腺病毒介导的KDRscFv融合sTRAIL基因抗肿瘤作用研究
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摘要
[目的]:研究腺病毒介导的重组IL2-KDRscFv、IL2-sTRAIL(114-281aa)及IL2- KDRscFv-sTRAIL对胃癌SGC-7901细胞、肝癌HepGII细胞、大肠癌SW480细胞及人正常肝细胞株LO2的杀伤作用,以及对裸鼠肿瘤体积、肿瘤微血管生成的抑制作用,观察KDRscFv融合sTRAIL是否有协同抗瘤效果,为应用TRAIL进行肿瘤基因治疗提供实验基础。
[方法]:采用重叠延伸PCR方法,分别在KDRscFv及sTRAIL(114-281aa)基因的N端融合IL2信号肽基因,以提高蛋白表达的可溶性。然后采用基因融合技术,构建IL2-KDRscFv与sTRAIL的融合基因。根据细菌内同源重组原理,首先构建编码TRAIL胞外区114~281位氨基酸、编码KDR单链抗体及编码二者融合基因的腺病毒穿梭质粒pAd-IL2-KDRscFv、pAd-IL2-sTRAIL及pAd-IL2-KDRscFv-sTRAIL,酶切线性化后转染BJ5183菌,与腺病毒骨架质粒pAdEasy-1在细菌内发生同源重组,将阳性重组子转染HEK293人胚肾细胞,获得高滴度的重组病毒颗粒后,转导人胃癌细胞株SGC-7901、人肝癌细胞株HepGII和结肠癌细胞株SW480以及人正常肝细胞株LO2,并采用荷瘤裸鼠瘤体内注射的方法,通过流式细胞仪、MTT、Western印迹法和免疫组化等方法测定重组腺病毒介导的目的蛋白在体内外的表达及观察肿瘤细胞的凋亡诱导作用和对肿瘤体积、肿瘤血管生成的抑制作用。
[结果]:
(1)成功地获得了三种重组腺病毒,在293细胞中大量扩增后,经氯化铯纯化浓缩后病毒滴度可达1012vp/ml。且均对真核细胞有高效感染效率。
(2)三种重组腺病毒对SGC-7901、SW480和HepGII细胞均有一定程度的凋亡诱导作用,其中以重组Ad-IL2-KDRscFv-sTRAIL腺病毒的作用最为明显。在感染复数为20,作用48小时情况下,可诱导39.16%的肝癌HepGII细胞发生凋亡,与PBS及Ad-GFP对照组相比,结果具有显著统计学差异。
(3)三种肿瘤细胞中,以肝癌HepGII细胞对负载有目的基因的腺病毒最为敏感,在感染复数为20,作用48小时情况下,Ad-IL2-sTRAIL可诱导19.88%、Ad-KDRsvFv可诱导9.09%的HepGII细胞凋亡,同样条件下胃癌SGC-7901细胞的凋亡率分别为8.09%、5.75%。
(4)三种腺病毒对人正常肝细胞LO2无明显凋亡诱导作用,与PBS对照及Ad-GFP载体对照组相比,结果无显著差别。
(5)三种腺病毒感染肿瘤细胞后,在细胞培养上清及收集的细胞沉淀中均可检测到目的蛋白的表达。
(6)体内实验中,瘤体内注射重组腺病毒,可明显抑制肿瘤体积增长,以Ad-IL-2-KDRscFv-sTRAIL腺病毒的作用最为明显,抑瘤率达75.60±4.8891%,而Ad-IL2-sTRAIL及Ad-IL2-KDRscFv的抑瘤率分别为63.69±6.6706%和56.17±7.3983%。
(7)瘤体内注射重组腺病毒,可使肿瘤组织微血管密度减少,以Ad-IL2 -KDRscFv-sTRAIL腺病毒的作用最为明显,与其它治疗组及对照组相比,结果具显著统计学差异。
(8)瘤体内注射腺病毒,仅在肝组织及肿瘤组织中检测到目的蛋白的表达,心、脾、肾、小肠、肺等组织为阴性表达。
(9)各组裸鼠的肝脏组织及其他组织经病理切片观测,未见到明显的病理改变。
[结论]:
(1)重组腺病毒介导的IL2-KDRscFv、IL2-sTRAIL(114-281aa)及IL2-KDRscFv- sTRAIL对胃癌SGC-7901细胞、肝癌HepGII细胞及大肠癌SW480细胞均有杀伤作用,其中以Ad-IL2-KDRscFv-sTRAIL对肿瘤细胞的凋亡诱导能力最强。
(2)体外实验证实,我们构建的三种腺病毒对人正常肝细胞株LO2是安全的。
(3)瘤体内注射腺病毒,可明显抑制肿瘤生长及肿瘤微血管生成,以Ad-IL2-KDRscFv-sTRAIL的作用最为显著,说明KDRscFv融合sTRAIL基因既可杀伤肿瘤细胞,又可抗肿瘤血管生成,从不同方面发挥协同抗肿瘤作用。
(4) Ad-IL2-KDRscFv-sTRAIL、Ad-IL2-sTRAIL及Ad-IL2-KDRscFv对心、肝、肾、脾、肺及小肠等组织无明显毒性,瘤体内注射是安全的。
Objective:To explore the lethal effect of adenovirus mediated IL2-sTRAILgene,IL2-KDRscFv gene and IL2-KDRscFv-sTRAIL gene (Ad-IL2-sTRAIL , Ad-IL2-KDRscFv and Ad-IL2-KDRscFv-sTRAIL) on gastric cancer cell line SGC-7901, hepatocellular carcinoma cell line HepGII , colon cancer cell line SW480 and normal human hepatocyte line LO2. Meanwhile, their effects on the growth and angiogenesis of established hepatocellular carcinoma nodules in nude mice were observed.
Methods : Both TRAIL and IL-2 cDNA were cloned f rom PBMC by RT-PCR, and KDRscFv gene was synthesized by Shanghai Sangon Biological Engineering Technology & Services Co, Ltd.The signal peptide of IL-2 was cloned to the N tip of KDRscFv and sTRAIL respectively with SOE,and the fusion gene of IL2-KDRscFv and sTRAIL was obtained by using a polypeptide linker ( Gly4Ser).After sequencing, the IL2-KDRscFv gene,IL2-sTRAILgene and the fusion gene of IL2-KDRscFv-sTRAIL fragment was cloned respectively into the shuttle plasmid pAdTrack - CMV to form the transfer vector and then transformed to competent BJ5183 cells previously transformed with pAdEasy-1 to carrying out homogenous recombination in bacteria. Screening recombinant plasmid pAdEasy-sTRA IL、pAdEasy-IL2-KDRscFv and pAdEasy -IL2-KDRscFv-sTRAIL and transfected to 293 cells in mediation of Lipofectamine to preparing replication-deficient adenovirus Ad-IL2- sTRAIL,Ad-IL2-KDRscFv and Ad-IL2-KDRscFv-sTRAIL. The recombinant adenovirus vector was identified by restriction enzyme digestion and polymerase chain reaction (PCR). The prepared Ad-IL2-sTRAIL,Ad-IL2-KDRscFv and Ad-IL2-KDRscFv-sTRAIL virus particles were purified by density gradient centrifugation with cesium chloride and determining the titer by OD260. The transcription of interest gene in 293 cells was detected by PCR.After the virus particles were constructed successfully,they were transfected into gastric cancer line SGC7901, hepatocellular carcinoma cell line HepGII , colon cancer cell line SW480 and normal human hepatocyte line LO2 respectively and the apoptosis rate was determinded by MTT assasy and flow cytometry.In vivo,the adenovirus were injected into tumor in nude mice and the expressions of interest proteins were detected by western blot and immunohistochemistry assay.
Results:
(1) Recombinant adenovirus Ad-IL2-sTRAIL , Ad-IL2-KDRscFv and Ad-IL2 -KDRscFv-sTRAIL were successfully constructed, and the titer of purified adenovirus particles was 1012 VP /ml .
(2) All the three adenovirus have killing effect on cancer cells and the one bearing the fusion gene of IL2-KDRscFv-sTRAIL had the most powerful effect. When the tumor cells were treated with adenovirus in concentration of 20 MOI for 48 hours ,Ad- IL2-KDRscFv-sTRAIL could induce the apoptosis of 39.16 % in HepGII cells ,which was significantly higher than that in the control group of PBS and the vector control group of GFP(p<0.05).
(3) Among the three cancer cell lines, hepatocellular carcinoma cell line HepGII had the most distinguished sensitivity to adenovirus.In concentration of 20 MOI for 48 hours, Ad-IL2-sTRAIL could kill 19.88% while Ad-IL2-KDRsvFv killed 9.09% HepGII cells.At the same condition, the apotosis rate of gastric cancer cell line SGC-7901was 8.09% and 5.75% respectively.
(4) All the three adenovirus had no killing effect on normal human hepatocyte line LO2 and there had no statistic distinction compared with the control group of PBS and the vector control group of Ad-GFP.(p>0.05).
(5) The interest proteins could be detected both in the culture supermatant and cell precips after the tumor cells were incubated with adenovirus.
(6) In vivo,injection of adenovirus into hepatocellular carcinoma nodules in nude mice could shrink its volume significantly. Ad-IL2-KDRscFv-sTRAIL had the most powerful lethal effect, and the tumor volume suppression rate was 75.60±4.8891%, while that of Ad-IL2-sTRAIL and Ad-IL2-KDRscFv was 63.69±6.6706% and 56.17±7.3983% respectively.
(7) The microvessel density( MVD) was significantly lower in the experiment groups than those in the control group ( P < 0. 01 ) and Ad-IL2-KDRscFv-sTRAIL had the most powerful inhibited effct.
(8) The interest proteins could only be detected in hepatic tissues and tumor tissues when the nude mice were treated with adenovirus.
(9) There had no obvious pathological change in the hepatic tissues and other tissues after treated with adenovirus.
Conclusions:
(1) Recombinant adenovirus Ad-IL2-sTRAIL , Ad-IL2-KDRscFv and Ad-IL2- KDRscFv-sTRAIL all have killing effect on cancer cells and among them IL2- KDRscFv- sTRAIL had the most powerful tumoricidal effect.
(2) In vitro, all the three adenovirus are safe to normal human hepatocyte line.
(3) In vivo studies, injection of adenovirus into tumor significantly inhibited the growth of the hepatocellular carcinoma nodules in nude mice, and the MVD were significantly lower too in the experiment groups than those in the control group and Ad-IL2-KDRscFv-sTRAIL had the most powerful role.
(4) The adenovirus mediated KDRscFv-sTRAIL fusion gene have double lethal effect on tumor cells and tumor angiogenesis and presented synergia effect.
(5) In vivo and vitro studies, all the three adenovirus are safe to normal cells and tissues.
[方法]:采用重叠延伸PCR方法,分别在KDRscFv及sTRAIL(114-281aa)基因的N端融合IL2信号肽基因,以提高蛋白表达的可溶性。然后采用基因融合技术,构建IL2-KDRscFv与sTRAIL的融合基因。根据细菌内同源重组原理,首先构建编码TRAIL胞外区114~281位氨基酸、编码KDR单链抗体及编码二者融合基因的腺病毒穿梭质粒pAd-IL2-KDRscFv、pAd-IL2-sTRAIL及pAd-IL2-KDRscFv-sTRAIL,酶切线性化后转染BJ5183菌,与腺病毒骨架质粒pAdEasy-1在细菌内发生同源重组,将阳性重组子转染HEK293人胚肾细胞,获得高滴度的重组病毒颗粒后,转导人胃癌细胞株SGC-7901、人肝癌细胞株HepGII和结肠癌细胞株SW480以及人正常肝细胞株LO2,并采用荷瘤裸鼠瘤体内注射的方法,通过流式细胞仪、MTT、Western印迹法和免疫组化等方法测定重组腺病毒介导的目的蛋白在体内外的表达及观察肿瘤细胞的凋亡诱导作用和对肿瘤体积、肿瘤血管生成的抑制作用。
[结果]:
(1)成功地获得了三种重组腺病毒,在293细胞中大量扩增后,经氯化铯纯化浓缩后病毒滴度可达1012vp/ml。且均对真核细胞有高效感染效率。
(2)三种重组腺病毒对SGC-7901、SW480和HepGII细胞均有一定程度的凋亡诱导作用,其中以重组Ad-IL2-KDRscFv-sTRAIL腺病毒的作用最为明显。在感染复数为20,作用48小时情况下,可诱导39.16%的肝癌HepGII细胞发生凋亡,与PBS及Ad-GFP对照组相比,结果具有显著统计学差异。
(3)三种肿瘤细胞中,以肝癌HepGII细胞对负载有目的基因的腺病毒最为敏感,在感染复数为20,作用48小时情况下,Ad-IL2-sTRAIL可诱导19.88%、Ad-KDRsvFv可诱导9.09%的HepGII细胞凋亡,同样条件下胃癌SGC-7901细胞的凋亡率分别为8.09%、5.75%。
(4)三种腺病毒对人正常肝细胞LO2无明显凋亡诱导作用,与PBS对照及Ad-GFP载体对照组相比,结果无显著差别。
(5)三种腺病毒感染肿瘤细胞后,在细胞培养上清及收集的细胞沉淀中均可检测到目的蛋白的表达。
(6)体内实验中,瘤体内注射重组腺病毒,可明显抑制肿瘤体积增长,以Ad-IL-2-KDRscFv-sTRAIL腺病毒的作用最为明显,抑瘤率达75.60±4.8891%,而Ad-IL2-sTRAIL及Ad-IL2-KDRscFv的抑瘤率分别为63.69±6.6706%和56.17±7.3983%。
(7)瘤体内注射重组腺病毒,可使肿瘤组织微血管密度减少,以Ad-IL2 -KDRscFv-sTRAIL腺病毒的作用最为明显,与其它治疗组及对照组相比,结果具显著统计学差异。
(8)瘤体内注射腺病毒,仅在肝组织及肿瘤组织中检测到目的蛋白的表达,心、脾、肾、小肠、肺等组织为阴性表达。
(9)各组裸鼠的肝脏组织及其他组织经病理切片观测,未见到明显的病理改变。
[结论]:
(1)重组腺病毒介导的IL2-KDRscFv、IL2-sTRAIL(114-281aa)及IL2-KDRscFv- sTRAIL对胃癌SGC-7901细胞、肝癌HepGII细胞及大肠癌SW480细胞均有杀伤作用,其中以Ad-IL2-KDRscFv-sTRAIL对肿瘤细胞的凋亡诱导能力最强。
(2)体外实验证实,我们构建的三种腺病毒对人正常肝细胞株LO2是安全的。
(3)瘤体内注射腺病毒,可明显抑制肿瘤生长及肿瘤微血管生成,以Ad-IL2-KDRscFv-sTRAIL的作用最为显著,说明KDRscFv融合sTRAIL基因既可杀伤肿瘤细胞,又可抗肿瘤血管生成,从不同方面发挥协同抗肿瘤作用。
(4) Ad-IL2-KDRscFv-sTRAIL、Ad-IL2-sTRAIL及Ad-IL2-KDRscFv对心、肝、肾、脾、肺及小肠等组织无明显毒性,瘤体内注射是安全的。
Objective:To explore the lethal effect of adenovirus mediated IL2-sTRAILgene,IL2-KDRscFv gene and IL2-KDRscFv-sTRAIL gene (Ad-IL2-sTRAIL , Ad-IL2-KDRscFv and Ad-IL2-KDRscFv-sTRAIL) on gastric cancer cell line SGC-7901, hepatocellular carcinoma cell line HepGII , colon cancer cell line SW480 and normal human hepatocyte line LO2. Meanwhile, their effects on the growth and angiogenesis of established hepatocellular carcinoma nodules in nude mice were observed.
Methods : Both TRAIL and IL-2 cDNA were cloned f rom PBMC by RT-PCR, and KDRscFv gene was synthesized by Shanghai Sangon Biological Engineering Technology & Services Co, Ltd.The signal peptide of IL-2 was cloned to the N tip of KDRscFv and sTRAIL respectively with SOE,and the fusion gene of IL2-KDRscFv and sTRAIL was obtained by using a polypeptide linker ( Gly4Ser).After sequencing, the IL2-KDRscFv gene,IL2-sTRAILgene and the fusion gene of IL2-KDRscFv-sTRAIL fragment was cloned respectively into the shuttle plasmid pAdTrack - CMV to form the transfer vector and then transformed to competent BJ5183 cells previously transformed with pAdEasy-1 to carrying out homogenous recombination in bacteria. Screening recombinant plasmid pAdEasy-sTRA IL、pAdEasy-IL2-KDRscFv and pAdEasy -IL2-KDRscFv-sTRAIL and transfected to 293 cells in mediation of Lipofectamine to preparing replication-deficient adenovirus Ad-IL2- sTRAIL,Ad-IL2-KDRscFv and Ad-IL2-KDRscFv-sTRAIL. The recombinant adenovirus vector was identified by restriction enzyme digestion and polymerase chain reaction (PCR). The prepared Ad-IL2-sTRAIL,Ad-IL2-KDRscFv and Ad-IL2-KDRscFv-sTRAIL virus particles were purified by density gradient centrifugation with cesium chloride and determining the titer by OD260. The transcription of interest gene in 293 cells was detected by PCR.After the virus particles were constructed successfully,they were transfected into gastric cancer line SGC7901, hepatocellular carcinoma cell line HepGII , colon cancer cell line SW480 and normal human hepatocyte line LO2 respectively and the apoptosis rate was determinded by MTT assasy and flow cytometry.In vivo,the adenovirus were injected into tumor in nude mice and the expressions of interest proteins were detected by western blot and immunohistochemistry assay.
Results:
(1) Recombinant adenovirus Ad-IL2-sTRAIL , Ad-IL2-KDRscFv and Ad-IL2 -KDRscFv-sTRAIL were successfully constructed, and the titer of purified adenovirus particles was 1012 VP /ml .
(2) All the three adenovirus have killing effect on cancer cells and the one bearing the fusion gene of IL2-KDRscFv-sTRAIL had the most powerful effect. When the tumor cells were treated with adenovirus in concentration of 20 MOI for 48 hours ,Ad- IL2-KDRscFv-sTRAIL could induce the apoptosis of 39.16 % in HepGII cells ,which was significantly higher than that in the control group of PBS and the vector control group of GFP(p<0.05).
(3) Among the three cancer cell lines, hepatocellular carcinoma cell line HepGII had the most distinguished sensitivity to adenovirus.In concentration of 20 MOI for 48 hours, Ad-IL2-sTRAIL could kill 19.88% while Ad-IL2-KDRsvFv killed 9.09% HepGII cells.At the same condition, the apotosis rate of gastric cancer cell line SGC-7901was 8.09% and 5.75% respectively.
(4) All the three adenovirus had no killing effect on normal human hepatocyte line LO2 and there had no statistic distinction compared with the control group of PBS and the vector control group of Ad-GFP.(p>0.05).
(5) The interest proteins could be detected both in the culture supermatant and cell precips after the tumor cells were incubated with adenovirus.
(6) In vivo,injection of adenovirus into hepatocellular carcinoma nodules in nude mice could shrink its volume significantly. Ad-IL2-KDRscFv-sTRAIL had the most powerful lethal effect, and the tumor volume suppression rate was 75.60±4.8891%, while that of Ad-IL2-sTRAIL and Ad-IL2-KDRscFv was 63.69±6.6706% and 56.17±7.3983% respectively.
(7) The microvessel density( MVD) was significantly lower in the experiment groups than those in the control group ( P < 0. 01 ) and Ad-IL2-KDRscFv-sTRAIL had the most powerful inhibited effct.
(8) The interest proteins could only be detected in hepatic tissues and tumor tissues when the nude mice were treated with adenovirus.
(9) There had no obvious pathological change in the hepatic tissues and other tissues after treated with adenovirus.
Conclusions:
(1) Recombinant adenovirus Ad-IL2-sTRAIL , Ad-IL2-KDRscFv and Ad-IL2- KDRscFv-sTRAIL all have killing effect on cancer cells and among them IL2- KDRscFv- sTRAIL had the most powerful tumoricidal effect.
(2) In vitro, all the three adenovirus are safe to normal human hepatocyte line.
(3) In vivo studies, injection of adenovirus into tumor significantly inhibited the growth of the hepatocellular carcinoma nodules in nude mice, and the MVD were significantly lower too in the experiment groups than those in the control group and Ad-IL2-KDRscFv-sTRAIL had the most powerful role.
(4) The adenovirus mediated KDRscFv-sTRAIL fusion gene have double lethal effect on tumor cells and tumor angiogenesis and presented synergia effect.
(5) In vivo and vitro studies, all the three adenovirus are safe to normal cells and tissues.
引文
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