發(fā)布時(shí)間：2018-05-11 06:09

  本文選題：膽囊癌 + TNF-α��； 參考：《福建醫(yī)科大學(xué)》2016年博士論文

【摘要】：【研究背景】本實(shí)驗(yàn)室前期研究發(fā)現(xiàn),炎癥因子TNF-α可促進(jìn)膽囊癌的微淋巴管生成;且通過免疫組化檢測分析發(fā)現(xiàn)VEGF-D(血管內(nèi)皮生長因子-D)的表達(dá)與膽囊癌的淋巴管生成及淋巴結(jié)轉(zhuǎn)移正相關(guān)。而VEGF-D是否與TNF-α介導(dǎo)的膽囊癌微淋巴管生成有關(guān),尚未見研究報(bào)道。因此,本課題擬圍繞兩部分內(nèi)容開展研究:1、TNF-α-VEGF-D軸對裸鼠膽囊癌原位移植瘤微淋巴管生成的影響;2、TNF-α促膽囊癌細(xì)胞VEGF-D表達(dá)的分子機(jī)制。旨在通過動(dòng)物實(shí)驗(yàn)、啟動(dòng)子活性分析及信號(hào)通路研究等闡明TNF-α-VEGF-D軸與膽囊癌微淋巴管生成的關(guān)系及分子機(jī)制。【方法】1、用本實(shí)驗(yàn)室已構(gòu)建的膽囊癌細(xì)胞株NOZ/sh VEGF-D(RNAi沉默VEGF-D)、NOZ/sh CTRL(轉(zhuǎn)染陰性對照序列)及空白對照NOZ細(xì)胞,建立裸鼠膽囊癌原位移植瘤模型。建模后2周開始,實(shí)驗(yàn)組腹腔注射TNF-α(2μg/kg),對照組注射等體積生理鹽水,每3天注射一次,連續(xù)注射3周后處死并解剖裸鼠,取原位癌組織及轉(zhuǎn)移淋巴結(jié)標(biāo)本制作石蠟切片,利用免疫組化及HE染色檢測微淋巴管密度(LVD)及轉(zhuǎn)移淋巴結(jié),分析TNF-α-VEGF-D軸對裸鼠膽囊癌原位移植瘤微淋巴管生成的影響。2、通過DNA重組技術(shù)構(gòu)建一系列含VEGF-D啟動(dòng)子截短片段的螢火蟲熒光素酶報(bào)告質(zhì)粒,用雙熒光素酶檢測系統(tǒng)分析VEGF-D啟動(dòng)子活性。3、應(yīng)用軟件TFbind、Promoter Scan對VEGF-D啟動(dòng)子上潛在的AP-1和/或NF-κB結(jié)合位點(diǎn)進(jìn)行預(yù)測。4、通過堿基定點(diǎn)突變、電泳遷移率變動(dòng)分析(EMSA)和染色質(zhì)免疫沉淀(Ch IP)確定VEGF-D基因啟動(dòng)子上的AP-1和/或NF-κB結(jié)合位點(diǎn)及TNF-α對啟動(dòng)子活性的影響。5、應(yīng)用RNAi沉默技術(shù)、蛋白特異阻斷劑抑制實(shí)驗(yàn)檢測TNF-α-VEGF-D軸上的信號(hào)通路分子。6、統(tǒng)計(jì)學(xué)分析方法:總體均數(shù)的比較采用t檢驗(yàn),顯著性水平α=0.05,P0.05為有統(tǒng)計(jì)學(xué)差異�！窘Y(jié)果】1、TNF-α-VEGF-D軸對裸鼠膽囊癌微淋巴管生成及淋巴轉(zhuǎn)移的影響:1)淋巴管密度計(jì)數(shù)結(jié)果顯示,TNF-α干預(yù)NOZ組、NOZ/sh CTRL組、NOZ/sh VEGF-D組小鼠后,三組小鼠的淋巴管密度分別為23.73±2.17、23.20±2.18、10.07±1.83,與無TNF-α干預(yù)組比較(三組分別為11.73±2.28、14.27±1.36、5.67±1.25),差異均有顯著性(P0.05)。但TNF-α對NOZ/sh VEGF-D組的促淋巴管生成作用顯著低于NOZ組和NOZ/sh CTRL組(P0.05)。表明TNF-α可通過VEGF-D促進(jìn)裸鼠膽囊癌原位移植瘤組織的微淋巴管生成。2)TNF-α干預(yù)NOZ組、NOZ/sh CTRL組、NOZ/sh VEGF-D組小鼠后,三組小鼠的淋巴結(jié)轉(zhuǎn)移發(fā)生率均比無TNF-α干預(yù)組增高,但TNF-α對NOZ/sh VEGF-D組的淋巴結(jié)轉(zhuǎn)移發(fā)生率低于NOZ組和NOZ/sh CTRL組,提示TNF-α可能通過VEGF-D促進(jìn)裸鼠膽囊癌淋巴轉(zhuǎn)移。2、TNF-α促膽囊癌細(xì)胞VEGF-D表達(dá)的分子機(jī)制1)成功構(gòu)建一系列含VEGF-D啟動(dòng)子截短片段的重組質(zhì)粒并經(jīng)測序鑒定序列正確;雙熒光素酶系統(tǒng)檢測結(jié)果顯示重組質(zhì)粒PGL4-988較PGL4-717、PGL4-444較PGL4-325、PGL4-154較PGL4-57,均呈現(xiàn)出更強(qiáng)的熒光活性,差異有統(tǒng)計(jì)學(xué)意義(均P0.05)。提示VEGF-D啟動(dòng)子轉(zhuǎn)錄起始位點(diǎn)ATG上游-988至-717nt、-444至-325nt、-154至-57nt三個(gè)區(qū)間可能存在調(diào)控VEGF-D轉(zhuǎn)錄活性的調(diào)控位點(diǎn)。2)TFbind、Promoter Scan軟件預(yù)測結(jié)果顯示,VEGF-D啟動(dòng)子轉(zhuǎn)錄起始位點(diǎn)ATG上游-444至-325nt區(qū)間存在兩個(gè)潛在的AP-1結(jié)合位點(diǎn):GTGTGTCAT(-401至-393nt)和CTGAGATAC(-345至-337nt),而-988至-717nt、-154至-57nt區(qū)間未檢測到AP-1位點(diǎn);三個(gè)區(qū)間均未檢測到NF-κB結(jié)合位點(diǎn)。3)定點(diǎn)誘變、電泳遷移率變動(dòng)分析(EMSA)和染色質(zhì)免疫沉淀(Ch IP)實(shí)驗(yàn)證實(shí)轉(zhuǎn)錄因子AP-1可直接與VEGF-D啟動(dòng)子-444至-325nt區(qū)間的兩個(gè)AP-1位點(diǎn)結(jié)合,且TNF-α可以增強(qiáng)AP-1與這兩個(gè)位點(diǎn)的結(jié)合。4)AP-1位點(diǎn)突變對TNF-α誘導(dǎo)VEGF-D啟動(dòng)子活性的影響:“PGL4-AP1mut1+TNF-α”組較“PGL4-444+TNF-α”組(2.77±0.23 vs 3.98±0.15)、“PGL4-AP1 mut2+TNF-α”組較“PGL4-444+TNF-α”組(3.14±0.33 vs 3.98±0.15),熒光活性明顯減弱,差異均有統(tǒng)計(jì)學(xué)意義(P0.05)。表明TNF-α可通過兩個(gè)AP-1結(jié)合位點(diǎn)調(diào)控VEGF-D的啟動(dòng)子活性。5)沉默AP-1對TNF-α誘導(dǎo)VEGF-D啟動(dòng)子活性及蛋白表達(dá)的影響:TNF-α誘導(dǎo)si AP-1 NOZ細(xì)胞的PGL4-444活性較NOZ細(xì)胞的弱(2.69±0.34 vs 5.88±0.15),差異有統(tǒng)計(jì)學(xué)意義(P0.05);TNF-α誘導(dǎo)si AP-1 NOZ細(xì)胞的VEGF-D蛋白表達(dá)較NOZ細(xì)胞的弱(0.59±0.13 vs 1.39±0.10),差異有統(tǒng)計(jì)學(xué)意義(P0.05)。表明TNF-α通過AP-1增強(qiáng)VEGF-D啟動(dòng)子活性并上調(diào)VEGF-D蛋白表達(dá)。6)MAPKs抑制劑對TNF-α誘導(dǎo)VEGF-D啟動(dòng)子活性的影響:“PD98059+TNF-α”組NOZ細(xì)胞的PGL4-444活性(1.74±0.23)較TNF-α組(5.88±0.15)明顯減弱(P0.05),“SP600125+TNF-α”組的PGL4-444活性(5.80±0.31)和“SB203580+TNF-α”組的PGL4-444活性(6.49±0.54)與TNF-α組比較差異均無顯著性(P0.05)。表明TNF-α通過ERK1/2通路增強(qiáng)VEGF-D啟動(dòng)子活性。7)MAPKs抑制劑對TNF-α誘導(dǎo)VEGF-D蛋白表達(dá)的影響:“PD98059+TNF-α”組NOZ細(xì)胞的VEGF-D蛋白表達(dá)(0.14±0.03)較TNF-α組(0.33±0.02)明顯減少(P0.05),“SP600125+TNF-α”組的VEGF-D蛋白表達(dá)(0.34±0.05)和“SB203580+TNF-α”組的VEGF-D蛋白表達(dá)(0.32±0.03)與TNF-α組比較差異均無顯著性(P0.05)。表明TNF-α通過ERK1/2通路上調(diào)VEGF-D蛋白表達(dá)。【結(jié)論】1、TNF-α可通過VEGF-D促進(jìn)裸鼠膽囊癌原位移植瘤的微淋巴管生成。2、VEGF-D啟動(dòng)子-444至-325nt區(qū)間存在兩個(gè)有活性的AP-1結(jié)合位點(diǎn),且TNF-α可增強(qiáng)AP-1與這兩個(gè)位點(diǎn)的結(jié)合;未檢測到NF-κB結(jié)合位點(diǎn)。3、TNF-α通過“ERK1/2-AP-1”通路增強(qiáng)VEGF-D啟動(dòng)子活性并上調(diào)VEGF-D蛋白表達(dá)。
[Abstract]:[background] a preliminary study in our laboratory found that inflammatory factor TNF- alpha could promote the formation of microlymphatic vessels in gallbladder carcinoma, and the expression of VEGF-D (vascular endothelial growth factor -D) is positively related to lymphatic formation and lymph node metastasis of gallbladder cancer by immunohistochemical detection. And whether VEGF-D is associated with TNF- alpha in gallbladder cancer Guan Shengcheng has not yet seen the research report. Therefore, this subject is intended to carry out a study around two parts: 1, the effect of TNF- alpha -VEGF-D axis on the formation of microlymphatic vessels in the orthotopic xenografts in nude mice; 2, the molecular mechanism of TNF- alpha promoting the expression of VEGF-D in gallbladder cancer cells. The relationship between TNF- alpha -VEGF-D axis and the formation of microlymphatic duct in gallbladder carcinoma. [Methods] 1. The model of the orthotopic xenografts in nude mice was established by using the gallbladder cancer cell line NOZ/sh VEGF-D (RNAi silent VEGF-D), NOZ/sh CTRL (transfected negative control sequence) and the blank control NOZ cells. After 2 weeks, the experimental group was established. Intraperitoneal injection of TNF- alpha (2 u g/kg), injection of equal volume of normal saline in the control group, injected once every 3 days, and after 3 weeks of continuous injection, were killed and dissected in nude mice. The paraffin sections were made in situ and metastatic lymph nodes. The microlymphatic vessel density (LVD) and metastatic lymph nodes were detected by immunohistochemistry and HE staining, and the TNF- alpha -VEGF-D axis on the nude mice was analyzed. The effect of.2 on the formation of microlymphangioma in the tumor in situ transplantation tumor, a series of firefly luciferase reporter plasmids containing VEGF-D promoter were constructed by DNA recombination technology, and the VEGF-D promoter activity.3 was analyzed with the dual luciferase detection system, the application software TFbind, Promoter Scan on the potential AP-1 and / or NF- kappa B binding on the VEGF-D promoter. The loci predict.4, through base directed mutagenesis, electrophoresis mobility change analysis (EMSA) and chromatin immunoprecipitation (Ch IP) determination of AP-1 and / or NF- kappa B binding sites on VEGF-D gene promoter and the effect of TNF- alpha on promoter activity,.5, RNAi silencing technique, and egg white specific blocker inhibition test on TNF- alpha axis .6, statistical analysis: t test, significant level of alpha =0.05, and P0.05 were statistically different. [results] 1, the effect of TNF- alpha -VEGF-D axis on the formation and lymphatic metastasis of gallbladder carcinoma in nude mice: 1) the lymphatic density count results showed that TNF- alpha intervention in NOZ group, NOZ/sh CTRL group, NOZ/sh VEGF-D After group mice, the lymphatic density of the three groups were 23.73 + 2.17,23.20 + 2.18,10.07 + 1.83 respectively, compared with the non TNF- alpha intervention group (three groups were 11.73 + 2.28,14.27 + 1.36,5.67 1.25), and the difference was significant (P0.05). But TNF- alpha was significantly lower than the NOZ group and NOZ/sh CTRL group. TNF- alpha could promote the microlymphatic.2 in the orthotopic xenografts in nude mice by VEGF-D. TNF- alpha intervention in the NOZ group, NOZ/sh CTRL group and NOZ/sh VEGF-D group mice, the incidence of lymph node metastasis in the three groups was higher than that in the non TNF- alpha intervention group, but the incidence of lymph node metastasis in the NOZ/sh group was lower than that of the TNF- alpha intervention group. RL group, suggesting that TNF- alpha may promote the lymphatic metastasis of gallbladder cancer in nude mice by VEGF-D and the molecular mechanism of VEGF-D expression of TNF- a gallbladder cancer cells 1.) a series of recombinant plasmids containing VEGF-D promoter truncated fragments were successfully constructed and the sequencing identification sequence was correct. The results of the double luciferase system test showed that the recombinant plasmid PGL4-988 was more than PGL4-717, PGL4-4. 44 compared with PGL4-325 and PGL4-154, compared with PGL4-57, they all showed stronger fluorescence activity, and the difference was statistically significant (P0.05). It suggested that the transcription start site of VEGF-D promoter was -988 to -717nt, -444 to -325nt, -154 to -57nt three regions may have regulatory sites regulating the transcriptional activity. There are two potential AP-1 binding sites in the upstream -444 to -325nt interval of the promoter of VEGF-D promoter ATG: GTGTGTCAT (-401 to -393nt) and CTGAGATAC (-345 to -337nt). Analysis (EMSA) and chromatin immunoprecipitation (Ch IP) experiments confirmed that transcription factor AP-1 can be directly associated with the two AP-1 loci of the VEGF-D promoter -444 to -325nt interval, and TNF- alpha can enhance the.4 of AP-1 with these two loci. The +TNF- Alpha Group (2.77 + 0.23 vs 3.98 + 0.15), "PGL4-AP1 mut2+TNF- alpha" group was compared to the "PGL4-444+TNF- alpha" group (3.14 + 0.33 vs 3.98 + 0.15), and the fluorescence activity was significantly reduced, the difference was statistically significant (P0.05). It showed that TNF- alpha could regulate the promoter activity of VEGF-D through two AP-1 binding sites. The effect of activity and protein expression: the PGL4-444 activity of TNF- alpha induced Si AP-1 NOZ cells was weaker than that of NOZ cells (2.69 + 0.34 vs 5.88 + 0.15), and the difference was statistically significant (P0.05); TNF- alpha induced Si AP-1 NOZ cells was weaker than that of the cells (0.59 + 0.13 1.39 + 0.10), and the difference was statistically significant. AP-1 enhanced the activity of VEGF-D promoter and up-regulated the expression of VEGF-D protein.6) the effect of MAPKs inhibitor on the activity of VEGF-D promoter induced by TNF- A: PGL4-444 activity of NOZ cells in "PD98059+TNF- a" group (1.74 + 0.23) was significantly lower than that in TNF- Alpha Group (5.88 + 0.15). The activity of PGL4-444 (6.49 + 0.54) in the group of alpha group was not significantly different from that in the TNF- Alpha Group (P0.05). It showed that TNF- alpha enhanced the activity of VEGF-D promoter through the ERK1/2 pathway. The effect of MAPKs inhibitor on the expression of VEGF-D protein induced by TNF- alpha: "PD98059+TNF- alpha" group of NOZ cells (0.14 + 0.03) was significantly lower than that of the group (0.33 + 0.02). Less (P0.05), the expression of the expression of VEGF-D protein (0.34 + 0.05) in the "SP600125+TNF- alpha" group and the expression of VEGF-D protein in the group of "SB203580+TNF- alpha" (0.32 + 0.03) had no significant difference from that of the TNF- Alpha Group (P0.05). It showed that TNF- a increased the expression of VEGF-D protein through the ERK1/2 pathway. [knot] 1, TNF- alpha could promote the orthotopic transplantation of gallbladder carcinoma in nude mice. The microlymphatic vessels of the tumor produce.2, and there are two active AP-1 binding sites in the -444 to -325nt interval of the VEGF-D promoter, and TNF- a enhances the binding of AP-1 to these two loci; NF- kappa B binding site.3 is not detected. TNF- alpha enhances the activity of the promoter through the "ERK1/2-AP-1" pathway and up-regulated the expression of the protein.

【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.8

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