肾癌特异启动子G250调控的条件增殖腺病毒介导RNA干扰靶向治疗肾癌研究
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摘要
目的构建G250启动子调控表达Ki67-siRNA的条件增殖型腺病毒G250-Ki67，体外实验研究该CRAd靶向抑制肾癌细胞的疗效，为其体内实验及临床应用提供实验基础。
方法腺病毒左臂质粒pG250-Ki67、pG250–EGFP及腺病毒右臂质粒pBHGE3大量制备及酶切鉴定。将鉴定正确的质粒分别与含有腺病毒的右臂质粒pBHGE3共转染低代293细胞，9～12d后出现病毒空斑，挑取空斑进行重组腺病毒小量扩增，后提取基因组DNA，PCR鉴定，正确者分别命名为G250-Ki67、G250-EGFP。G250-Ki67、G250-EGFP及实验室前期构建的增殖缺陷型腺病毒Ad-Ki67大规模转染低代293细胞，扩增后纯化，并测定滴度。G250-Ki67、G250-EGFP、Ad-Ki67分别转染肾癌786-0细胞（G250阳性表达，G250+）、ACHN细胞（G250阴性表达，G250－）及正常肾小管上皮HK-2细胞。Western Blot法及免疫组化法检测腺病毒E1A蛋白在肾癌细胞中的表达。结晶紫染色法检测腺病毒对肾癌细胞的细胞毒作用。RT-PCR法检测腺病毒对肾癌细胞Ki67基因的沉默效果。MTT法检测腺病毒对肾癌细胞增殖的影响。Annexin V-PE/7-AAD法检测腺病毒对肾癌细胞凋亡的影响。
结果1.酶切鉴定左臂质粒pG250-Ki67、pG250-EGFP及右臂质粒pBHGE3正确。PCR鉴定表明重组腺病毒G250-Ki67及G250-EGFP包含目的基因，且无野生型腺病毒污染。G250-Ki67、G250-EGFP及Ad-Ki67病毒的滴度分别为：2.3×1011PFU/ml、2.11×1011PFU/ml、1.97×1011PFU/ml。
2.腺病毒G250-Ki67、G250-EGFP在肾癌786-0（G250+）细胞中均表达E1A蛋白；在肾癌ACHN（G250－）细胞中，荷载G250启动子腺病毒均不表达E1A。在正常肾小管HK-2细胞中均未检测到E1A的表达； Ad-Ki67感染的786-0、ACHN细胞没有EIA的表达。
3.G250-Ki67抑制肾癌细胞Ki67表达能力明显高于Ad-Ki67，且特异性比Ad-Ki67更高（P＜0.05）。
4.三种病毒对786-O、ACHN细胞均有杀伤作用，MOI=1的G250-Ki67可以将肾癌786-0细胞部分杀灭，MOI=10时全部杀灭。MOI=100的G250-Ki67可以将肾癌ACHN细胞部分杀灭，G250-EGFP对肾癌ACHN细胞无明显杀伤作用。MOI=100时三种病毒对正常肾小管HK-2细胞均无杀伤作用。Ad-Ki67杀伤作用最弱，Ad-Ki67在MOI=10时对786-O、ACHN细胞无影响。
5.G250-Ki67、G250-EGFP、Ad-Ki67对肾癌786-0细胞增殖均有抑制作用，并且存在浓度及时间依赖性，当MOI=0.1时，抑制作用较弱，随着浓度增高，抑制作用逐渐增强，MOI=100时抑制作用最强。MOI=10时，随着天数增加，抑制逐渐增强，第四天抑制作用最强。Ad-Ki67对肾癌ACHN细胞增殖有抑制作用，G250-Ki67、G250-EGFP对肾癌ACHN细胞增殖无明显抑制作用。
6. AnnexinV-PE/7-AAD法检测细胞凋亡，在肾癌786-0细胞中，与其它组比较，G250-Ki67对肾癌786-0细胞凋亡诱导能力最强（P＜0.05）。在肾癌ACHN细胞中，荷载G250启动子腺病毒诱导ACHN细胞凋亡的作用较弱。各组病毒诱导正常HK-2细胞凋亡的作用较弱且组无明显差异（P＞0.05）。
结论成功构建G250-Ki67，其在肾癌细胞内大量扩增且高效表达Ki67-siRNA、抑制肾癌细胞增殖、诱导肾癌细胞凋亡，为肾癌靶向治疗奠定了基础。
目的研究G250启动子调控的荷载Ki67小干扰RNA的条件增殖腺病毒（G250-Ki67）对人肾癌细胞裸鼠皮下移植瘤生长的影响，为临床肾癌的病毒-基因联合治疗提供依据。
方法将培养至对数生长期的786-0细胞注射裸鼠皮下，构建裸鼠皮下移植瘤模型，建模成功后将裸鼠随机分为4组，每组10只，分别用G250-Ki67病毒、G250-EGFP病毒、Ad-Ki67病毒及PBS进行治疗，病毒每次注射0.2ml（7×108PFU），PBS注射0.2ml，隔天注射一次，共三次。在治疗结束的第7天，每组随机脱颈处死4只动物，取下瘤体组织，免疫组化法检测瘤体内Ki67蛋白及E1A蛋白的表达，Western检测E1A，HE染色观察肿瘤细胞生长情况，TUNEL法检测组织细胞凋亡，其余动物继续饲养，定期测量肿瘤体积，绘制肿瘤时间-体积生长抑制曲线，在治疗的第35天时处死全部动物，测量最终体积，取下肝脏组织，HE染色观察病毒治疗的毒性作用。
结果成功构建人肾透明细胞癌裸鼠皮下移植瘤模型。免疫组化结果显示G2505-Ki67组Ki67蛋白的表达明显低于其余各组，抑制Ki67表达作用由强到弱依次为G250-Ki67＞Ad-Ki67＞G250-EGFP＞PBS，G250-Ki67组与其余各组之间比较，差异有统计学意义（P<0.05）；Western及免疫组化法显示，病毒复制蛋白E1A在PBS组与Ad-Ki67组无表达，而G250-EGFP组及G250-Ki67组可见蛋白表达阳性信号，提示病毒在这两组肿瘤的瘤体内复制；瘤组织HE染色中PBS组细胞浆染色松散色浅，可见胞核呈双叶或多叶分裂像，提示细胞增殖活跃，而G250-Ki67，G250-EGFP及Ad-Ki67组可见到不同程度的细胞核深染，很少有核分裂像，显示肿瘤组织生长抑制，抑制作用由强到弱依次为G250-Ki67＞G250-EGFP＞Ad-Ki67＞PBS；TUNEL检测各治疗组凋亡率分别为PBS组（3.78±1.64）%，G250-EGFP组（27.25±1.10）%，Ad-Ki67组（31.43±2.57）%，G250-Ki67组（65.32±3.24）%，G250-Ki67组与其余三组之间比较差异有统计学意义（P<0.05）；肿瘤生长抑制曲线显示G250-Ki67组与其余组比较，抑制肿瘤生长效果最强；病理HE染色，各处理组肝脏未见明显差异。
结论条件增殖腺病毒G250-Ki67能靶向抑制肿瘤组织增殖、促进其凋亡，可有效抑制人肾癌裸鼠移植瘤Ki67蛋白表达，进而抑制肿瘤的生长，为肾癌的病毒-基因联合治疗的提供实验依据。
Objective To construct the conditionally replicative adenovirus (CRAds)expressing short interference RNA targeting Ki67gene (Ki67-siRNA) with G250promoter, study the therapic effect on renal cell carcinoma in vitro. The results willpromote better understanding of the anti-tumor effect in vivo and clinical application.
Methods The plasmids of pG250-Ki67, pG250-EGFP and pBHGE3were verifiedby restriction enzymes analysis and purified. The pG250-Ki67and pG250-EGFPplasmids were transfected to293cells together with plasmid pBHGE3to abtain therecombined CRAds: G250-Ki67and G250-EGFP. The viral plaques appeared9-12daysafter infection. Extracted DNA from the recombined adenoviruses, verified by PCR.The viral plaques were purified and propagated on low passage HEK293cells. Thefunctional PFU titers were determined by plaque assay on low passage HEK293cells.The expression of E1A protein in786-0, ACHN and HK-2cell lines were detected byWestern blot and immunohistochemistry. Cytotoxic effects of G250-Ki67, G250-EGFPand Ad-Ki67on786-0, ACHN and HK-2cell lines were detected by crystal violetstaining. The effect of Ki67-siRNA gene was observed by RT-PCR analysis. Cellproliferation was assayed by MTT method. The apoptosis of tumor cells was measuredby Annexin V-PE/7-AAD.
Results1.The plasmids of pG250-Ki67and pG250-EGFP were constructedsuccessfully and proved by restriction analysis. G250-Ki67and G250-EGFP had beenrecombined successfully and not polluted by wild-type adenovirus tested by PCR. Theirfunctional PFU titers were2.3×1011PFU/ml,2.11×1011PFU/ml and1.97×1011PFU/ml.
2. G250-Ki67and G250-EGFP expressed E1A protein in786-0cell lines，but notin ACHN cell lines. There were no expression of E1A protein in786-0cell lines andACHN cell lines which infected by Ad-Ki67. All virus could not expressed E1A proteinin HK-2cell lines.
3. The expression of Ki67gene in786-0cell lines was suppressed by G250-Ki67and Ad-Ki67. G250-Ki67exerted more specific and stronger inhibitory effect on theexpression of Ki67in786-0cells than Ad-Ki67dose（P＜0.05）.
4. Cytotoxic effects: G250-Ki67, G250-EGFP and Ad-Ki67infected786-0, ACHNand HK-2cell lines respectively with different MOI. All virus had killing effect on786-0cell lines and ACHN cell lines. Both G250-Ki67and ZD55-Ki67had lethal effecton786-0cell lines, G250-Ki67could kill all786-0cell lines when MOI was10, whilelethal effect of G250-EGFP was poor. G250-Ki67could kill all ACHN cell lines partlywhen MOI was100, while G250-EGFP could not. Ad-Ki67had no obviously lethaleffect on786-0and ACHN cell lines. G250-Ki67, G250-EGFP and Ad-Ki67had noobviously lethal effect on HK-2cell lines.
5. G250-Ki67, G250-EGFP and Ad-Ki67could inhibit the proliferation of786-0cell line. The inhibition effect depended on the concentration and time. The inhibitioneffects were weak with the MOI=0.1, improved with increasing concentration, and theeffects reach utmost when the MOI=100. G250-Ki67, G250-EGFP and Ad-Ki67infected786-0cell lines with MOI=10respectively, cell survival rates increased as timewent by, and the inhibition effects reached utmost at the forth day after infection.Ad-Ki67also had inhibition effect on the proliferation of ACHN cells, whileG250-Ki67and G250-EGFP had no obviously inhibition effect on the proliferation ofACHN cells. The result among every group had significant difference (P<0.05).
6. Cell apoptosis were detected byAnnexinV-PE/7-AAD. G250-Ki67had the mostpotent apoptosis induction effect on786-0cell line, comparing with the G250-EGFPand Ad-Ki67. Cell apoptosis induced by G250promoter controlled CRAds in ACHNcell lines were weak. G250-Ki67, G250-EGFP and Ad-Ki67had no obviously apoptosisinduction effect on HK-2cell lines.. The result among every group had significantdifference (P<0.05).
Conclusion CRAds expressing Ki67-siRNA with G250promoter regulation andcontrol could high amplify and express Ki67-siRNA in renal cancer cells, inhibit renalcancer cells proliferation and induce apoptosis, targeted therapy for the renal cellcarcinoma. It may be used for further investigation of Gene-Viro therapy of cancer.
Objective To investigate the effects of G250promoter controlled conditionallyreplicative adenovirus (CRAds) expressing short interference RNA targeting Ki67gene(Ki67-siRNA) on the growth of human renal cell carcinoma in nude mice, provideexperimental foundation in possible clinical use of CRAds for renal cell carcinoma．
Methods Human clear cell renal cell carcinoma(786-0) cells were cultured in1640medium to exponential phase of growth and then transplanted under the skin ofBALB/c nude mice to develop the tumor model of human renal cell carcinoma. Afterthe model were successfully developed，40mice were randomly divided into fourgroups：G250-Ki67group, G250-EGFP group, Ad-Ki67group and PBS control group.Different virus included G250-Ki67,G250-EGFP and Ad-Ki67were directly injectedinto tumor on alternate days for3times at the dose of7×108PFU（0.2ml）each time.PBS control group used0.2ml PBS instead.4nude mice in each group were randomlykilled at the7th day after the injection of virus and tumors were dislodged.Immunohistochemistry staining was used to detect the protein expression of Ki67andE1A; the expression of E1A protein was detected by Western Blot; HE staining wasused to observe the tumor cells growth, the apoptosis of tumor cells was measured byTerminal dUTP nick-end labeling (TUNEL). The tumor volume of the rest animals weremeasured regularly to observe the tumor growth conditions. All animals were killed andthe livers were dislodged to detect the toxic effects with HE staining at the35th dayafter the treatment.
Results The tumor model of human clear cell renal cell carcinoma weresuccessfully developed. Immunohistochemistry staining shows that the expressions ofki67protein of G250-Ki67group was markedly lower than the rest groups, there weresignificant difference, compared with other groups; Western blot andimmunohistochemistry staining show that there were expressions of E1A protein only inG250-Ki67group and G250-EGFP group, which was imperative for virus replication,the differences between the two groups was significant. The results of HE staining of tumors showed that PBS group stained light color and nucleus was split like adouble-leaf or leaves, which prompted the active cell proliferation. As a comparison,different levels of deeply nucleus staining and few mitotic could be seen in Ad-Ki67group, G250-EGFP group and G250-Ki67group, which indicated tumor growthinhibition. The inhibition effect from strong to weak followed by G250-Ki67group,Ad-Ki67group, G250-EGFP group and PBS group. The apoptosis in each treatmentgroup with TUNEL methods was PBS group（3.78±1.64）%，G250-EGFP group（27.25±1.10）%，AD-Ki67group（31.43±2.57）%，G250-Ki67group（65.32±3.24）%, G250-Ki67group with the remaining differences between the three groups wasstatistically significant （P<0.05).Inhibition of tumor growth curve showed thatG250-Ki67group had the strongest inhibition to tumor growth compared with othergroups. We did not find any change in nude mice liver with HE staining.
Conclusion Oncolytic adenovirus G250-Ki67could inhibit tumor proliferationand promote apoptosis. As a result, it could inhibit the growth of tumor model of humanclear cell renal cell carcinoma in nude mice. This provided experimental basis forVirus-Gene therapy of kidney cancer.
方法腺病毒左臂质粒pG250-Ki67、pG250–EGFP及腺病毒右臂质粒pBHGE3大量制备及酶切鉴定。将鉴定正确的质粒分别与含有腺病毒的右臂质粒pBHGE3共转染低代293细胞，9～12d后出现病毒空斑，挑取空斑进行重组腺病毒小量扩增，后提取基因组DNA，PCR鉴定，正确者分别命名为G250-Ki67、G250-EGFP。G250-Ki67、G250-EGFP及实验室前期构建的增殖缺陷型腺病毒Ad-Ki67大规模转染低代293细胞，扩增后纯化，并测定滴度。G250-Ki67、G250-EGFP、Ad-Ki67分别转染肾癌786-0细胞（G250阳性表达，G250+）、ACHN细胞（G250阴性表达，G250－）及正常肾小管上皮HK-2细胞。Western Blot法及免疫组化法检测腺病毒E1A蛋白在肾癌细胞中的表达。结晶紫染色法检测腺病毒对肾癌细胞的细胞毒作用。RT-PCR法检测腺病毒对肾癌细胞Ki67基因的沉默效果。MTT法检测腺病毒对肾癌细胞增殖的影响。Annexin V-PE/7-AAD法检测腺病毒对肾癌细胞凋亡的影响。
结果1.酶切鉴定左臂质粒pG250-Ki67、pG250-EGFP及右臂质粒pBHGE3正确。PCR鉴定表明重组腺病毒G250-Ki67及G250-EGFP包含目的基因，且无野生型腺病毒污染。G250-Ki67、G250-EGFP及Ad-Ki67病毒的滴度分别为：2.3×1011PFU/ml、2.11×1011PFU/ml、1.97×1011PFU/ml。
2.腺病毒G250-Ki67、G250-EGFP在肾癌786-0（G250+）细胞中均表达E1A蛋白；在肾癌ACHN（G250－）细胞中，荷载G250启动子腺病毒均不表达E1A。在正常肾小管HK-2细胞中均未检测到E1A的表达； Ad-Ki67感染的786-0、ACHN细胞没有EIA的表达。
3.G250-Ki67抑制肾癌细胞Ki67表达能力明显高于Ad-Ki67，且特异性比Ad-Ki67更高（P＜0.05）。
4.三种病毒对786-O、ACHN细胞均有杀伤作用，MOI=1的G250-Ki67可以将肾癌786-0细胞部分杀灭，MOI=10时全部杀灭。MOI=100的G250-Ki67可以将肾癌ACHN细胞部分杀灭，G250-EGFP对肾癌ACHN细胞无明显杀伤作用。MOI=100时三种病毒对正常肾小管HK-2细胞均无杀伤作用。Ad-Ki67杀伤作用最弱，Ad-Ki67在MOI=10时对786-O、ACHN细胞无影响。
5.G250-Ki67、G250-EGFP、Ad-Ki67对肾癌786-0细胞增殖均有抑制作用，并且存在浓度及时间依赖性，当MOI=0.1时，抑制作用较弱，随着浓度增高，抑制作用逐渐增强，MOI=100时抑制作用最强。MOI=10时，随着天数增加，抑制逐渐增强，第四天抑制作用最强。Ad-Ki67对肾癌ACHN细胞增殖有抑制作用，G250-Ki67、G250-EGFP对肾癌ACHN细胞增殖无明显抑制作用。
6. AnnexinV-PE/7-AAD法检测细胞凋亡，在肾癌786-0细胞中，与其它组比较，G250-Ki67对肾癌786-0细胞凋亡诱导能力最强（P＜0.05）。在肾癌ACHN细胞中，荷载G250启动子腺病毒诱导ACHN细胞凋亡的作用较弱。各组病毒诱导正常HK-2细胞凋亡的作用较弱且组无明显差异（P＞0.05）。
结论成功构建G250-Ki67，其在肾癌细胞内大量扩增且高效表达Ki67-siRNA、抑制肾癌细胞增殖、诱导肾癌细胞凋亡，为肾癌靶向治疗奠定了基础。
目的研究G250启动子调控的荷载Ki67小干扰RNA的条件增殖腺病毒（G250-Ki67）对人肾癌细胞裸鼠皮下移植瘤生长的影响，为临床肾癌的病毒-基因联合治疗提供依据。
方法将培养至对数生长期的786-0细胞注射裸鼠皮下，构建裸鼠皮下移植瘤模型，建模成功后将裸鼠随机分为4组，每组10只，分别用G250-Ki67病毒、G250-EGFP病毒、Ad-Ki67病毒及PBS进行治疗，病毒每次注射0.2ml（7×108PFU），PBS注射0.2ml，隔天注射一次，共三次。在治疗结束的第7天，每组随机脱颈处死4只动物，取下瘤体组织，免疫组化法检测瘤体内Ki67蛋白及E1A蛋白的表达，Western检测E1A，HE染色观察肿瘤细胞生长情况，TUNEL法检测组织细胞凋亡，其余动物继续饲养，定期测量肿瘤体积，绘制肿瘤时间-体积生长抑制曲线，在治疗的第35天时处死全部动物，测量最终体积，取下肝脏组织，HE染色观察病毒治疗的毒性作用。
结果成功构建人肾透明细胞癌裸鼠皮下移植瘤模型。免疫组化结果显示G2505-Ki67组Ki67蛋白的表达明显低于其余各组，抑制Ki67表达作用由强到弱依次为G250-Ki67＞Ad-Ki67＞G250-EGFP＞PBS，G250-Ki67组与其余各组之间比较，差异有统计学意义（P<0.05）；Western及免疫组化法显示，病毒复制蛋白E1A在PBS组与Ad-Ki67组无表达，而G250-EGFP组及G250-Ki67组可见蛋白表达阳性信号，提示病毒在这两组肿瘤的瘤体内复制；瘤组织HE染色中PBS组细胞浆染色松散色浅，可见胞核呈双叶或多叶分裂像，提示细胞增殖活跃，而G250-Ki67，G250-EGFP及Ad-Ki67组可见到不同程度的细胞核深染，很少有核分裂像，显示肿瘤组织生长抑制，抑制作用由强到弱依次为G250-Ki67＞G250-EGFP＞Ad-Ki67＞PBS；TUNEL检测各治疗组凋亡率分别为PBS组（3.78±1.64）%，G250-EGFP组（27.25±1.10）%，Ad-Ki67组（31.43±2.57）%，G250-Ki67组（65.32±3.24）%，G250-Ki67组与其余三组之间比较差异有统计学意义（P<0.05）；肿瘤生长抑制曲线显示G250-Ki67组与其余组比较，抑制肿瘤生长效果最强；病理HE染色，各处理组肝脏未见明显差异。
结论条件增殖腺病毒G250-Ki67能靶向抑制肿瘤组织增殖、促进其凋亡，可有效抑制人肾癌裸鼠移植瘤Ki67蛋白表达，进而抑制肿瘤的生长，为肾癌的病毒-基因联合治疗的提供实验依据。
Objective To construct the conditionally replicative adenovirus (CRAds)expressing short interference RNA targeting Ki67gene (Ki67-siRNA) with G250promoter, study the therapic effect on renal cell carcinoma in vitro. The results willpromote better understanding of the anti-tumor effect in vivo and clinical application.
Methods The plasmids of pG250-Ki67, pG250-EGFP and pBHGE3were verifiedby restriction enzymes analysis and purified. The pG250-Ki67and pG250-EGFPplasmids were transfected to293cells together with plasmid pBHGE3to abtain therecombined CRAds: G250-Ki67and G250-EGFP. The viral plaques appeared9-12daysafter infection. Extracted DNA from the recombined adenoviruses, verified by PCR.The viral plaques were purified and propagated on low passage HEK293cells. Thefunctional PFU titers were determined by plaque assay on low passage HEK293cells.The expression of E1A protein in786-0, ACHN and HK-2cell lines were detected byWestern blot and immunohistochemistry. Cytotoxic effects of G250-Ki67, G250-EGFPand Ad-Ki67on786-0, ACHN and HK-2cell lines were detected by crystal violetstaining. The effect of Ki67-siRNA gene was observed by RT-PCR analysis. Cellproliferation was assayed by MTT method. The apoptosis of tumor cells was measuredby Annexin V-PE/7-AAD.
Results1.The plasmids of pG250-Ki67and pG250-EGFP were constructedsuccessfully and proved by restriction analysis. G250-Ki67and G250-EGFP had beenrecombined successfully and not polluted by wild-type adenovirus tested by PCR. Theirfunctional PFU titers were2.3×1011PFU/ml,2.11×1011PFU/ml and1.97×1011PFU/ml.
2. G250-Ki67and G250-EGFP expressed E1A protein in786-0cell lines，but notin ACHN cell lines. There were no expression of E1A protein in786-0cell lines andACHN cell lines which infected by Ad-Ki67. All virus could not expressed E1A proteinin HK-2cell lines.
3. The expression of Ki67gene in786-0cell lines was suppressed by G250-Ki67and Ad-Ki67. G250-Ki67exerted more specific and stronger inhibitory effect on theexpression of Ki67in786-0cells than Ad-Ki67dose（P＜0.05）.
4. Cytotoxic effects: G250-Ki67, G250-EGFP and Ad-Ki67infected786-0, ACHNand HK-2cell lines respectively with different MOI. All virus had killing effect on786-0cell lines and ACHN cell lines. Both G250-Ki67and ZD55-Ki67had lethal effecton786-0cell lines, G250-Ki67could kill all786-0cell lines when MOI was10, whilelethal effect of G250-EGFP was poor. G250-Ki67could kill all ACHN cell lines partlywhen MOI was100, while G250-EGFP could not. Ad-Ki67had no obviously lethaleffect on786-0and ACHN cell lines. G250-Ki67, G250-EGFP and Ad-Ki67had noobviously lethal effect on HK-2cell lines.
5. G250-Ki67, G250-EGFP and Ad-Ki67could inhibit the proliferation of786-0cell line. The inhibition effect depended on the concentration and time. The inhibitioneffects were weak with the MOI=0.1, improved with increasing concentration, and theeffects reach utmost when the MOI=100. G250-Ki67, G250-EGFP and Ad-Ki67infected786-0cell lines with MOI=10respectively, cell survival rates increased as timewent by, and the inhibition effects reached utmost at the forth day after infection.Ad-Ki67also had inhibition effect on the proliferation of ACHN cells, whileG250-Ki67and G250-EGFP had no obviously inhibition effect on the proliferation ofACHN cells. The result among every group had significant difference (P<0.05).
6. Cell apoptosis were detected byAnnexinV-PE/7-AAD. G250-Ki67had the mostpotent apoptosis induction effect on786-0cell line, comparing with the G250-EGFPand Ad-Ki67. Cell apoptosis induced by G250promoter controlled CRAds in ACHNcell lines were weak. G250-Ki67, G250-EGFP and Ad-Ki67had no obviously apoptosisinduction effect on HK-2cell lines.. The result among every group had significantdifference (P<0.05).
Conclusion CRAds expressing Ki67-siRNA with G250promoter regulation andcontrol could high amplify and express Ki67-siRNA in renal cancer cells, inhibit renalcancer cells proliferation and induce apoptosis, targeted therapy for the renal cellcarcinoma. It may be used for further investigation of Gene-Viro therapy of cancer.
Objective To investigate the effects of G250promoter controlled conditionallyreplicative adenovirus (CRAds) expressing short interference RNA targeting Ki67gene(Ki67-siRNA) on the growth of human renal cell carcinoma in nude mice, provideexperimental foundation in possible clinical use of CRAds for renal cell carcinoma．
Methods Human clear cell renal cell carcinoma(786-0) cells were cultured in1640medium to exponential phase of growth and then transplanted under the skin ofBALB/c nude mice to develop the tumor model of human renal cell carcinoma. Afterthe model were successfully developed，40mice were randomly divided into fourgroups：G250-Ki67group, G250-EGFP group, Ad-Ki67group and PBS control group.Different virus included G250-Ki67,G250-EGFP and Ad-Ki67were directly injectedinto tumor on alternate days for3times at the dose of7×108PFU（0.2ml）each time.PBS control group used0.2ml PBS instead.4nude mice in each group were randomlykilled at the7th day after the injection of virus and tumors were dislodged.Immunohistochemistry staining was used to detect the protein expression of Ki67andE1A; the expression of E1A protein was detected by Western Blot; HE staining wasused to observe the tumor cells growth, the apoptosis of tumor cells was measured byTerminal dUTP nick-end labeling (TUNEL). The tumor volume of the rest animals weremeasured regularly to observe the tumor growth conditions. All animals were killed andthe livers were dislodged to detect the toxic effects with HE staining at the35th dayafter the treatment.
Results The tumor model of human clear cell renal cell carcinoma weresuccessfully developed. Immunohistochemistry staining shows that the expressions ofki67protein of G250-Ki67group was markedly lower than the rest groups, there weresignificant difference, compared with other groups; Western blot andimmunohistochemistry staining show that there were expressions of E1A protein only inG250-Ki67group and G250-EGFP group, which was imperative for virus replication,the differences between the two groups was significant. The results of HE staining of tumors showed that PBS group stained light color and nucleus was split like adouble-leaf or leaves, which prompted the active cell proliferation. As a comparison,different levels of deeply nucleus staining and few mitotic could be seen in Ad-Ki67group, G250-EGFP group and G250-Ki67group, which indicated tumor growthinhibition. The inhibition effect from strong to weak followed by G250-Ki67group,Ad-Ki67group, G250-EGFP group and PBS group. The apoptosis in each treatmentgroup with TUNEL methods was PBS group（3.78±1.64）%，G250-EGFP group（27.25±1.10）%，AD-Ki67group（31.43±2.57）%，G250-Ki67group（65.32±3.24）%, G250-Ki67group with the remaining differences between the three groups wasstatistically significant （P<0.05).Inhibition of tumor growth curve showed thatG250-Ki67group had the strongest inhibition to tumor growth compared with othergroups. We did not find any change in nude mice liver with HE staining.
Conclusion Oncolytic adenovirus G250-Ki67could inhibit tumor proliferationand promote apoptosis. As a result, it could inhibit the growth of tumor model of humanclear cell renal cell carcinoma in nude mice. This provided experimental basis forVirus-Gene therapy of kidney cancer.
引文
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