RNA激活介导E-钙粘蛋白上调表达的抗肿瘤作用及其机制的研究
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摘要
第一部分小激活RNA的设计与筛选
目的基于小激活RNAs (saRNAs)的肿瘤治疗策略,为p12、p27、p57三个抑癌基因筛选出具有激活功能并相对高效的候选saRNAs分子。方法利用国外文献提供的saRNA设计规则,为每个靶基因设计2～3对候选saRNA分子,对照组双链RNA设计成与人基因组序列非同源。将上述合成的候选saRNAs分子转染膀胱癌5637、T24细胞系或前列腺癌PC3、DU145细胞系,每一种细胞系均包括对照组(转染对照组saRNAs)和saRNAs组(转染候选saRNAs)。利用RT-PCR法检测转染后靶基因mRNA表达水平,根据靶基因表达水平筛选出功能性saRNAs,我们将“功能性saRNAs"定义为使靶基因mRNA表达量增加至少两倍(RT-PCR法)。
结果转染各候选saRNAs后各靶基因1mRNA的表达水平相对于对照组无明显增强,没有达到“功能性saRNAs"的标准。
结论saRNAs的筛选还比较困难,其设计规则有待进一步完善。
第二部分E-钙粘蛋白小激活RNA的抗肿瘤作用
目的评价已证实的E-钙粘蛋白(E-cadherin)小激活RNA (dsEcad-215)对膀胱癌5637细胞及前列腺癌PC3细胞的肿瘤抑制作用。
方法将与E-cadherin基因启动子DNA序列互补的双链RNA分子(dsEcad-215)分别转染入5637细胞和PC3细胞中,采用RT-PCR法及Western blotting法检测E-cadherin在mRNA及蛋白水平上的表达；采用Transwell小室法及划痕法检测dsEcad-215转染后肿瘤细胞侵袭、迁移能力的改变。
结果dsEcad-215转染5637细胞和PC3细胞72 h后E-cadherin表达显著上调,RNAa有效；5637细胞和PC3细胞对细胞外基质的侵袭能力及迁移能力也明显下降。
结论RNAa技术激活E-cadherin基因表达并抑制膀胱癌及前列腺癌细胞侵袭、转移等恶性行为,可作为恶性肿瘤基因治疗的一种有效手段。
第三部分小激活RNA上调E-钙粘蛋白表达的机制研究
目的探讨dsEcad-215上调E-cadherin基因表达的相关分子机制
方法采用基因特异性RT-PCR检测5637细胞E-cadherin启动子相关非编码正义或反义RNA的表达,以及dsEcad-215转染后其表达量的变化；利用染色质免疫共沉淀技术检测dsEcad-215转染后E-cadherin启动子区域相关组蛋白修饰状态的变化；采用RT-PCR法检测dsEcad-215作用后干扰素通路OAS1及OAS3基因表达的变化。
结果E-cadherin启动子区域存在非编码正义和反义RNA; dsEcad-215转染后E-cadherin启动子相关非编码反义和反义RNA的表达未发生明显变化,E-cadherin启动子区域组蛋白3赖氨酸9(H3K9)和组蛋白3赖氨酸4(H3K4)二甲基化的水平明显降低,干扰素通路中OAS1和OAS3基因的表达没有明显升高。
结论dsEcad-215转染5637细胞后并没有影响非编码正义和反义RNA的表达水平,而可能与其结合后改变其空间结构和功能从而影响组蛋白甲基化的修饰,如H3K9和H3K4两个位点二甲基化水平减弱而激活转录。dsEcad-215没有激活干扰素途径而诱发非特异性反应。
第四部分小激活RNA上调E-钙粘蛋白表达抑制肿瘤细胞侵袭及迁移的机制研究
目的探讨E-cadherin上调表达抑制肿瘤细胞侵袭、迁移的相关分子机制
方法利用Western blot检测Ecad-215转染后β-catenin蛋白在膀胱癌5637细胞及前列腺癌PC3细胞胞膜、胞浆及胞核中表达变化；利用细胞免疫荧光法进一步验证β-catenin蛋白在细胞内的重新分布；利用RT-PCR法检测mmp-7及cyclin D1基因mRNA的表达水平。
结果dsEcad-215转染5637及PC3细胞72h后,细胞质和胞核β-catenin蛋白表达水平降低,胞膜β-catenin蛋白表达水平升高,而总的蛋白表达水平不变；细胞免疫荧光实验进一步证实dsEcad-215作用后P-catenin蛋白从胞质、胞核重新分布于细胞膜上。mmp-7和cycylin D1基因mRNA表达水平降低。
结论dsEcad-215上调E-cadherin表达,引起β-catenin蛋白从胞核胞浆转移至胞膜,导致其靶基因转录活性降低,从而抑制肿瘤细胞侵袭。
Part 1 The design and screening of small activating RNA
Aim To screen the relatively efficient candidate small activating RNAs (saRNAs) molecules that can activate the target tumor-suppressor genes including p12, p27 and p57.
Materials and methods Based on the design rules provided by the foreign literature, we designed 2-3 pairs of small double-stranded RNA (dsRNA) for each target gene, and the control dsRNA is non-homologous to the whole human genome. The candidate dsRNAs were transfected into 5637 or T24 bladder cancer cell lines and PC3 or DU145 prostate cancer cell lines. The expression of target gene was determined with RT-PCR measuring the mRNA levels. The functional saRNA which defined as to increase target gene expression twice was selected.
Results All the candidate dsRNAs did not activate the target gene significantly and fulfill the standard of functional saRNAs.
Conclusion It is difficult to screen out the functional saRNAs and the design rules of saRNA should be revised.
Part 2 The antitumor effects of E-cadherin activation by saRNA
Aim To evaluate the antitumor effects of confirmed functional saRNA (dsEcad-215) on 5637 bladder cancer cells and PC3 prostate cancer cells.
Materials and methods dsEcad-215 which is complementary to the E-cadherin promoter was transfected into 5637 and PC3 cells for 72 h. The mRNA and protein expression levels of E-cadherin were determined with RT-PCR and Western blotting. The invasive and migrative ability of tumor cells were measured using Transwell chamber and scratch test.
Results The expression of E-cadherin increased after transfection of dsEcad-215, suggesting that the RNAa was effective. The invasive ability to extracellular matrix and migration capacity of 5637 and PC3 cells decreased significantly.
Conclusion Induction of E-cadherin expression by saRNA leads to suppression of migration and invasion of 5637 and PC3 cells in vitro.The RNAa could be used as an effective tool of gene therapy against cancer.
Part 3 The mechanism of up-regulation of E-cadherin by saRNA
Aim To explore the molecular mechanisms of up-regulation of E-cadherin by RNA activation.
Materials and methods The E-cadherin promoter-associated non-coding sense or antisense RNA was detected with gene-specific RT-PCR. The histone modification status of E-cadherin promoter region after dsEcad-215 transfection was determined with chromatin immunoprecipitation. Using RT-PCR assay, the OAS1 and OAS3 expression which involved in interferon pathway were measured.
Results Both promoter-associated non-coding sense and antisense RNAs were detected, and transfection of dsEcad-215 caused no change of expression. Chromatin immunoprecipitation demonstrated that loss of histone 3 dimethylation at lysine-9 and lysine-4 were associated with gene activation. dsEcad-215 did not induced the expression of OAS1 or OAS3.
Conclusion Transfection with dsEcad-215 in 5637 cells did not affect the non-coding sense and antisense RNA expression levels. dsEcad-215 may bind to the non-coding RNAs, and changed its spatial structure and function thus affecting the modification of histone methylation, such as loss of H3K9 and H3K4 dimethylation levels, resulting in transcription activation. dsEcad-215 did not induced the interferon pathways.
Part 4 The mechanism of inhibition of cell invasion and migration by E-cadherin activation
Aim To investigate the molecular mechanisms of inhibition of cell invasion and migration by E-cadherin activation.
Materials and methods The relocalization ofβ-catenin was determined by measuring its expression in cell membrane, cytoplasm and nuclei in PC3 cells. The immunofluorescence assay was used to validate the re-distribution ofβ-catenin. The mRNA expression levels of mmp7, and cyclin D1 were measured using RT-PCR.
Results After transfection with dsEcad-215 for 72 h, there was a decrease in cytoplasmic and nuclearβ-catenin concentration, and an increase ofβ-catenin concentration in membrane fraction in PC3 cells treated with dsEcad-215 compared with control and mock groups, whereas totalβ-catenin in the cell homogenate was not affected. The immunofluorescence data further demonstrated that dsEcad-215 induced plasma membrane relocation ofβ-catenin. mmp7 and cyclinDl were downregulated by 72 h of exposure to 50 nM dsEcad-215 compared with control and mock groups.
Conclusion Our study showed that upregulation of E-cadherin by saRNA caused the relocalization ofβ-catenin from cytoplasm and nucleus to the plasma membrane in PC3 cells, and then suppressed the transactivation of downstreamβ-catenin/TCF target genes, thus inhibited cell invasion and migration.
目的基于小激活RNAs (saRNAs)的肿瘤治疗策略,为p12、p27、p57三个抑癌基因筛选出具有激活功能并相对高效的候选saRNAs分子。方法利用国外文献提供的saRNA设计规则,为每个靶基因设计2～3对候选saRNA分子,对照组双链RNA设计成与人基因组序列非同源。将上述合成的候选saRNAs分子转染膀胱癌5637、T24细胞系或前列腺癌PC3、DU145细胞系,每一种细胞系均包括对照组(转染对照组saRNAs)和saRNAs组(转染候选saRNAs)。利用RT-PCR法检测转染后靶基因mRNA表达水平,根据靶基因表达水平筛选出功能性saRNAs,我们将“功能性saRNAs"定义为使靶基因mRNA表达量增加至少两倍(RT-PCR法)。
结果转染各候选saRNAs后各靶基因1mRNA的表达水平相对于对照组无明显增强,没有达到“功能性saRNAs"的标准。
结论saRNAs的筛选还比较困难,其设计规则有待进一步完善。
第二部分E-钙粘蛋白小激活RNA的抗肿瘤作用
目的评价已证实的E-钙粘蛋白(E-cadherin)小激活RNA (dsEcad-215)对膀胱癌5637细胞及前列腺癌PC3细胞的肿瘤抑制作用。
方法将与E-cadherin基因启动子DNA序列互补的双链RNA分子(dsEcad-215)分别转染入5637细胞和PC3细胞中,采用RT-PCR法及Western blotting法检测E-cadherin在mRNA及蛋白水平上的表达；采用Transwell小室法及划痕法检测dsEcad-215转染后肿瘤细胞侵袭、迁移能力的改变。
结果dsEcad-215转染5637细胞和PC3细胞72 h后E-cadherin表达显著上调,RNAa有效；5637细胞和PC3细胞对细胞外基质的侵袭能力及迁移能力也明显下降。
结论RNAa技术激活E-cadherin基因表达并抑制膀胱癌及前列腺癌细胞侵袭、转移等恶性行为,可作为恶性肿瘤基因治疗的一种有效手段。
第三部分小激活RNA上调E-钙粘蛋白表达的机制研究
目的探讨dsEcad-215上调E-cadherin基因表达的相关分子机制
方法采用基因特异性RT-PCR检测5637细胞E-cadherin启动子相关非编码正义或反义RNA的表达,以及dsEcad-215转染后其表达量的变化；利用染色质免疫共沉淀技术检测dsEcad-215转染后E-cadherin启动子区域相关组蛋白修饰状态的变化；采用RT-PCR法检测dsEcad-215作用后干扰素通路OAS1及OAS3基因表达的变化。
结果E-cadherin启动子区域存在非编码正义和反义RNA; dsEcad-215转染后E-cadherin启动子相关非编码反义和反义RNA的表达未发生明显变化,E-cadherin启动子区域组蛋白3赖氨酸9(H3K9)和组蛋白3赖氨酸4(H3K4)二甲基化的水平明显降低,干扰素通路中OAS1和OAS3基因的表达没有明显升高。
结论dsEcad-215转染5637细胞后并没有影响非编码正义和反义RNA的表达水平,而可能与其结合后改变其空间结构和功能从而影响组蛋白甲基化的修饰,如H3K9和H3K4两个位点二甲基化水平减弱而激活转录。dsEcad-215没有激活干扰素途径而诱发非特异性反应。
第四部分小激活RNA上调E-钙粘蛋白表达抑制肿瘤细胞侵袭及迁移的机制研究
目的探讨E-cadherin上调表达抑制肿瘤细胞侵袭、迁移的相关分子机制
方法利用Western blot检测Ecad-215转染后β-catenin蛋白在膀胱癌5637细胞及前列腺癌PC3细胞胞膜、胞浆及胞核中表达变化；利用细胞免疫荧光法进一步验证β-catenin蛋白在细胞内的重新分布；利用RT-PCR法检测mmp-7及cyclin D1基因mRNA的表达水平。
结果dsEcad-215转染5637及PC3细胞72h后,细胞质和胞核β-catenin蛋白表达水平降低,胞膜β-catenin蛋白表达水平升高,而总的蛋白表达水平不变；细胞免疫荧光实验进一步证实dsEcad-215作用后P-catenin蛋白从胞质、胞核重新分布于细胞膜上。mmp-7和cycylin D1基因mRNA表达水平降低。
结论dsEcad-215上调E-cadherin表达,引起β-catenin蛋白从胞核胞浆转移至胞膜,导致其靶基因转录活性降低,从而抑制肿瘤细胞侵袭。
Part 1 The design and screening of small activating RNA
Aim To screen the relatively efficient candidate small activating RNAs (saRNAs) molecules that can activate the target tumor-suppressor genes including p12, p27 and p57.
Materials and methods Based on the design rules provided by the foreign literature, we designed 2-3 pairs of small double-stranded RNA (dsRNA) for each target gene, and the control dsRNA is non-homologous to the whole human genome. The candidate dsRNAs were transfected into 5637 or T24 bladder cancer cell lines and PC3 or DU145 prostate cancer cell lines. The expression of target gene was determined with RT-PCR measuring the mRNA levels. The functional saRNA which defined as to increase target gene expression twice was selected.
Results All the candidate dsRNAs did not activate the target gene significantly and fulfill the standard of functional saRNAs.
Conclusion It is difficult to screen out the functional saRNAs and the design rules of saRNA should be revised.
Part 2 The antitumor effects of E-cadherin activation by saRNA
Aim To evaluate the antitumor effects of confirmed functional saRNA (dsEcad-215) on 5637 bladder cancer cells and PC3 prostate cancer cells.
Materials and methods dsEcad-215 which is complementary to the E-cadherin promoter was transfected into 5637 and PC3 cells for 72 h. The mRNA and protein expression levels of E-cadherin were determined with RT-PCR and Western blotting. The invasive and migrative ability of tumor cells were measured using Transwell chamber and scratch test.
Results The expression of E-cadherin increased after transfection of dsEcad-215, suggesting that the RNAa was effective. The invasive ability to extracellular matrix and migration capacity of 5637 and PC3 cells decreased significantly.
Conclusion Induction of E-cadherin expression by saRNA leads to suppression of migration and invasion of 5637 and PC3 cells in vitro.The RNAa could be used as an effective tool of gene therapy against cancer.
Part 3 The mechanism of up-regulation of E-cadherin by saRNA
Aim To explore the molecular mechanisms of up-regulation of E-cadherin by RNA activation.
Materials and methods The E-cadherin promoter-associated non-coding sense or antisense RNA was detected with gene-specific RT-PCR. The histone modification status of E-cadherin promoter region after dsEcad-215 transfection was determined with chromatin immunoprecipitation. Using RT-PCR assay, the OAS1 and OAS3 expression which involved in interferon pathway were measured.
Results Both promoter-associated non-coding sense and antisense RNAs were detected, and transfection of dsEcad-215 caused no change of expression. Chromatin immunoprecipitation demonstrated that loss of histone 3 dimethylation at lysine-9 and lysine-4 were associated with gene activation. dsEcad-215 did not induced the expression of OAS1 or OAS3.
Conclusion Transfection with dsEcad-215 in 5637 cells did not affect the non-coding sense and antisense RNA expression levels. dsEcad-215 may bind to the non-coding RNAs, and changed its spatial structure and function thus affecting the modification of histone methylation, such as loss of H3K9 and H3K4 dimethylation levels, resulting in transcription activation. dsEcad-215 did not induced the interferon pathways.
Part 4 The mechanism of inhibition of cell invasion and migration by E-cadherin activation
Aim To investigate the molecular mechanisms of inhibition of cell invasion and migration by E-cadherin activation.
Materials and methods The relocalization ofβ-catenin was determined by measuring its expression in cell membrane, cytoplasm and nuclei in PC3 cells. The immunofluorescence assay was used to validate the re-distribution ofβ-catenin. The mRNA expression levels of mmp7, and cyclin D1 were measured using RT-PCR.
Results After transfection with dsEcad-215 for 72 h, there was a decrease in cytoplasmic and nuclearβ-catenin concentration, and an increase ofβ-catenin concentration in membrane fraction in PC3 cells treated with dsEcad-215 compared with control and mock groups, whereas totalβ-catenin in the cell homogenate was not affected. The immunofluorescence data further demonstrated that dsEcad-215 induced plasma membrane relocation ofβ-catenin. mmp7 and cyclinDl were downregulated by 72 h of exposure to 50 nM dsEcad-215 compared with control and mock groups.
Conclusion Our study showed that upregulation of E-cadherin by saRNA caused the relocalization ofβ-catenin from cytoplasm and nucleus to the plasma membrane in PC3 cells, and then suppressed the transactivation of downstreamβ-catenin/TCF target genes, thus inhibited cell invasion and migration.
引文
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