摘要
原发性肝癌是全世界发病率较高的恶性肿瘤之一,从90年代起已上升为我国第二位癌症杀手。其疗效并不理想。其中复发、转移是导致肝癌死亡率居高不下的最主要原因。肝癌的侵袭、复发、转移是一个十分复杂的肿瘤生物学问题。研究原发性肝癌复发转移的分子机制并积极探索有效的抗复发转移的治疗措施,对于进一步改善肝癌患者存活率具有重要意义。
脑源性神经营养因子(brain derived neurotrophic factor,BDNF)与神经生长因子(nerve growth factor,NGF)、神经营养素-3,4,5(neurotrophin-3,4,5)来源于同一基因家族,在神经细胞的生长发育、损伤修复中发挥重要作用。近年来人们已认识到BDNF在许多非神经组织表达,且与多种恶性肿瘤有着密切的联系。酪氨酸激酶受体B(tyrosine kinase receptor B,TrkB)为BDNF的特异性受体,也在多种恶性肿瘤中高表达。二者与肿瘤血管生成、肿瘤细胞增殖、迁移、侵袭、凋亡及对抗化疗药物等有关。抗凋亡基因Bc1-2在多种恶性肿瘤中高表达,同时与细胞周期调控、增殖、凋亡、迁移、侵袭转移等密切相关。
因此,本课题研究BDNF与TrkB在临床肝癌病例中的表达情况,分析其表达与各临床病理因素间的关系,并综合利用一系列体外、体内方法研究BDNF与原发性肝癌侵袭、转移及对抗凋亡的机制。
本研究的目的如下：1.检测肝癌组织中BDNF和TrkB蛋白的表达,探讨其表达与各临床病理因素的关系；2.在体外检测BDNF对肝癌细胞系Bel-7402增殖、凋亡、迁移、粘附、侵袭等生物学行为的影响,同时检测其对Bc1-2基因表达的影响；3.BDNF对5-Fu诱导人肝癌细胞Bel-7402凋亡的抑制效应及BDNF对肝癌细胞系Be1-7402裸鼠皮下移植瘤作用。
第一章BDNF、TrkB在原发性肝癌中的表达及其临床意义
目的：检测48例肝癌及其相应癌旁组织和8例正常肝组织中BDNF和TrkB蛋白的表达,分析其表达与临床病理因素的关系。
方法：通过免疫组化SP法,检测48例肝癌及其相应癌旁组织和8例正常肝组织石蜡切片标本中BDNF和TrkB蛋白的表达。
结果：(1)正常肝组织中无BDNF和TrkB蛋白的表达。(2)肝癌组织中BDNF蛋白的表达率分别为60.4%(29／48),癌旁组织中BDNF的阳性表达率为27.1％(13/48) (P<0.01).BDNF表达与Edmondson分级、有无包膜有关(P<0.05),而与性别、年龄、乙肝表面抗原、甲胎蛋白、肿瘤结节数目、肿瘤直径、是否有肝硬化、肝内静脉侵犯无关(P>0.05)。(3)TrkB蛋白在肝癌组织中的表达率为52.1%(25／48),在癌旁组织中的阳性表达率为18.8%(9／48)(P<0.01),TrkB的表达与Edmondson分级及肿瘤结节数有关(P<0.05),而与性别、年龄、乙肝表面抗原、甲胎蛋白、肿瘤直径、是否有肝硬化、肝内静脉侵犯、有无包膜无关(P>0.05)。(4)BDNF与TrkB在肝癌中的表达呈正相关(r=0.332,P<0.05)。(5)BDNF阳性表达者2年内复发率为65.5％(19/29),阴性表达者复发率为26.3％(5/19)(P<0.01)；TrkB呈阳性表达者2年内复发率为64.0%(16／25),阴性表达者复发率为34.8%(8／23)(P<0.05)。(6)BDNF阳性表达组术后中位生存时间为25.8月,阴性表达组为45.6月(P<0.01)；TrkB阳性表达组术后中位生存时间为25.4月,阴性表达组为40.5月(P<0.01)。
结论：(1)BDNF和TrkB在肝癌组织中呈高表达,而在正常肝组织中无表达；(2)BDNF表达与肝癌Edmondson分级、有无包膜有关；TrkB表达与肝癌Edmondson分级、肿瘤结节数目有关；BDNF与TrkB的表达呈正相关。(3)BDNF与TrkB的高表达可能预示着肝癌易复发及预后不良。
第二章 BDNF对肝癌细胞系Bel-7402作用的实验研究
目的：探讨外源性BDNF对肝癌细胞系Bel-7402生物学行为和Bcl-2基因表达的影响。
方法：实验分组：对照组、低浓度组、中浓度组和高浓度组。在迁移、侵袭试验及MTT、RT-PCR试验中将正常肝细胞系L-02做为正常对照。各组分别予含终浓度为0ng/ml、25ng／ml、50ng／ml和100ng/mlBDNF RPMI-1640培养基培养。(1)MTT比色法检测不同浓度的外源性BDNF对肝癌细胞系增殖效应的影响；(2)用Poly-HEMA处理过的培养板建立失巢凋亡悬浮细胞培养模型,并通过流式细胞术检测各组失巢凋亡率；(3)粘附实验检测不同浓度的外源性BDNF对肝癌细胞异质粘附能力影响；(4)细胞划痕实验检测外源性BDNF对Bel-7402细胞体外迁移能力的影响；(5)Transwell侵袭小室法检测不同浓度的外源性BDNF对肝癌细胞侵袭能力影响；(6)RT-PCR和Western Blot分别检测BDNF、TrkB、Bcl-2 mRNA和蛋白表达。
结果：(1)MTT比色法检查发现：各浓度的外源性BDNF均能增强肝癌细胞的增殖能力(p<0.01)；(2)流式细胞术检测失巢凋亡率显示：各浓度的BDNF均能增强细胞抵抗失巢凋亡的能力(p<0.01),各试验组之间无显著性差别(p>0.05)；(3)粘附实验显示：各浓度的BDNF均能增强细胞的粘附能力(p<0.01),各试验组之间无显著性差别(p>0.05)；(4)BDNF能促进肝癌细胞系Bel-7402细胞体外迁移袭能力(p<0.01)。(5)Transwell侵袭小室法显示：BDNF能增强Bel-7402细胞侵袭能力(p<0.01)；(6)RT-PCR. Western Blot显示：Bel-7402细胞系表达BDNF.TrkB、Bcl-2基因。各浓度的BDNF均可上调细胞Bcl-2 mRNA及其蛋白的表达。
结论：1.BDNF和TrkB蛋白在肝癌细胞系Bel-7402中呈阳性表达；2.外源性BDNF能促进肝癌细胞系Bel-7402增殖,增强其抵抗失巢凋亡的能力,并能增强其粘附、迁移及侵袭能力；3.外源性BDNF能上调肝癌细胞系Bel-7402 Bcl-2mRNA和蛋白的表达。
第三章BDNF对5-Fu诱导人肝癌细胞系Bel-7402凋亡的抑制效应及BDNF对肝癌细胞系Bel-7402裸鼠皮下移植瘤作用的实验研究
目的：探讨外源性BDNF对5-Fu诱导人肝癌细胞系Bel-7402凋亡的抑制效应及对肝癌细胞系Bel-7402裸鼠移植瘤生长、Bcl-2表达的影响。
方法：(1)体外试验：取对数生长期的Bel-7402细胞,分为对照组及试验组。对照组仅含RPMI1640培养液。试验组分为两组：A(5-Fu)组和B(5-Fu+BDNF)组。通过MTT、克隆形成试验、流式细胞术检测BDNF对5-Fu诱导人肝癌细胞系Bel-7402凋亡的影响。(2)体内试验：制备肝癌裸鼠皮下移植瘤模型,实验分组：将20只裸鼠随机分成对照组和实验组,每组10只。实验组在接种部位皮下注射外源性BDNF,对照组在相同部位皮下注射等量生理盐水,检测指标：①移植瘤生长速度,移植瘤体积和重量；②HE染色,观察组织学形态；③免疫组织化学(SP法)检测BDNF和TrkB蛋白表达；④RT-PCR和Western Blot分别检测Bcl-2]mRNA和蛋白表达。
结果：(1)MTT、克隆形成试验、流式细胞术试验发现,外源性BDNF能有效抑制5-Fu诱导Bel-7402细胞的凋亡效应。(2)外源性BDNF能有效促进移植瘤的生长(P<0.05)；(3)HE染色显示：两组移植瘤均有肝癌典型组织学表现；(4)免疫组织化学显示：两组移植瘤组织中均存在BDNF和TrkB蛋白表达；(5)RT-PCR、Western-Blot显示：BDNF能上调移植瘤组织中Bcl-2基因的表达(P<0.05)。
结论(1)外源性BDNF能有效抑制5-Fu所诱导Bel-7402细胞的凋亡效应。(2)外源性BDNF能促进肝癌细胞系Bel-7402裸鼠皮下移植瘤的生长；(3)肝癌细胞系Bel-7402裸鼠皮下移植瘤组织中表达BDNF和TrkB蛋白；(4)外源性BDNF能上调Bel-7402裸鼠皮下移植瘤组织Bcl-2mRNA和蛋白的表达。
Objective:The expression of BDNF and TrkB was detected by immunohistochemistry in 8 cases of normal liver tissue、48 cases of liver cancer and their para-cancer tissue respectively to analyze the relationship between BDNF、TrkB expression and the clinical pathological features and recurrence、survival rate.
Methods:Immunohistochemistry was performed to investigate the expression of BDNF and TrkB in 8 cases of normal liver tissue and 48 cases of liver cancer and its para-cacner tissue.
Results:There was no BDNF and TrkB protein expression observed in normal liver tissue, while expressed in liver cancer,with the rate of 60.4%(29/48)and 52.1%(25/48),which was higher than their para-cancer tissues(P<0.05)respectively.Significant relations with Edmondson Grade in BDNF and TrkB positive group and capsule formation in BDNF positive group and multiple nodules of tumor in TrkB positive group were observed respectiverly(P<0.05).There was positive correlation between BDNF and TrkB(r=0.332,P<0.05).and both of which showed significant relations with the two year's recurrence rate (P<0.05)and survival time(P<0.01);And they were not associated with no significant relation with age、gender、HBsAg、AFP、cirrosis and the size of tumor in patients with liver cancer.
Conclusion:(1)The protein expression of BDNF and TrkB are higher in liver cancer than in their para-liver cancer. Which were not expressed in normal liver tissue.(2)The positive rates of BDNF and TrkB are tightly associated with Edmondson Grade together and capsule formation、multiple nodules of tumor in each positive group respectively. There was positive correlation between BDNF and TrkB(r=0.332, P<0.05).(3)the high expression of BDNF and TrkB maybe signify the earlier recurrence and poor prognosis.
Objective:To investigate the effects of exogenous BDNF on biological behavior and expression of Bcl-2 in liver cancer cell line Bel-7402.
Methods:control group, low concentration group, middle concentration group and high concentration group were cultured with RPMI 1640 containing Ong/ml 25ng/ml,50ng/ml and 100ng/ml BDNF respectively.Forethermore,the normal liver cell line L-02 was used as normal control group in the mobility、invasion and MTT、RT-PCR assay (1)Cell proliferation of Bel-7402 was estimated by MTT assay;(2) by the way of establishing suspension culture model by culture plate treated with Poly-HEMA, the cell anoikis rate was analyzed by flow cytometry(FCM);(3)Adhesion ability was analyzed by adhesion assay;(4) the mobility ability was detected by scrape migration assay;(5)Invasion ability was analyzed by Transwell chamber assay;(6) Expression level of mRNA and protein of BDNF,TrkB and Bcl-2 were investigated by RT-PCR and Western Blot respectively.
Results:Promoting cell proliferation and the ability of adhesion were observed in MTT and Adhesion assay (P<0.01),and the ability to resist anoikis enhanced by BDNF showed in Flow cytometry (FCM) (P<0.01),and transwell chamber assay and scrape migration assay also showed that BDNF could enhance the ability of invasion and mobility of Bel-7402 in no concentration-dependent manner way (P<0.01). Expression of Bcl-2 mRNA and its protein of in Bel-7402 was up-regulated by BDNF showed in RT-PCR and Western Blot (p<0.05), and there was no significant difference among different groups.
Conclusion:(1)BDNF and TrkB protein are expressed in liver cancer Bel-7402 cell line;(2) Exogenous BDNF can promote cell proliferation,as well as enhance the ability to resist anoikis and the ability of adhesion、mobility and invasion in liver cancer Bel-7402 cell line;(3)Exogenous BDNF can up-regulate the expression of Bcl-2 gene and protein in Bel-7402 cell.
Objective:To investigate anti-apoptosis effects of BDNF induced by 5-Fu in vitro and the effects of exogenous BDNF on the growth of transplanted tumor of Bel-7402 in nude mice.
Methods(1)assay in vitro:ontrol group,A(5-Fu) group and B (5-fu+BDNF)group were established to detect anti-apoptosis effects of BDNF induced by 5-Fu on Bel-7402 cell line by MTT assay,clone formation assay and FCM respectively.(2)assay in vivo:for establishing mouse transplanted tumour model,0.9% sodium chloride solution and BDNF were injected subcutaneously into nude mice of control group and BDNF group respectively for the purpose of establishing mouse transplanted tumour model,and growth rate of tumor(including size and weight) was detected, the histological morphous was observed by HE staining, the expression of BDNF and TrkB was detected by immunohistochemistry, finally the expression level of mRNA and protein of Bcl-2 was investigated by RT-PCR and Western Blot.
Results:(1)MTT assay,clone formation assay and FCM showed BDNF could inhabit the apoptosis effects induced by 5-Fu in Bel-7402 cell line.(2)Transplanted human liver cancer were developed in all nude mice,growth of tumor was significantly promoted by BDNF. The tumor volume and weight in BDNF group were significant more than control group (P<0.05).(3)HE staining showed typical histological morphous of liver cancer of transplantation tumor tissue.(3)Immunohistochemical staining showed:there were expressions of BDNF and TrkB protein in transplantation tumor tissue.(4)RT-PCR and Western Blot showed that BDNF could up-regulate the expression of mRNA and protein of Bcl-2 in transplantation tumor(P<0.05).
Conclusion:(1)Exogenous BDNF has the anti-apoptosis effects induced by 5-Fu in Bel-7402 cell line.(2)Exogenous BDNF can promote the growth of transplantation tumor. (3)There are expression of BDNF and TrkB in transplanted tumor tissue. (4)Exogenous BDNF can up-regulate the expression of Bcl-2 gene in transplanted tumor
引文
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