别为88.9%(16/18)、57.1%(8/14)和41.7%(15/36),蛋白阳性表达率分别为83.3%(15/18)、50%(7/14)和38.9%(14/36),三组间相比差异均有统计学意义。maspin蛋白表达与肝癌的组织分化程度和远处转移有关(P均0.05),而与肿瘤大小无关(P0.05)。结论maspin在肝癌组织中呈低表达,maspin基因的缺失可能是肝癌发生、发展和转移的原因之一。     

Survivin,Caspase-3蛋白在原发性肝癌中的表达及意义

目的:研究原发性肝癌组织及癌旁组织中survivin、caspase-3的表达及其与细胞凋亡的关系.方法:收集原发性肝癌组织及相应癌旁组织标本40例,免疫组织化学方法检测其survivin、caspase-3蛋白表达,原位末端转移酶标记(TUNEL)法检测凋亡指数.结果:85%(34/40)的肝癌组织表达survivin蛋白,而癌旁非肝癌组织内无1例呈阳性表达.survivin蛋白表达的阳性率在肝内转移者为93.5%,显著高于无肝内转移者(55.6%,P＜0.05);在门静脉癌栓浸润者为92.8%,显著高于无门静脉癌栓浸润者(66.7%,P＜0.05).37.5%(15/40)的肝癌组织内可见到caspase-3阳性表达,77.5%(31/40)癌旁组织可见不同程度caspase-3阳性表达,两者比较差异有显著性意义(P＜0.05).所有肝癌组织标本中均可检测到凋亡细胞,但survivin表达阳性者的凋亡指数(1.152%±0.326%)显著低于survivin表达阴性者(4.502%±0.830%,P＜0.05);而caspase-3表达阴性者的凋亡指数(5.016%±0.370%)显著高于caspase-3表达阴性者(1.927%±0.237%,P＜0.05).34例survivin表达阳性组织中有10例见caspase-3表达阳性(29.4%),而6例survivin表达阴性组织中有5例见caspase-3阳性表达(83.3%),两者比较差异有显著性意义(P＜0.05).结论:survivin在肝癌组织中选择性表达,与肿瘤转移、血管浸润等恶性生物学行为有关,survivin对凋亡的抑制可能是其参与肝癌发生的重要机制,其作用机制可能涉及到caspase-3蛋白的抑制.     

DC-SIGN在原发性肝癌组织中的表达及意义

目的探讨树突细胞特异性细胞间黏附分子3结合的非整合素(DC-SIGN)在原发性肝癌组织中的表达及意义。方法选择原发性肝癌患者手术切除的肝癌组织标本30例及对应的距离肝癌组织2 cm以上的癌旁肝组织标本30例。采用免疫组化法检测肝癌组织和癌旁组织DC-SIGN蛋白表达,采用RT-PCR检测肝癌组织和癌旁组织DC-SIGN mRNA表达。结果肝癌组织DC-SIGN光密度值高于明显癌旁组织,差异有统计学意义(P0.05)。肝癌组织DC-SIGN mRNA相对表达量明显高于癌旁组织(P0.05)。肝癌组织DC-SIGN蛋白表达与肝癌包膜、TNM分期、血清甲胎蛋白(AFP)水平有关(P0.05),与肝癌患者年龄、性别、组织分化、肿瘤大小、肝外转移、静脉侵犯无关(P0.05)。肝癌组织DC-SIGN mRNA水平与肝癌包膜、肝癌TNM分期、血清甲胎蛋白水平有关(P0.05),与肝癌患者的年龄、性别、组织分化、肿瘤大小、静脉侵犯无关(P0.05)。结论原发性肝癌组织中DCSIGN表达量升高,DC-SIGN表达量和肝癌的包膜是否完整及肝癌TNM分期有关。     

Immunohistochemical studies on the expression of P-glycoprotein and p53 in relation to histological differentiation and cell proliferation in hepatocellular carcinoma

Localization of P-glycoprotein (P-gp) and p53 was immunohistochemically examined in 41 patients with hepatocellular carcinoma (HCC) in order to determine the relationship between the expression of P-gp and p53 and the degree of histological differentiation or cell proliferation in HCC. P-gp showed different patterns of expression between cancerous and cirrhotic liver hepatocytes, and the expression in cancerous tissue also varied according to the degree of histological differentiation. In cirrhotic liver hepatocytes, expression of P-gp was found on bile canalicular membranes. In the case of cancerous tissue, P-gp was localized on the canalicular membranes in well-differentiated HCC showing a trabecular pattern, as recognized cirrhotic liver hepatocytes. In moderately differentiated HCC showing pseudo-glandular patterns, predominant expression of P-gp was found on the luminal side of cell membranes of the glandular ducts. The P-gp expression rate was 87.5% in well-differentiated HCC, 84% in moderately differentiated HCC, and 37.5% in poorly differentiated HCC, indicating a marked decrease with decreasing degree of differentiation. On the other hand, the rate of mutation of p53, a tumor suppressor gene, was 12.5% in well-differentiated HCC, 52.0% in moderately differentiated HCC, and 85.5% in poorly differentiated HCC, showing a significant increase with decreasing degree of differentiation (P<0.005). The labeling index (LI) of proliferating cell nuclear antigen (PCNA) tended to increase with the progression of chronic liver disease, with a markedly high value of 24.0±1.5% in cases of HCC. The PCNA LI was 15.6±11.9% in well-differentiated HCC, 23.1±15.1% in moderately differentiated HCC, and 50.1±13.3% in poorly differentiated HCC, which indicated a significantly increase in poorly differentiated HCC (P<0.001). Thus, it became apparent that abnormal expressions of P-gp and p53 and the cell proliferation in HCC vary according to the degree of histological differentiation of the malignancy. This suggests that more effective chemotherapy for HCC can be potentially developed by considering the pattern and level of expression of P-gp as a mechanism of drug resistance and the extent of histological differentiation.     

Expression of P-glycoprotein and p53 in advanced hepatocellular carcinoma treated by single agent chemotherapy: Clinical correlation

Hepatocellular carcinoma (HCC), a chemoresistant tumour, is the most common fatal cancer in Taiwan. Hepatocellular carcinoma frequently expresses a high level of P-glycoprotein (P-gp), which is a specific phenotype of a multidrug-resistance gene, and harbours mutations of the tumour suppressor gene p53. A modulatory relationship between p53 and P-gp has been reported. In this study, we analysed the expression of P-gp in relation to chemotherapeutic response and p53 protein expression in advanced HCC. Prechemotherapeutic tumour samples were obtained from 25 patients with HCC which had been treated with either etoposide (VP-16) or doxorubicin. P-glycoprotein and p53 in HCC were visualized by immunohistochemical staining using the monoclonal antibodies JSB-1 and DO1, respectively. We investigated the correlation of P-gp expression with chemotherapeutic responses, clinicopathological features and p53 protein expression. In our study, seven cases achieved partial remission, and the remaining 18 cases had a poor response to chemotherapy. Expression of P-gp was observed in 13 tumours (52%). Positive P-gp protein expression was significantly associated with non-responders (8% or 1/13 vs 50% or 6/12, P= 0.03). Thus, P-gp expression inversely correlated with chemotherapeutic response. Expression of p53 protein was seen in 12 cases and did not correlate with chemosensitivity or P-gp expression. In summary, P-gp expression correlates with the chemosensitivity of HCC that has been treated with VP-16 or doxorubicin and p53 mutations do not appear to be a major determinant of P-gp expression in advanced HCC.     

核移位YB-1蛋白、P-gp及PCNA在肝癌中的表达及意义

目的探讨核移位YB-1蛋白、P糖蛋白（P-gP）、增殖核抗原（PCNA）在肝细胞肝癌（hepatocellularcarcinoma,HCC）组织中的表达及其在肝癌发生发展中的作用。方法采用免疫组化法检测YB-1、P-gP、PCNA蛋白在58例HCC组织、20例正常肝组织中的表达。结果在肝癌组织中核移位YB-1与P-gP、PCNA蛋白阳性率分别为31％（18／58）、83％（48／58）、100％（58／58）,与正常肝组织相比有显著差异（P〈0．05）。核移位YB-1蛋白及PCNA积分与肝癌病理分级、门静脉癌栓、肿瘤大小有关（P〈0．05）;P-gP蛋白与肝癌病理分级有关（P〈0．05）。核移位YB-1蛋白与P-gP、PCNA蛋白表达呈正相关（P〈0．05）。结论YB-1蛋白可能通过核移位途径上调P-gP、PCNA蛋白表达,从而促进肝癌的发生发展及其恶性表型的维持,YB一1蛋白有可能成为肝癌治疗的新靶点。     

大鼠肝癌发生过程中癌基因和抑癌基因的表达

目的 探讨癌基因ｒａｓ和抑制基因Ｐ５３蛋白在实验性肝癌中的表达与内在联系。方法 应用原位杂交和免疫组织化学（ＳＡＢＣ０法,在３８例化学致癌剂二乙基亚硝胺（ＤＥＮＡ）诱发大鼠原发性肝细胞癌及癌前增殖结节中。Ｐ５３蛋白和ｒａｓ家族基因蛋白表达。结果 化学诱癌生成为６８．４２％,癌前增生性病例为３１．５８％,在癌与增生性病变中ｒａｓ基因收搞表达分别为８８．４６％和７５％,两组无显著差异,但与癌的恶笥分化     

HIF-1α和P-gp在胰腺癌中的表达及其临床意义

目的研究HIF-1α和P-gp蛋白在胰腺癌组织中的表达并探讨其临床病理学意义及两者之间的相关性。方法采用免疫组织化学（SP）法检测58例胰腺癌组织、12例慢性胰腺炎组织和10例正常胰腺组织中HIF-1α和P-gp蛋白的表达。结果HIF-1α的阳性表达主要在细胞核或细胞浆内,呈棕黄色颗粒,P-gp则表现为在细胞膜或细胞浆内出现棕黄色颗粒。HIF-1α和P-gp在胰腺癌组织中的阳性表达率分别为68.97%（40/58）和58.62%（34/58）,显著高于两者在正常胰腺组织和慢性胰腺炎组织中的表达,差异有统计学意义（P〈0.0125）。HIF-1α和P-gp的异常表达均与胰腺癌的淋巴结转移和TNM分期相关（P〈0.05）,与患者的性别、年龄、肿瘤部位、分化程度和病理分型无关（P〉0.05）。HIF-1α和P-gp蛋白的表达之间存在正相关性（r=0.671,P=0.031）。结论胰腺癌组织中存在HIF-1α和P-gp蛋白表达的上调,并且它们的表达存在正相关性。联合检测两个指标对临床化疗疗效判断和患者预后估计具有积极的指导作用。     

肝细胞癌p53及nm23-H1 mRNA表达的意义

目的探讨ｐ５３,ｎｍ２３Ｈ１与原发性肝细胞癌（ＨＣＣ）发生发展的关系．方法运用原位分子杂交技术对４９例ＨＣＣ中ｐ５３和ｎｍ２３Ｈ１基因ｍＲＮＡ进行检测,并结合临床病理特征进行分析．结果ｐ５３ｍＲＮＡ杂交阳性２３例,占４６９％;ｐ５３ｍＲＮＡ过表达与肿瘤的肝内转移．包膜侵犯及Ｅｄｍｏｎｄｓｏｎ分级相关（Ｐ＜００５）;ｎｍ２３Ｈ１ｍＲＮＡ阳性表达２７例,占５５１％;ｎｍ２３Ｈ１ｍＲＮＡ表达与肿瘤肝内转移及ＴＮＭ分期呈负相关（Ｐ＜００５）;同时发现ｐ５３ｍＲＮＡ过表达和ｎｍ２３Ｈ１ｍＲＮＡ低表达在ＨＣＣ肝内转移中具有协同作用．结论ｐ５３和ｎｍ２３Ｈ１参与ＨＣＣ的发生发展,ｐ５３过表达及ｎｍ２３Ｈ１低表达提示ＨＣＣ肝内转移．     

FADD and TRADD expression and apoptosis in primary hepatocellular carcinoma

AIM To investigate the clinical features of FADD and TRADD expressions in primary hepatocellular carcinoma ( HCC ) and to determine their relationship with hepatic apoptosis. METHODS FADD and TRADD expressions were detected by immunohistochemistry and hepatic apoptosis were determined by in situ endlabeling ( ISEL). RESULTS Ten (25.6%) cases of HCC were detected to express FADD protein. The positive rate in HCC is lower than that in non-cancerous adjacent liver tissues (62.5%) (P＜0.05). In those of grade Ⅰ - Ⅱ, 8 (38.1%) cases were FADD positive, while only 2/18 (11. 1%) cases of grade Ⅲ - Ⅳ had detectable FADD protein (P＜0.05). No relationship was found between FADD expression and other clinical features,such as gender, age, tumor size, differentiation or metastasis. ISEL positive cells can be seen in all cases of HCC. The hepatic apoptosis was associated with FADD expression as more apoptotic cells were detected in those cases which had moderately to strongly positive FADD, as compared with negative or weak positive FADD cases (P＜ 0.05). No relationship was found between FADD expression and hepatic apoptosis in non-cancerous adjacent liver tissues. Fifteen of 39 (38.5%) cases of HCC were found positive for TRADD protein, and similar positive rate (37.5%) in non-cancerous adjacent liver tissues (P ＞0.05). The expression of TRADD is correlated with HCC differentiation,as only 22.2% of moderately to highly differentiated HCC showed positive TRADD protein, while as high as 52.4% of poorly differentiated HCC had TRADD (P＜0.05). No relationship was found between TRADD expression and gender, age, tumor size or grade or metastasis, although 42.9% of HCC of grade Ⅰ/Ⅱ showed positive TRADD which was slightly higher than that of grade Ⅲ/Ⅳ (33.3%,P ＞ 0.05). Hepatic apoptosis was not related to TRADD expression in HCC or non-cancerous adjacent liver tissues. CONCLUSION Loss of FADD expression plays an important role in HCC carcinogenesis, and expression of TRADD also contributes to HCC development. The cell apoptosis in HCC is associated with FADD expression. However, the expression of TRADD does not correlate well with hepatic apoptosis in HCC.     

CD44 V6和VEGF在肝癌组织中的表达及其预后价值的研究

目的探讨CD44 V6和VEGF在肝细胞癌(HCC)中的表达及其在临床预后中的价值。方法对随访的40例原发性肝癌临床病理学资料进行回顾性分析分类,并按照1年内有无复发和转移分组,然后进行常规HE染色及CD44 V6、VEGF的免疫组化染色(S_P法)。结果结果CD44 V6和VEGF主要定位于癌细胞的胞膜,部分胞质同时出现阳性表达;在40例肝癌组织中,CD44 V6和VEGF的阳性表达率分别为75%(30/40)和77.5%(31/40);CD44 V6、VEGF在复发和转移组的表达均高达88.9%(16/18,16/18),明显高于未复发和转移组,和肿瘤侵袭转移的发生有相关性(P<0.05),癌组织中的表达均明显高于癌旁组织,而在肿瘤大小及组织学分级间未见明显差异。结论资料提示肝癌组织中CD44 V6和VEGF过表达分析,有助于肝癌侵袭、转移预测和肝癌预后判断。     

肝细胞癌组织中骨桥蛋白的表达及其与血管生成的关系

目的探讨骨桥蛋白（OPN）在肝细胞癌（肝癌）组织中的表达与血管生成的关系。方法采用免疫组化法检测64例肝癌组织、10例肝硬化组织及10例正常组织中的OPN，分析其与肝癌临床病理特征和微血管密度（MVD）的关系。结果OPN在肝癌组织的表达明显高于肝硬化组织及正常组织（P〈0．05），OPN和肝癌的早期复发转移有关（P〈0．01），OPN的表达和MVD呈正相关（r=0．321，P〈0．01）。结论OPN在肝癌组织中里高表达与早期复发转移相关；OPN可能参与了肿瘤的血管生成。