卵巢上皮癌相关抗原的筛选、鉴定、血清学检测及抗原基因生物学功能的初步研究
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摘要
卵巢癌是严重危胁女性生命健康的恶性肿瘤,具有起病隐藏、复发死亡率高的特点。因早期缺乏典型临床症状,75%患者确诊时已是晚期,这些患者的5年生存率也从临床Ⅰ期患者的95%下降到约20～25%,因此早期诊断对于提高生存率、改善患者预后具有重要的意义。然而,目前仍缺乏有效的早期诊断方法,没有能有效用于卵巢癌早期诊断的标志物。SEREX技术的建立不仅为肿瘤抗原的筛选提供了一种新的方法,而且通过对肿瘤抗原自身抗体的检测为肿瘤的诊断提供了新的血清标志物。目前对肿瘤抗原自身抗体的研究主要集中在IgG型抗体,对于IgM型抗体的报导很少。本研究在已有的研究基础上,用SMARTA法对从卵巢浆液性囊腺癌腹水肿瘤cDNA表达文库中筛选出10个抗原克隆进行血清学检测,对其中6个(TM4SF1、C1D、TIZ、OV-142、FXR1、OV-189)在卵巢癌血清中阳性率明显高于正常对照血清的抗原克隆进行测序分析;用RT-PCR法检测它们在卵巢癌组织中的表达情况;构建、表达、纯化了原核重组融合蛋白;建立了间接ELISA法,检测了血清中这些抗原IgG、IgM型自身抗体的相对含量,分析了这些卵巢肿瘤相关抗原自身抗体(谱)在卵巢癌诊断及预后中的作用;并对其中一个相关抗原基因FXR1在卵巢癌细胞中的生物学功能进行了初步研究。
第一部分卵巢上皮癌相关抗原异体血清筛选及生物学信息分析
目的:检测候选卵巢上皮癌相关抗原克隆与卵巢癌、正常对照血清中相应IgG、IgM型自身抗体反应情况,并对阳性反应率差异显著的抗原克隆进行测序及生物信息学分析。
方法:用SMARTA法对10个候选卵巢上皮癌相关抗原克隆与62例卵巢癌、62例正常对照血清中IgG、IgM型自身抗体反应情况进行定性检测,从中选出在癌血清中抗体阳性反应率与正常对照血清相比差异显著的抗原克隆,进行核苷酸测序,在相关网站上进行生物信息学分析。
结果:其中6个抗原克隆与卵巢癌血清中自身抗体阳性反应率显著高于正常对照血清,在癌血清中的阳性率为12.9%～27.4%,在正常血清中的阳性率为1.6%～11.3%,其中IgM型自身抗体的阳性率为19.4%～27.4%。对这6个抗原克隆进行核苷酸测序,经比对分析发现这6个抗原克隆其中4个是已知基因(TM4SF1、C1D、TIZ、FXR1),一个是与卵巢癌相关基因高度相似的基因(OV-142),一个是Genbank中无相似序列的新基因(OV-189)。TM4SF1蛋白是一种有四个疏水跨膜区的细胞表面蛋白,该蛋白在对调节细胞生长、活化、迁移的信号转换中起媒介作用,在肺癌、结肠癌、乳腺癌、卵巢上皮性癌等上皮细胞恶性肿瘤中高表达,是一种细胞表面抗原,可作为抗体免疫治疗的靶向。C1D基因编码的是一个保守的DNA绑定蛋白,C1D蛋白是一个隐藏的凋亡激活剂,是多发性肌炎硬皮病重叠综合征的自身抗原。FXR1蛋白是一种RNA绑定蛋白,可在在核与胞浆间穿梭,与多聚核糖体有关,具有细胞生长依赖的翻译活性功能,有可能是硬皮病的一种自身抗原,并且在肺鳞状细胞癌中检测到FXR1基因的过表达。TIZ是一个锌指蛋白,通过调节肿瘤坏死因子受体相关因子6(TRAF6)的信号活性,在破骨细胞分化过程中起一定作用。尚未见有C1D、TIZ、FXR1与卵巢癌相关的报导。其中OV-142有可能是BARD1基因的剪切变异体,可能有MHC-Ⅰ类抗原表位肽,可能成为卵巢癌免疫治疗的新靶点。初步认为OV-189是LINE中有转录活性的一种—L1家族中的一个新成员,可能有MHC-Ⅰ类抗原表位肽,有可能成为卵巢癌免疫治疗的靶点。
结论:我们的研究显示卵巢上皮癌相关抗原不仅能够介导IgG体液免疫反应而且能够诱导机体产生特异性的IgM自身抗体,这些抗原克隆在异体癌血清中较高的抗体阳性反应率,提示这些抗原的自身抗体有可能成为卵巢癌诊断的血清标志物。这些抗原基因有进一步研究的价值。
第二部分RT-PCR检测卵巢上皮癌相关抗原基因在卵巢癌组织中的相对表达水平
目的:检测卵巢上皮癌相关抗原基因在卵巢癌、良性卵巢肿瘤、正常卵巢组织中的相对表达水平。
方法:用RT-PCR方法检测上述6个卵巢上皮癌相关抗原基因在36例卵巢癌、15例良性卵巢肿瘤及13例正常卵巢组织中的相对表达水平。
结果:这6个抗原基因在癌、良性肿瘤、正常卵巢组织中几乎都有表达,只是在癌组织中的表达水平明显高于良性肿瘤及正常卵巢组织。显示出三种表达趋势:一类是癌组织中的表达水平显著高于正常卵巢组织,而良性肿瘤组织中的表达水平高于正常组织,癌组织中的表达水平稍高于良性肿瘤组织(TIZ、C1D、TM4SF1、OV-142);一类是癌组织中的表达水平显著高于良性肿瘤及正常卵巢组织,而良性与正常组织中表达相当(OV-189);一类是癌组织中的表达水平明显高于良性,癌与良性肿瘤组织中的表达水平均显著高于正常组织,且晚期癌组织中表达水平显著高于早期,分化差的组织表达水平显著高于分化好的(FXR1)。
结论:我们在mRNA水平证实这6个卵巢上皮癌SEREX抗原基因均与癌组织有很好的相关性。
第三部分卵巢上皮癌相关抗原蛋白的表达、纯化
目的:在原核表达系统中构建、表达、纯化这6个抗原蛋白。
方法:用RT-PCR克隆这些抗原基因的CDS,在pET-30b(+)系统中构建原核表达质粒,经IPTG诱导在大肠杆菌中表达重组融合蛋白,采用Ni-NTA His-Bind Resins和SDS-PAGE制备胶电洗脱进行纯化,复性、浓缩得到有活性的目的蛋白。
结论:成功构建、表达、纯化了这6个抗原蛋白,得到浓度在0.3～0.8mg/ml之间,纯度都在90%以上、有活性的重组融合抗原蛋白。
第四部分卵巢癌上皮癌相关抗原自身抗体谱的研究
目的:用自己制备的抗原蛋白建立间接ELISA法,检测这些卵巢上皮癌相关抗原在血清中相应自身抗体的相对含量,并分析它们的临床价值。
方法:建立间接ELISA法,检测126例治疗前、24例治疗后卵巢癌、42例良性卵巢肿瘤、20例乳腺癌、20例食管癌、20例肺癌癌患者、142例正常女性对照血清中卵巢上皮癌相关抗原IgG、IgM型自身抗体的相对含量。绘制ROC曲线,确定cut off值,单独或用Logistic回归分析法联合分析这些自身抗体/抗体谱的临床价值。同时测量CA125的含量,比较自身抗体谱与CA125在卵巢癌诊断上的效能。
结果:分析单个自身抗体时,卵巢癌血清中这些抗原IgG型自身抗体反应的阳性率为34.1%～47.6%,非癌患者的阳性率为13.0%～17.9%;癌血清中IgM型自身抗体反应的阳性率为39.7%～53.2%,非癌患者的阳性率为12.0%～33.2%,分析单个卵巢癌相关抗原自身抗体在卵巢癌诊断时意义均不大,但TIZ、FXR1、OV-189抗原IgM型自身抗体在早期病人中的阳性率均高于晚期病人,两者相比较差异有统计学意义。当联合多个自身抗体(抗体谱):TM4SF1 IgG、C1D IgG、TIZ IgG、TIZ IgM、FXR1 IgG、FXR1 IgM分析时敏感为75.4%,特异性为78.2%,准确性为76.5%,与单独分析CA125相比较敏感性明显提高(61.1%),特异性降低(89.1%),准确性相当(77.7%),但该自身抗体谱在早期(76.6%versus 51.1%)尤其是Ⅰ期(83.3%versus 44.4%)卵巢癌诊断的敏感性显著高于CA125,差异有统计学意义。将多个卵巢癌相关抗原自身抗体(TM4SF1 IgG、TM4SF1 IgM、C1D IgG、TIZ IgM、FXR1 IgG)与CA125联合分析时,诊断卵巢癌的敏感性为86%,特异性为91%,准确率为88.7%,与CA125相比,在敏感性、特异性、准确性均提高,阳性预测值、阳性似然比、阴性预测值明显提高,阴性似然明显降低;并且与CA125联合后在上皮性癌(包括浆液、粘液性癌)的诊断敏感性显著高于CA125,统计学上差异有显著性;同时对于早期、晚期卵巢癌的诊断敏感性亦显著高于CA125,统计学上差异有显著性。比较了配对的24例卵巢癌患者治疗前后卵巢癌自身抗体谱变化情况,结果显示治疗后自身抗体谱的阳性率显著低于治疗前。乳腺癌、食管癌、肺癌血清的检测,结果发现卵巢癌自身抗体谱的阳性率分别为30%、20%、25%。
结论:卵巢癌患者血清中存在IgG型、IgM型肿瘤自身抗体,并且可用于卵巢癌早期诊断。联合多个卵巢癌肿瘤自身抗体可达到与CA125相当的诊断效果,且该自身抗体谱在早期特别是Ⅰ期卵巢癌的诊断上优于CA125。将多个自身抗体与CA125联合可显著提高卵巢癌的诊断效能。卵巢上皮癌相关抗原自身抗体谱对疗效也有一定的监测作用。
第五部分真核转染上调FXR1基因表达对卵巢癌细胞生物学行为影响的初步研究
目的:了解上调FXR1基因表达对卵巢癌细胞系H08910生物学行为的影响。
方法:RT-PCR扩增FXR1 CDS,构建FXR1真核表达载体,脂质体介导下转染H08910细胞,经G418筛选获得稳定转染株,检测转染后细胞相应生物学行为。
结果:成功构建了FXR1基因的真核表达载体,并稳定转染了H08910细胞。生长曲线显示上调FXR1基因表达可促进细胞的生长;克隆形成实验显示上调FXR1基因表达可促进细胞增殖,基质粘附实验显示上调FXR1基因表达可加强细胞对基质的粘附能力,流式细胞周期检测亦发现与对照(80%)相比,转染FXR1基因后G1期细胞(67.1%)比例明显减少,这说明转染FXR1后细胞的增殖更旺盛。同时发现FXR1对细胞侵袭、迁移的能力无明显影响。凋亡检测虽提示转染FXR1基因后早期凋亡细胞的比例较对照增多,但总的凋亡细胞比例太少仅0.31%,意义可能不大。
结论:真核载体稳定转染技术是一种可靠、行之有效的研究基因功能的方法。上调FXR1基因表达可能有促进卵巢癌细胞的生长、增殖、加强细胞对基质粘附能力的作用。
第六部分RNA干扰FXR1基因对卵巢癌细胞系生物学行业影响的初步研究
目的:了解抑制FXR1基因表达对卵巢癌细胞系A2780生物学行为的影响。
方法:设计、合成、筛选有效的FXR1基因siRNA,将有效siRNA商业化构建siRNA表达载体,脂质体介导下转染A2780细胞,经G418筛选获得稳定转染株,检测转染后细胞相应生物学行为。
结果:设计并成功筛选出了抑制效率达80%的FXR1基因siRNA,将商业构建的siRNA表达载体成功稳定转染了A2780细胞,抑制效率约60%。细胞生长曲线显示出下调FXR1表达可轻度抑制细胞的生长;克隆形成实验结果显示,下调FXR1基因的表达对A2780细胞的增殖能力有的抑制作用;流式细胞周期分析发现下调FXR1基因的表达G1期细胞比例为49.2%多于转染阴性对照组(40%),S期与G2期比对照比例稍少,提示抑制FXR1基因的表达可延缓细胞增殖;同时发现下调FXR1基因的表达对A2780细胞体外侵袭、迁移能力、基质粘附能力及凋亡无明显影响。
结论:RNAi技术是一种强有力的研究基因功能的方法。抑制FXR1基因的表达可轻度抑制A2780细胞的生长、明显抑制细胞增殖。
EOC is the most lethal gynecological malignancy.Unfortunately,the majority of EOCs remain clinically undetected until patients have developed late stage disease and only a mere 25%of cancers are detected as stageⅠdisease.Once stageⅢandⅣovarian cancer,which is define by peritoneal and extra peritoneal metastatic spread,is diognosed,the survival decreases from 95%at stageⅠto approximately 20～25%.Therefor,clinical outcome and possibly survival may be significantly improved by the identification of stageⅠdisease. Nevertheless,there are not efficient methods or biomarkers that could bc used to detected ovarian cancer at early stage.SEREX provides a new way to screening caner antigens. Autoantibody against cancer antigen may be a new biomarker in detecting cancer.Currently, majority study focus on IgG autoantibody.There is rarely report about IgM autoantibody.We performed heterological sero-immunoscreening of 10 EOC associated antigen clones from ascites EOC cells cDNA library.Six clone(TM4SF1、C1D、TIZ、OV-142、FXR1、OV-189) which positive ratio in ovarian cancer is significantly higher than in cancer-free were sequenced and bioinformatics analyzed.The expression pattern of these 6 EOC associated antigens in EOC tissues were evaluated by RT-PCR.We constructed and expressed these 6 recombinant fusion antigen proteins in Escherichia coli.Antigen proteins were purified by Ni-NTA His-Bind Resins and electroeluting.We developed and optimized a novel enzyme immunoassay method(indirect ELISA)to measure IgG、IgM autoantibodies against EOC associated antigens in serum and evaluated the clinical value of autoantibody spectrum in detecting ovarian cancer.The biological function of FXR1 in EOC cell line was studied by upregulated and downregulated(RNAi)FXR1 expression.
Part 1:Heterological sero-immunoscreening of EOC associated antigen and bioinformatics analysis
Objective:The goal of the study was to investigate the reaction of EOC associated antigens with IgG、IgM autoantibody in serum from patients with ovarian cancer and healthy women.The antigen clones which postive ratio in serum from cancer were significantly higher than in serum from healthy women were sequenced and bioinformatics analyzed.
Methods:Serological mini-arrays of recombinant tumor antigens(SMARTA)was used to investigate the reaction of 10 EOC associated antigen clones with IgG、IgM autoantibodies in serum from 62 patients with ovarian cancer and 62 healthy women.The postive clones were sequenced and bioinformatics analyzed in NCBI.
Results:The positive ratio of Six clone(OV-59、84、106、142、178、189)reacted with IgG、IgM autoantibodies in patients(12.9%～27.4%)was significantly higher than control(1.6%～11.3%).After sequenced and analyzed,results showed that 4 of 6 clone were known genes.OV-159(TM4SF1):The protein encoded by this gene is a member of the transmembrane 4 superfamily,also known as the tetraspanin family characterized by the presence of four hydrophobic domains.TM4SF1 protein mediate signal transduction events that play a role in the regulation of cell development,activation,growth and motility. TM4SF1 is a cell surface antigen and is highly expressed in different carcinomas and is a target for antibody-mediated therapy.OV-84(C1D):The protein encoded by this gene is a conserved DNA binding and apoptosis-inducing protein and a major autoantigen in patients with the PM-scleroderma overlap syndrome.OV-178(FXR1):The protein encoded by this gene is an RNA binding protein.FXR1 protein shuttle between the nucleus and cytoplasm and associate with polyribosomes and have cell-growth-dependent translation activation.FXR1 protein may be a autoantigen in patient with scleroderma.FXR1 gene is most frequently overexpressed in the center of the amplified domain(3q26-27)in squamous cell carcinomas of lung.OV-106(TIZ):The novel zinc finger protein TIZ may play a role during osteoclast differentiation by modulating TRAF6 signaling activity.OV-142 has highly homology with BARD1 and is a splice variant of BARD1.OV-142 presume protein maybe has MHC-Ⅰbinding peptide and is maybe a potential immumotherapy target of ovarian cancer.OV-189 is a new gene has no homology sequence in genbank.We preliminarily presume that OV-189 is a new member of L1 family that is one class of LINE. OV-189 presume protein maybe has MHC-Ⅰbinding peptide and is maybe a potential immumotherapy target of ovarian cancer.
Conclusion:Our date show EOC associated antigen not only elicit humoral immunity mediated by IgG,also induce specific IgM autoantibody in ovarian cancer patients.The high positive ratio of autoantibody against EOC associated antigen in serum from patients with ovarian cancer indicates that these autoantibodis are potent biomarker in detection ovarian cancer.
Part 2:Evaluating the expression pattern of EOC associated antigen genes in ovarian cancer tissues by RT-PCR
Objective:The goal of the study was to evaluate the expression pattern of EOC associated antigen genes in ovarian cancer tissues.
Methods:The relatived expression level of 6 EOC associated antigen genes were assayed in 36 ovarian cancer tissues,15 ovarian benign tumor tussues,13 normal ovarian tussues by semiquantitative RT-PCR.
Results:All of 6 EOC associated antigen genes almost expressed in all specimens.But the relative expression level of 6 genes in EOC tissues were higher than in benign tissues and normal ovarian tissues.The expression trends of 6 genes were grouped into three classes:1) The expression level of genes in EOC tissues was significantly higher than in normal ovarian tissues and slightly higher than in benign tissues.The expression level of genes in benign tissues was moderately higher than in normal ovarian tissues.For example:TIZ、C1D、TM4SF1、OV-142;2)The expression level of genes in EOC tissues was significantly higher than in normal ovarian tissues and benign tissues.The expression level of genes in benign tissues and normal ovarian tissues was equivalent.For example OV-189;3)The expression level of genes in EOC tissues was significantly higher than in normal ovarian tissues and benign tissues.The expression level of genes in benign tissues was significantly higher than in normal ovarian tissues.The expression level of genes in advanced EOC tissues was significantly higher than in early stage EOC tissues.The expression level of genes in high grade(2-3)EOC tissues was significantly higher than in low grade EOC tissues For example FXR1.
Conclusion:Our data demonstrated that 6 EOC associated antigen genes were associated with EOC.
Part 3:Expression and purification of recombination associated antigens of EOC
Objective:The goal of the study was to express and purify recombination associated antigens of ECO.
Methods:CDSes of ECO associated antigen genes were amplified by PCR.Products of PCR were digested with corresponding restriction endonuclease and subcloned into pET-30b(+).Recombination plasmids were identified by restriction endonuclease analysis and DNA sequencing.Positive plasmids were transformed into E.coli BL21(DE3)for expression under induction with IPTG.Recombination fusion proteins were purified by Ni-NTA His-Bind Resins and electroeluting.Products of purification were refolded and then identified by SDS-PAGE and Western blot.
Results:We successfully constructed the recombination plasmids of EOC associated antigen genes and expressed the recombination fusion proteins in pET-30b(+)system.The results showed that 6 recombination antigen proteins with purity over 90%and concentration from 0.3 mg/ml to 0.8mg/ml were obtained.The recombinant antigen proteins were activity and can be used for following study.
Part 4:Study on autoantibody spectrum against EOC associated antigens
Objective:The objective of this study was to evaluate the clinical value of autoantibody spectrum in detecting ovarian cancer.
Methods:We developed and optimized a novel enzyme immunoassay method(indirect ELISA)to measure IgG、IgM autoantibodies against EOC associated antigens in serum. Circulating autoantibodies were measured in serum from 150 patients with ovarian cancer (126 prior treatment,24 post-treatment),42 patients with benign ovarian masses,142 healthy women,20 female patients with breast cancer,20 female patients with esophageal cancer,20 female patients with lung cancer.Cut off value of IgG、IgM autoantibodies were determined by ROC curve.CA125 was measured in serum by IRMA.We evaluated the clinical value of autoantibody in detecting ovarian cancer alone,combining multiple autoantibody (autoantibody spectrum),combining multiple autoantibody with CA125.
Results:Our data indicated that serum contains IgG、IgM autoantibodies against EOC associated antigens.The positive ratio of IgG autoantibodies in serum from ovarian cancer patients and cancer-free patients were 34.1%～47.6%and 13.0%～17.9%,respectively.The positive ratio of IgM autoantibodies in serum from ovarian cancer patients and cancer-free patients were 39.7%～53.2%and 12.0%～33.2%,respectively.There was not significantly clinical utility when individual autoantibodies analyzed separately.The positive ratio of IgM autoantibodies against C1D、TIZ、FXR1、OV-189 in early ovarian cancer were significantly higher than in advanced ovarian cancer.Combining five autoantibodies(TM4SF1 IgG、C1D IgG、TIZ IgG、TIZ IgM、FXR1 IgG、FXR1 IgM)showed significantly improved sensitivity (75.4%)、lower specificity(78.2%)and similar accuracy(76.5%)in detecting ovarian cancer compared to those of CA125(61.1%,89.1%,77.7%).But the autoantibody spectrum showed significantly improved sensitivity in classifying early stage(76.6%),especially stageⅠ(83.3%) ovarian cancer compared to those of CA125(51.1%,44.4%).The positive ratio of the autoantibody spectrum wsa significantly lower in 24 post-treatment serum(37.5%)compared to the pairing prior treatment serum(70.8%).The positive ratio of the autoantibody spectrum in serum from breast cancer,esophageal cancer and lung cancer were 30%,20%,25%, respectively.Combining five autoantibodies(TM4SF1 IgG、TM4SF1 IgM、C1D IgG、TIZ IgM、FXR1 IgG)with CA125 showed significantly improved sensitivity(86%),specificity (91%)and accuracy(88.7%)in detecting ovarian cancer compared to those of CA125(61.1%, 89.1%,77.7%).
Conclusion:Our data indicated that serum contained IgG、IgM autoantibodies against EOC associated antigens.The autoantibody spectrum(TM4SF1 IgG、C1D IgG、TIZ IgG、TIZ IgM、FXR1 IgG、FXR1 IgM)was associated with ovarian cancer with significantly improved sensitivity,lower specificity and similar accuracy in detecting ovarian cancer compared to those of CA125.This autoantibody spectrum showed significantly higher sensitivity in classifying early stage,especially stageⅠovarian cancer than CA125 alone. Combining five autoantibodies(TM4SF1 IgG、TM4SF1 IgM、C1D IgG、TIZ IgM、FXR1 IgG)with CA125 showed significantly higher sensitivity,specificity and accuracy than CA125 alone.The autoantibody spectrum was a potent biomarker in detecting EOC.
Part 5:Preliminary study of the biological behaviour change of EOC cell line HO8910 by upregulated FXR1 expression
Objective:The goal of this study was to investigate the biological behaviour change of EOC cells HO8910 by upregulated FXR1 expression.
Methods:FXR1 CDS was amplified by RT-PCR.The PCR product was digested with corresponding restriction enzymes and subcloned into PCDNA3.1 plasmid.HO8910 cells transfected with PCDNA3.1/FXR1 or PCDNA3.1 were selected in G418 to generate HO8910/ PCDNA3.1/FXR1 and HO8910/PCDNA3.1.Cells growth curve,clone formation assay,adhesion assay,vitro migration and ivasion assay,flow cytometric assay for cells cycle and apoptotic were examined.
Results:We successfully constructed recombinant PCDNA3.1/FXR1 plasmid.The stable transfection strains of HO8910 transfected with PCDNA3.1/FXR1 or PCDNA3.1 were obtained in G418 and identified by RT-PCR and Western blot.Cell growth curve showed upregulated FXR1 expression in HO8910 significantly increased their energy for growth. Clone formation assay showed upregulated FXR1 expression in HO8910 significantly increased cells proliferation.Upregulated FXR1 expression in HO8910 significantly increased cells adhesion and did not affect vitro migration,invasion.Flow cytometric assay showed that upregulated FXR1 expression in HO8910 decreased percentage(67.1%)of G1 phase cells compared with negtive control(80%)and did not affect cells apoptotic.
Conclusion:Upregulated FXR1 expression in HO8910 significantly increased cells energy for growth,proliferation and adhesion.
Part 6:Preliminary study of the biological behaviour change of EOC cell line A2780 by RNAi FXR1 expression
Objective:The goal of this study was to investigate the biological behaviour change of EOC cell line by RNAi FXR1 expression.
Methods:Three paires siRNAs targeting FXR1 were designed and Synthesised.The highest inhibition efficient siRNA was selected by transient transfection and subcloned into siRNA expression vector PGPU6/GFP/Neo.A2780 cells transfected with positive siRNA expression vector and negtive control were selected in G418 for stable transfection strains. Cell growth curve,clone formation assay,adhesion assay,vitro migration and ivasion assay, flow cytometric assay for cells cycle and apoptotic were examined.
Results:The inhibition ratio of siRNA subcloned into PGPU6/GFP/Neo is 80%.The stable transfection strains of A2780 transfected with siRNA expression vector PGPU6/GFP/Neo were obtained in G418.The highest inhibition ratio of the stable transfection strains is 60%.Downregulated FXR1 expression in A2780 mild decreased their energy for growth and significantly decreased their energy for clone formation. Downregulated FXR1 expression in A2780 did not affect the migration,invasion and adhesion.Flow cytometric assay showed that downregulated FXR1 expression on A2780 increased percentage(49.2%)of G1 phase cells compared with negtive control(40%)and did not affect cells apoptotic.
Conclusion:Downregulated FXR1 expression in A2780 mild decreased cells energy for growth and significantly decreased cells proliferation and did not affact adhesion.
第一部分卵巢上皮癌相关抗原异体血清筛选及生物学信息分析
目的:检测候选卵巢上皮癌相关抗原克隆与卵巢癌、正常对照血清中相应IgG、IgM型自身抗体反应情况,并对阳性反应率差异显著的抗原克隆进行测序及生物信息学分析。
方法:用SMARTA法对10个候选卵巢上皮癌相关抗原克隆与62例卵巢癌、62例正常对照血清中IgG、IgM型自身抗体反应情况进行定性检测,从中选出在癌血清中抗体阳性反应率与正常对照血清相比差异显著的抗原克隆,进行核苷酸测序,在相关网站上进行生物信息学分析。
结果:其中6个抗原克隆与卵巢癌血清中自身抗体阳性反应率显著高于正常对照血清,在癌血清中的阳性率为12.9%～27.4%,在正常血清中的阳性率为1.6%～11.3%,其中IgM型自身抗体的阳性率为19.4%～27.4%。对这6个抗原克隆进行核苷酸测序,经比对分析发现这6个抗原克隆其中4个是已知基因(TM4SF1、C1D、TIZ、FXR1),一个是与卵巢癌相关基因高度相似的基因(OV-142),一个是Genbank中无相似序列的新基因(OV-189)。TM4SF1蛋白是一种有四个疏水跨膜区的细胞表面蛋白,该蛋白在对调节细胞生长、活化、迁移的信号转换中起媒介作用,在肺癌、结肠癌、乳腺癌、卵巢上皮性癌等上皮细胞恶性肿瘤中高表达,是一种细胞表面抗原,可作为抗体免疫治疗的靶向。C1D基因编码的是一个保守的DNA绑定蛋白,C1D蛋白是一个隐藏的凋亡激活剂,是多发性肌炎硬皮病重叠综合征的自身抗原。FXR1蛋白是一种RNA绑定蛋白,可在在核与胞浆间穿梭,与多聚核糖体有关,具有细胞生长依赖的翻译活性功能,有可能是硬皮病的一种自身抗原,并且在肺鳞状细胞癌中检测到FXR1基因的过表达。TIZ是一个锌指蛋白,通过调节肿瘤坏死因子受体相关因子6(TRAF6)的信号活性,在破骨细胞分化过程中起一定作用。尚未见有C1D、TIZ、FXR1与卵巢癌相关的报导。其中OV-142有可能是BARD1基因的剪切变异体,可能有MHC-Ⅰ类抗原表位肽,可能成为卵巢癌免疫治疗的新靶点。初步认为OV-189是LINE中有转录活性的一种—L1家族中的一个新成员,可能有MHC-Ⅰ类抗原表位肽,有可能成为卵巢癌免疫治疗的靶点。
结论:我们的研究显示卵巢上皮癌相关抗原不仅能够介导IgG体液免疫反应而且能够诱导机体产生特异性的IgM自身抗体,这些抗原克隆在异体癌血清中较高的抗体阳性反应率,提示这些抗原的自身抗体有可能成为卵巢癌诊断的血清标志物。这些抗原基因有进一步研究的价值。
第二部分RT-PCR检测卵巢上皮癌相关抗原基因在卵巢癌组织中的相对表达水平
目的:检测卵巢上皮癌相关抗原基因在卵巢癌、良性卵巢肿瘤、正常卵巢组织中的相对表达水平。
方法:用RT-PCR方法检测上述6个卵巢上皮癌相关抗原基因在36例卵巢癌、15例良性卵巢肿瘤及13例正常卵巢组织中的相对表达水平。
结果:这6个抗原基因在癌、良性肿瘤、正常卵巢组织中几乎都有表达,只是在癌组织中的表达水平明显高于良性肿瘤及正常卵巢组织。显示出三种表达趋势:一类是癌组织中的表达水平显著高于正常卵巢组织,而良性肿瘤组织中的表达水平高于正常组织,癌组织中的表达水平稍高于良性肿瘤组织(TIZ、C1D、TM4SF1、OV-142);一类是癌组织中的表达水平显著高于良性肿瘤及正常卵巢组织,而良性与正常组织中表达相当(OV-189);一类是癌组织中的表达水平明显高于良性,癌与良性肿瘤组织中的表达水平均显著高于正常组织,且晚期癌组织中表达水平显著高于早期,分化差的组织表达水平显著高于分化好的(FXR1)。
结论:我们在mRNA水平证实这6个卵巢上皮癌SEREX抗原基因均与癌组织有很好的相关性。
第三部分卵巢上皮癌相关抗原蛋白的表达、纯化
目的:在原核表达系统中构建、表达、纯化这6个抗原蛋白。
方法:用RT-PCR克隆这些抗原基因的CDS,在pET-30b(+)系统中构建原核表达质粒,经IPTG诱导在大肠杆菌中表达重组融合蛋白,采用Ni-NTA His-Bind Resins和SDS-PAGE制备胶电洗脱进行纯化,复性、浓缩得到有活性的目的蛋白。
结论:成功构建、表达、纯化了这6个抗原蛋白,得到浓度在0.3～0.8mg/ml之间,纯度都在90%以上、有活性的重组融合抗原蛋白。
第四部分卵巢癌上皮癌相关抗原自身抗体谱的研究
目的:用自己制备的抗原蛋白建立间接ELISA法,检测这些卵巢上皮癌相关抗原在血清中相应自身抗体的相对含量,并分析它们的临床价值。
方法:建立间接ELISA法,检测126例治疗前、24例治疗后卵巢癌、42例良性卵巢肿瘤、20例乳腺癌、20例食管癌、20例肺癌癌患者、142例正常女性对照血清中卵巢上皮癌相关抗原IgG、IgM型自身抗体的相对含量。绘制ROC曲线,确定cut off值,单独或用Logistic回归分析法联合分析这些自身抗体/抗体谱的临床价值。同时测量CA125的含量,比较自身抗体谱与CA125在卵巢癌诊断上的效能。
结果:分析单个自身抗体时,卵巢癌血清中这些抗原IgG型自身抗体反应的阳性率为34.1%～47.6%,非癌患者的阳性率为13.0%～17.9%;癌血清中IgM型自身抗体反应的阳性率为39.7%～53.2%,非癌患者的阳性率为12.0%～33.2%,分析单个卵巢癌相关抗原自身抗体在卵巢癌诊断时意义均不大,但TIZ、FXR1、OV-189抗原IgM型自身抗体在早期病人中的阳性率均高于晚期病人,两者相比较差异有统计学意义。当联合多个自身抗体(抗体谱):TM4SF1 IgG、C1D IgG、TIZ IgG、TIZ IgM、FXR1 IgG、FXR1 IgM分析时敏感为75.4%,特异性为78.2%,准确性为76.5%,与单独分析CA125相比较敏感性明显提高(61.1%),特异性降低(89.1%),准确性相当(77.7%),但该自身抗体谱在早期(76.6%versus 51.1%)尤其是Ⅰ期(83.3%versus 44.4%)卵巢癌诊断的敏感性显著高于CA125,差异有统计学意义。将多个卵巢癌相关抗原自身抗体(TM4SF1 IgG、TM4SF1 IgM、C1D IgG、TIZ IgM、FXR1 IgG)与CA125联合分析时,诊断卵巢癌的敏感性为86%,特异性为91%,准确率为88.7%,与CA125相比,在敏感性、特异性、准确性均提高,阳性预测值、阳性似然比、阴性预测值明显提高,阴性似然明显降低;并且与CA125联合后在上皮性癌(包括浆液、粘液性癌)的诊断敏感性显著高于CA125,统计学上差异有显著性;同时对于早期、晚期卵巢癌的诊断敏感性亦显著高于CA125,统计学上差异有显著性。比较了配对的24例卵巢癌患者治疗前后卵巢癌自身抗体谱变化情况,结果显示治疗后自身抗体谱的阳性率显著低于治疗前。乳腺癌、食管癌、肺癌血清的检测,结果发现卵巢癌自身抗体谱的阳性率分别为30%、20%、25%。
结论:卵巢癌患者血清中存在IgG型、IgM型肿瘤自身抗体,并且可用于卵巢癌早期诊断。联合多个卵巢癌肿瘤自身抗体可达到与CA125相当的诊断效果,且该自身抗体谱在早期特别是Ⅰ期卵巢癌的诊断上优于CA125。将多个自身抗体与CA125联合可显著提高卵巢癌的诊断效能。卵巢上皮癌相关抗原自身抗体谱对疗效也有一定的监测作用。
第五部分真核转染上调FXR1基因表达对卵巢癌细胞生物学行为影响的初步研究
目的:了解上调FXR1基因表达对卵巢癌细胞系H08910生物学行为的影响。
方法:RT-PCR扩增FXR1 CDS,构建FXR1真核表达载体,脂质体介导下转染H08910细胞,经G418筛选获得稳定转染株,检测转染后细胞相应生物学行为。
结果:成功构建了FXR1基因的真核表达载体,并稳定转染了H08910细胞。生长曲线显示上调FXR1基因表达可促进细胞的生长;克隆形成实验显示上调FXR1基因表达可促进细胞增殖,基质粘附实验显示上调FXR1基因表达可加强细胞对基质的粘附能力,流式细胞周期检测亦发现与对照(80%)相比,转染FXR1基因后G1期细胞(67.1%)比例明显减少,这说明转染FXR1后细胞的增殖更旺盛。同时发现FXR1对细胞侵袭、迁移的能力无明显影响。凋亡检测虽提示转染FXR1基因后早期凋亡细胞的比例较对照增多,但总的凋亡细胞比例太少仅0.31%,意义可能不大。
结论:真核载体稳定转染技术是一种可靠、行之有效的研究基因功能的方法。上调FXR1基因表达可能有促进卵巢癌细胞的生长、增殖、加强细胞对基质粘附能力的作用。
第六部分RNA干扰FXR1基因对卵巢癌细胞系生物学行业影响的初步研究
目的:了解抑制FXR1基因表达对卵巢癌细胞系A2780生物学行为的影响。
方法:设计、合成、筛选有效的FXR1基因siRNA,将有效siRNA商业化构建siRNA表达载体,脂质体介导下转染A2780细胞,经G418筛选获得稳定转染株,检测转染后细胞相应生物学行为。
结果:设计并成功筛选出了抑制效率达80%的FXR1基因siRNA,将商业构建的siRNA表达载体成功稳定转染了A2780细胞,抑制效率约60%。细胞生长曲线显示出下调FXR1表达可轻度抑制细胞的生长;克隆形成实验结果显示,下调FXR1基因的表达对A2780细胞的增殖能力有的抑制作用;流式细胞周期分析发现下调FXR1基因的表达G1期细胞比例为49.2%多于转染阴性对照组(40%),S期与G2期比对照比例稍少,提示抑制FXR1基因的表达可延缓细胞增殖;同时发现下调FXR1基因的表达对A2780细胞体外侵袭、迁移能力、基质粘附能力及凋亡无明显影响。
结论:RNAi技术是一种强有力的研究基因功能的方法。抑制FXR1基因的表达可轻度抑制A2780细胞的生长、明显抑制细胞增殖。
EOC is the most lethal gynecological malignancy.Unfortunately,the majority of EOCs remain clinically undetected until patients have developed late stage disease and only a mere 25%of cancers are detected as stageⅠdisease.Once stageⅢandⅣovarian cancer,which is define by peritoneal and extra peritoneal metastatic spread,is diognosed,the survival decreases from 95%at stageⅠto approximately 20～25%.Therefor,clinical outcome and possibly survival may be significantly improved by the identification of stageⅠdisease. Nevertheless,there are not efficient methods or biomarkers that could bc used to detected ovarian cancer at early stage.SEREX provides a new way to screening caner antigens. Autoantibody against cancer antigen may be a new biomarker in detecting cancer.Currently, majority study focus on IgG autoantibody.There is rarely report about IgM autoantibody.We performed heterological sero-immunoscreening of 10 EOC associated antigen clones from ascites EOC cells cDNA library.Six clone(TM4SF1、C1D、TIZ、OV-142、FXR1、OV-189) which positive ratio in ovarian cancer is significantly higher than in cancer-free were sequenced and bioinformatics analyzed.The expression pattern of these 6 EOC associated antigens in EOC tissues were evaluated by RT-PCR.We constructed and expressed these 6 recombinant fusion antigen proteins in Escherichia coli.Antigen proteins were purified by Ni-NTA His-Bind Resins and electroeluting.We developed and optimized a novel enzyme immunoassay method(indirect ELISA)to measure IgG、IgM autoantibodies against EOC associated antigens in serum and evaluated the clinical value of autoantibody spectrum in detecting ovarian cancer.The biological function of FXR1 in EOC cell line was studied by upregulated and downregulated(RNAi)FXR1 expression.
Part 1:Heterological sero-immunoscreening of EOC associated antigen and bioinformatics analysis
Objective:The goal of the study was to investigate the reaction of EOC associated antigens with IgG、IgM autoantibody in serum from patients with ovarian cancer and healthy women.The antigen clones which postive ratio in serum from cancer were significantly higher than in serum from healthy women were sequenced and bioinformatics analyzed.
Methods:Serological mini-arrays of recombinant tumor antigens(SMARTA)was used to investigate the reaction of 10 EOC associated antigen clones with IgG、IgM autoantibodies in serum from 62 patients with ovarian cancer and 62 healthy women.The postive clones were sequenced and bioinformatics analyzed in NCBI.
Results:The positive ratio of Six clone(OV-59、84、106、142、178、189)reacted with IgG、IgM autoantibodies in patients(12.9%～27.4%)was significantly higher than control(1.6%～11.3%).After sequenced and analyzed,results showed that 4 of 6 clone were known genes.OV-159(TM4SF1):The protein encoded by this gene is a member of the transmembrane 4 superfamily,also known as the tetraspanin family characterized by the presence of four hydrophobic domains.TM4SF1 protein mediate signal transduction events that play a role in the regulation of cell development,activation,growth and motility. TM4SF1 is a cell surface antigen and is highly expressed in different carcinomas and is a target for antibody-mediated therapy.OV-84(C1D):The protein encoded by this gene is a conserved DNA binding and apoptosis-inducing protein and a major autoantigen in patients with the PM-scleroderma overlap syndrome.OV-178(FXR1):The protein encoded by this gene is an RNA binding protein.FXR1 protein shuttle between the nucleus and cytoplasm and associate with polyribosomes and have cell-growth-dependent translation activation.FXR1 protein may be a autoantigen in patient with scleroderma.FXR1 gene is most frequently overexpressed in the center of the amplified domain(3q26-27)in squamous cell carcinomas of lung.OV-106(TIZ):The novel zinc finger protein TIZ may play a role during osteoclast differentiation by modulating TRAF6 signaling activity.OV-142 has highly homology with BARD1 and is a splice variant of BARD1.OV-142 presume protein maybe has MHC-Ⅰbinding peptide and is maybe a potential immumotherapy target of ovarian cancer.OV-189 is a new gene has no homology sequence in genbank.We preliminarily presume that OV-189 is a new member of L1 family that is one class of LINE. OV-189 presume protein maybe has MHC-Ⅰbinding peptide and is maybe a potential immumotherapy target of ovarian cancer.
Conclusion:Our date show EOC associated antigen not only elicit humoral immunity mediated by IgG,also induce specific IgM autoantibody in ovarian cancer patients.The high positive ratio of autoantibody against EOC associated antigen in serum from patients with ovarian cancer indicates that these autoantibodis are potent biomarker in detection ovarian cancer.
Part 2:Evaluating the expression pattern of EOC associated antigen genes in ovarian cancer tissues by RT-PCR
Objective:The goal of the study was to evaluate the expression pattern of EOC associated antigen genes in ovarian cancer tissues.
Methods:The relatived expression level of 6 EOC associated antigen genes were assayed in 36 ovarian cancer tissues,15 ovarian benign tumor tussues,13 normal ovarian tussues by semiquantitative RT-PCR.
Results:All of 6 EOC associated antigen genes almost expressed in all specimens.But the relative expression level of 6 genes in EOC tissues were higher than in benign tissues and normal ovarian tissues.The expression trends of 6 genes were grouped into three classes:1) The expression level of genes in EOC tissues was significantly higher than in normal ovarian tissues and slightly higher than in benign tissues.The expression level of genes in benign tissues was moderately higher than in normal ovarian tissues.For example:TIZ、C1D、TM4SF1、OV-142;2)The expression level of genes in EOC tissues was significantly higher than in normal ovarian tissues and benign tissues.The expression level of genes in benign tissues and normal ovarian tissues was equivalent.For example OV-189;3)The expression level of genes in EOC tissues was significantly higher than in normal ovarian tissues and benign tissues.The expression level of genes in benign tissues was significantly higher than in normal ovarian tissues.The expression level of genes in advanced EOC tissues was significantly higher than in early stage EOC tissues.The expression level of genes in high grade(2-3)EOC tissues was significantly higher than in low grade EOC tissues For example FXR1.
Conclusion:Our data demonstrated that 6 EOC associated antigen genes were associated with EOC.
Part 3:Expression and purification of recombination associated antigens of EOC
Objective:The goal of the study was to express and purify recombination associated antigens of ECO.
Methods:CDSes of ECO associated antigen genes were amplified by PCR.Products of PCR were digested with corresponding restriction endonuclease and subcloned into pET-30b(+).Recombination plasmids were identified by restriction endonuclease analysis and DNA sequencing.Positive plasmids were transformed into E.coli BL21(DE3)for expression under induction with IPTG.Recombination fusion proteins were purified by Ni-NTA His-Bind Resins and electroeluting.Products of purification were refolded and then identified by SDS-PAGE and Western blot.
Results:We successfully constructed the recombination plasmids of EOC associated antigen genes and expressed the recombination fusion proteins in pET-30b(+)system.The results showed that 6 recombination antigen proteins with purity over 90%and concentration from 0.3 mg/ml to 0.8mg/ml were obtained.The recombinant antigen proteins were activity and can be used for following study.
Part 4:Study on autoantibody spectrum against EOC associated antigens
Objective:The objective of this study was to evaluate the clinical value of autoantibody spectrum in detecting ovarian cancer.
Methods:We developed and optimized a novel enzyme immunoassay method(indirect ELISA)to measure IgG、IgM autoantibodies against EOC associated antigens in serum. Circulating autoantibodies were measured in serum from 150 patients with ovarian cancer (126 prior treatment,24 post-treatment),42 patients with benign ovarian masses,142 healthy women,20 female patients with breast cancer,20 female patients with esophageal cancer,20 female patients with lung cancer.Cut off value of IgG、IgM autoantibodies were determined by ROC curve.CA125 was measured in serum by IRMA.We evaluated the clinical value of autoantibody in detecting ovarian cancer alone,combining multiple autoantibody (autoantibody spectrum),combining multiple autoantibody with CA125.
Results:Our data indicated that serum contains IgG、IgM autoantibodies against EOC associated antigens.The positive ratio of IgG autoantibodies in serum from ovarian cancer patients and cancer-free patients were 34.1%～47.6%and 13.0%～17.9%,respectively.The positive ratio of IgM autoantibodies in serum from ovarian cancer patients and cancer-free patients were 39.7%～53.2%and 12.0%～33.2%,respectively.There was not significantly clinical utility when individual autoantibodies analyzed separately.The positive ratio of IgM autoantibodies against C1D、TIZ、FXR1、OV-189 in early ovarian cancer were significantly higher than in advanced ovarian cancer.Combining five autoantibodies(TM4SF1 IgG、C1D IgG、TIZ IgG、TIZ IgM、FXR1 IgG、FXR1 IgM)showed significantly improved sensitivity (75.4%)、lower specificity(78.2%)and similar accuracy(76.5%)in detecting ovarian cancer compared to those of CA125(61.1%,89.1%,77.7%).But the autoantibody spectrum showed significantly improved sensitivity in classifying early stage(76.6%),especially stageⅠ(83.3%) ovarian cancer compared to those of CA125(51.1%,44.4%).The positive ratio of the autoantibody spectrum wsa significantly lower in 24 post-treatment serum(37.5%)compared to the pairing prior treatment serum(70.8%).The positive ratio of the autoantibody spectrum in serum from breast cancer,esophageal cancer and lung cancer were 30%,20%,25%, respectively.Combining five autoantibodies(TM4SF1 IgG、TM4SF1 IgM、C1D IgG、TIZ IgM、FXR1 IgG)with CA125 showed significantly improved sensitivity(86%),specificity (91%)and accuracy(88.7%)in detecting ovarian cancer compared to those of CA125(61.1%, 89.1%,77.7%).
Conclusion:Our data indicated that serum contained IgG、IgM autoantibodies against EOC associated antigens.The autoantibody spectrum(TM4SF1 IgG、C1D IgG、TIZ IgG、TIZ IgM、FXR1 IgG、FXR1 IgM)was associated with ovarian cancer with significantly improved sensitivity,lower specificity and similar accuracy in detecting ovarian cancer compared to those of CA125.This autoantibody spectrum showed significantly higher sensitivity in classifying early stage,especially stageⅠovarian cancer than CA125 alone. Combining five autoantibodies(TM4SF1 IgG、TM4SF1 IgM、C1D IgG、TIZ IgM、FXR1 IgG)with CA125 showed significantly higher sensitivity,specificity and accuracy than CA125 alone.The autoantibody spectrum was a potent biomarker in detecting EOC.
Part 5:Preliminary study of the biological behaviour change of EOC cell line HO8910 by upregulated FXR1 expression
Objective:The goal of this study was to investigate the biological behaviour change of EOC cells HO8910 by upregulated FXR1 expression.
Methods:FXR1 CDS was amplified by RT-PCR.The PCR product was digested with corresponding restriction enzymes and subcloned into PCDNA3.1 plasmid.HO8910 cells transfected with PCDNA3.1/FXR1 or PCDNA3.1 were selected in G418 to generate HO8910/ PCDNA3.1/FXR1 and HO8910/PCDNA3.1.Cells growth curve,clone formation assay,adhesion assay,vitro migration and ivasion assay,flow cytometric assay for cells cycle and apoptotic were examined.
Results:We successfully constructed recombinant PCDNA3.1/FXR1 plasmid.The stable transfection strains of HO8910 transfected with PCDNA3.1/FXR1 or PCDNA3.1 were obtained in G418 and identified by RT-PCR and Western blot.Cell growth curve showed upregulated FXR1 expression in HO8910 significantly increased their energy for growth. Clone formation assay showed upregulated FXR1 expression in HO8910 significantly increased cells proliferation.Upregulated FXR1 expression in HO8910 significantly increased cells adhesion and did not affect vitro migration,invasion.Flow cytometric assay showed that upregulated FXR1 expression in HO8910 decreased percentage(67.1%)of G1 phase cells compared with negtive control(80%)and did not affect cells apoptotic.
Conclusion:Upregulated FXR1 expression in HO8910 significantly increased cells energy for growth,proliferation and adhesion.
Part 6:Preliminary study of the biological behaviour change of EOC cell line A2780 by RNAi FXR1 expression
Objective:The goal of this study was to investigate the biological behaviour change of EOC cell line by RNAi FXR1 expression.
Methods:Three paires siRNAs targeting FXR1 were designed and Synthesised.The highest inhibition efficient siRNA was selected by transient transfection and subcloned into siRNA expression vector PGPU6/GFP/Neo.A2780 cells transfected with positive siRNA expression vector and negtive control were selected in G418 for stable transfection strains. Cell growth curve,clone formation assay,adhesion assay,vitro migration and ivasion assay, flow cytometric assay for cells cycle and apoptotic were examined.
Results:The inhibition ratio of siRNA subcloned into PGPU6/GFP/Neo is 80%.The stable transfection strains of A2780 transfected with siRNA expression vector PGPU6/GFP/Neo were obtained in G418.The highest inhibition ratio of the stable transfection strains is 60%.Downregulated FXR1 expression in A2780 mild decreased their energy for growth and significantly decreased their energy for clone formation. Downregulated FXR1 expression in A2780 did not affect the migration,invasion and adhesion.Flow cytometric assay showed that downregulated FXR1 expression on A2780 increased percentage(49.2%)of G1 phase cells compared with negtive control(40%)and did not affect cells apoptotic.
Conclusion:Downregulated FXR1 expression in A2780 mild decreased cells energy for growth and significantly decreased cells proliferation and did not affact adhesion.
引文
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