siRNA抑制Aurora-A激酶的表达治疗肝细胞肝癌的实验研究
摘要
Aurora-A激酶是新近发现的调节中心体、微管功能的丝氨酸/苏氨酸蛋白激酶,在中心体成熟、纺锤体形成、染色体分离,即有丝分裂的正常进行中发挥至关重要的作用。研究表明Aurora-A的过表达可导致中心体异常扩增,染色体的不稳定和非整倍体细胞的形成并导致肿瘤的发生。目前,Aurora-A已被认为是一个与多种恶性肿瘤发生相关的癌基因。众多研究发现,Aurora-A在乳腺癌、胰腺癌、食管癌、胃癌、肺癌、膀胱癌等多种人类恶性肿瘤中高表达。其表达水平与肿瘤的组织学分级、临床分期和患者预后具有相关性。抑制Aurora-A激酶活性,可有效地阻碍细胞的生长、增殖,并引起肿瘤细胞的凋亡。
肝细胞肝癌(Hepatocellular Carcinoma,HCC)是我国最常见的高发肿瘤之一,因其恶性程度高、易复发、易转移,故预后差、死亡率高。尽管目前对于HCC的治疗方案日趋完善,但仍难取得令人满意的疗效。近年来,有研究发现肝癌细胞染色体20q区域常常存在扩增,而该区域正是Aurora-A基因位置所在,从而高度提示HCC的发生可能和Aurora-A表达异常有关。因此,本课题将分为3部分对Aurora-A和HCC的关系进行研究:1.应用Real-Time实时定量PCR检测Aurora-A在HCC患者肿瘤组织及癌旁正常组织中mRNA的表达差异,并分析其表达水平与各种临床病理指标和预后的相关性;2.应用RNA干扰技术体外沉默HepG2等肝癌细胞株Aurora-A基因,观察肝癌细胞增殖、凋亡、侵袭转移等生物学行为的改变;3.深入探讨抑制Aurora-A表达影响肝癌细胞生物学行为的内在机制。
研究发现,50%(16/32)的HCC患者肝癌组织Aurora-A mRNA表达量明显高于癌旁正常对照组织,两者的差异从1.6倍至148倍不等,且Aurora-A mRNA高表达与患者的年龄、性别、乙肝病毒的感染以及术前AFP水平及肿瘤的大小、组织学分级无明显相关,而和TNM分期显著相关。另外,生存分析发现Aurora-AmRNA高表达患者的预后较差。进而应用RNA干扰抑制Aurora-A在HepG2、MHCC-97H、SMMC-7721三种肝癌细胞株中的表达,MTT实验发现三种肝癌细胞株的生长均受到不同程度的抑制,且表现为一定的时间依赖性;流式细胞术检测显示细胞发生G2/M期阻滞并发生凋亡;此外,HepG2细胞经过Aurora-A RNA干扰后体外迁移和侵袭能力下降,表现为划痕愈合不良以及穿越Matrigel基质胶能力减弱。对抑制Aurora-A表达体外改变肝癌细胞生物学行为的机制研究发现,Aurora-A RNA干扰下调Cyclin B1表达导致细胞发生G2/M期阻滞;同时Aurora-A表达受抑解除了其在过表达状态下对野生型p53(wt-p53)的抑制作用,恢复了wt-p53的正常作用,诱导细胞凋亡,下调MMP-9表达,抑制细胞侵袭能力。
综上所述,我们认为Aurora-A与肝癌细胞的各种生物学行为关系密切,其在肝癌组织中的高表达将直接影响HCC患者的预后。随着对Aurora-A的功能及其与HCC相互关系的逐步阐明,Aurora-A有可能成为肝癌治疗中的一个潜在靶点。然而根据抑制Aurora-A活性仅能使表达wt-p53的肝癌细胞发生凋亡的现象,我们推测其在发生p53突变的患者上的应用效果可能不佳。
Aurora-A kinase,a member of the evolutionary conserved Aurora serine/threonine kinase family,plays a vital role in regulation of centrosome maturation,bipolar spindle assembly,chromosome segregation,mitotic entry and exit.However,it has been shown that overexpression of Aurora-A induces unexpected centrosome duplication and chromosomal instability,leading to aneuploidy and cell transformation.Now,Aurora-A is considered to be a bona fide oncogene related to a variety of human tumors.There is also increased evidence of significant high levels of Aurora-A mRNA and protein expression in human malignancies from different organs,including breast,pancreas, esophagus,stomach,lung and bladder.Besides,its overexpression is correlated to tumor histological grade,clinical staging and the prognosis.Some studies observed that targeted disruption of Aurora-A might induce tumor growth suppression and finally apoptosis.
Hepatocellular carcinoma(HCC) is one of the most frequent malignant tumors in China with a still poor prognosis and increasing mortality for its aggressive invasion and metastasis.In spite of improvements in diagnosis and treatment methods,the efficacy remains unsatisfied.Recently,amplification of chromosome 20q was found frequently in HCC,where Aurora-A is located,indicating a close relationship between Aurora-A and HCC.In order to determine the involvement of Aurora-A in HCC and to explore the molecule mechanism of Aurora-A for the tumorigenesis of HCC,we designed this study as follows:1.Analysis of Aurora-A mRNA expression in HCC patients' tumor tissues and paired tumor-adjacent liver parenchyma by real-time PCR, as well as the clinicopathologic relation of Aurora-A expression in HCC;2.Observation of biological phenotypes in hepatocellular cancer cell lines HepG2,MHCC-97H, SMMC-7721 and Hep3B after specific knockdown of Aurora-A expression by using RNA interference(RNAi) technique;3.Exploration of the molecule mechanisms by which inhibition of Aurora-A expression exerts potent antitumor activity.
We observed,among 32 HCCs,Aurora-A mRNA was overexpressed in 16(50%) patients,and the expression ratio between tumor tissue and paired tumor-adjacent liver parenchyma ranged from 1.6 to 148.Besides,Aurora-A mRNA overexpression in HCC did not correlate to age,gender,hepatitis B virus infection,serumα-fetoprotein elevation and tumor histologic grade,but was significantly associated with increasing TNM staging and worse survival rate.After specific knockdown of Aurora-A expression by RNAi,growth of cultured HepG2,MHCC-97H and SMMC-7721 cells was time-dependantly suppressed showed by MTT assay.Flow cytometry then showed a significant accumulation of cells in the G2/M phase and finally apoptosis.In addition, the failure of HepG2 cells to heal a scar or to penetrate the Matrigel detected by scratch assay and transwell assay indicated the inhibition of metastasis and invasion of HepG2 cells by specific knockdown of Aurora-A expression.Furthermore,we discovered that the expression of Cyclin B1 was downregulated by Aurora-A RNAi,which resulted in G2/M phase arrest.Meanwhile,we demonstrated for the first time in hepatoma cells that specific knockdown of Aurora-A expression by RNAi restored the tumor suppressor activity of wild type p53(wt-p53) which had been inhibited by overexpressed Aurora-A in hepatoma cells,and then resulted in apoptosis and inhibition of invasion by DNA binding and transactivation activity of released wt-p53.
In conclusion,Aurora-A kinase is closely associated with the biological phenotypes of hepatoma cells,and its overexpression in HCC might represent a worse prognosis. By further understanding of its function in HCC makes Aurora-A to become a potent gene therapy target to suppress the progression of HCC.Interestingly,we suppose that the therapeutic effect by inhibition of Aurora-A in HCC patients with mutant p53 might not so good as those with wt-p53,according to the outcome that Aurora-A RNAi could only induce apoptosis in hepatoma cells with wt-p53.
肝细胞肝癌(Hepatocellular Carcinoma,HCC)是我国最常见的高发肿瘤之一,因其恶性程度高、易复发、易转移,故预后差、死亡率高。尽管目前对于HCC的治疗方案日趋完善,但仍难取得令人满意的疗效。近年来,有研究发现肝癌细胞染色体20q区域常常存在扩增,而该区域正是Aurora-A基因位置所在,从而高度提示HCC的发生可能和Aurora-A表达异常有关。因此,本课题将分为3部分对Aurora-A和HCC的关系进行研究:1.应用Real-Time实时定量PCR检测Aurora-A在HCC患者肿瘤组织及癌旁正常组织中mRNA的表达差异,并分析其表达水平与各种临床病理指标和预后的相关性;2.应用RNA干扰技术体外沉默HepG2等肝癌细胞株Aurora-A基因,观察肝癌细胞增殖、凋亡、侵袭转移等生物学行为的改变;3.深入探讨抑制Aurora-A表达影响肝癌细胞生物学行为的内在机制。
研究发现,50%(16/32)的HCC患者肝癌组织Aurora-A mRNA表达量明显高于癌旁正常对照组织,两者的差异从1.6倍至148倍不等,且Aurora-A mRNA高表达与患者的年龄、性别、乙肝病毒的感染以及术前AFP水平及肿瘤的大小、组织学分级无明显相关,而和TNM分期显著相关。另外,生存分析发现Aurora-AmRNA高表达患者的预后较差。进而应用RNA干扰抑制Aurora-A在HepG2、MHCC-97H、SMMC-7721三种肝癌细胞株中的表达,MTT实验发现三种肝癌细胞株的生长均受到不同程度的抑制,且表现为一定的时间依赖性;流式细胞术检测显示细胞发生G2/M期阻滞并发生凋亡;此外,HepG2细胞经过Aurora-A RNA干扰后体外迁移和侵袭能力下降,表现为划痕愈合不良以及穿越Matrigel基质胶能力减弱。对抑制Aurora-A表达体外改变肝癌细胞生物学行为的机制研究发现,Aurora-A RNA干扰下调Cyclin B1表达导致细胞发生G2/M期阻滞;同时Aurora-A表达受抑解除了其在过表达状态下对野生型p53(wt-p53)的抑制作用,恢复了wt-p53的正常作用,诱导细胞凋亡,下调MMP-9表达,抑制细胞侵袭能力。
综上所述,我们认为Aurora-A与肝癌细胞的各种生物学行为关系密切,其在肝癌组织中的高表达将直接影响HCC患者的预后。随着对Aurora-A的功能及其与HCC相互关系的逐步阐明,Aurora-A有可能成为肝癌治疗中的一个潜在靶点。然而根据抑制Aurora-A活性仅能使表达wt-p53的肝癌细胞发生凋亡的现象,我们推测其在发生p53突变的患者上的应用效果可能不佳。
Aurora-A kinase,a member of the evolutionary conserved Aurora serine/threonine kinase family,plays a vital role in regulation of centrosome maturation,bipolar spindle assembly,chromosome segregation,mitotic entry and exit.However,it has been shown that overexpression of Aurora-A induces unexpected centrosome duplication and chromosomal instability,leading to aneuploidy and cell transformation.Now,Aurora-A is considered to be a bona fide oncogene related to a variety of human tumors.There is also increased evidence of significant high levels of Aurora-A mRNA and protein expression in human malignancies from different organs,including breast,pancreas, esophagus,stomach,lung and bladder.Besides,its overexpression is correlated to tumor histological grade,clinical staging and the prognosis.Some studies observed that targeted disruption of Aurora-A might induce tumor growth suppression and finally apoptosis.
Hepatocellular carcinoma(HCC) is one of the most frequent malignant tumors in China with a still poor prognosis and increasing mortality for its aggressive invasion and metastasis.In spite of improvements in diagnosis and treatment methods,the efficacy remains unsatisfied.Recently,amplification of chromosome 20q was found frequently in HCC,where Aurora-A is located,indicating a close relationship between Aurora-A and HCC.In order to determine the involvement of Aurora-A in HCC and to explore the molecule mechanism of Aurora-A for the tumorigenesis of HCC,we designed this study as follows:1.Analysis of Aurora-A mRNA expression in HCC patients' tumor tissues and paired tumor-adjacent liver parenchyma by real-time PCR, as well as the clinicopathologic relation of Aurora-A expression in HCC;2.Observation of biological phenotypes in hepatocellular cancer cell lines HepG2,MHCC-97H, SMMC-7721 and Hep3B after specific knockdown of Aurora-A expression by using RNA interference(RNAi) technique;3.Exploration of the molecule mechanisms by which inhibition of Aurora-A expression exerts potent antitumor activity.
We observed,among 32 HCCs,Aurora-A mRNA was overexpressed in 16(50%) patients,and the expression ratio between tumor tissue and paired tumor-adjacent liver parenchyma ranged from 1.6 to 148.Besides,Aurora-A mRNA overexpression in HCC did not correlate to age,gender,hepatitis B virus infection,serumα-fetoprotein elevation and tumor histologic grade,but was significantly associated with increasing TNM staging and worse survival rate.After specific knockdown of Aurora-A expression by RNAi,growth of cultured HepG2,MHCC-97H and SMMC-7721 cells was time-dependantly suppressed showed by MTT assay.Flow cytometry then showed a significant accumulation of cells in the G2/M phase and finally apoptosis.In addition, the failure of HepG2 cells to heal a scar or to penetrate the Matrigel detected by scratch assay and transwell assay indicated the inhibition of metastasis and invasion of HepG2 cells by specific knockdown of Aurora-A expression.Furthermore,we discovered that the expression of Cyclin B1 was downregulated by Aurora-A RNAi,which resulted in G2/M phase arrest.Meanwhile,we demonstrated for the first time in hepatoma cells that specific knockdown of Aurora-A expression by RNAi restored the tumor suppressor activity of wild type p53(wt-p53) which had been inhibited by overexpressed Aurora-A in hepatoma cells,and then resulted in apoptosis and inhibition of invasion by DNA binding and transactivation activity of released wt-p53.
In conclusion,Aurora-A kinase is closely associated with the biological phenotypes of hepatoma cells,and its overexpression in HCC might represent a worse prognosis. By further understanding of its function in HCC makes Aurora-A to become a potent gene therapy target to suppress the progression of HCC.Interestingly,we suppose that the therapeutic effect by inhibition of Aurora-A in HCC patients with mutant p53 might not so good as those with wt-p53,according to the outcome that Aurora-A RNAi could only induce apoptosis in hepatoma cells with wt-p53.
引文
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