慢性乙型肝炎相关肝癌发生、发展过程中的表观遗传学机制研究
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摘要
原发性肝癌(以下简称肝癌)是世界上最常见的恶性肿瘤之一,特别是东南亚及非洲更是常见。在恶性肿瘤引起的死亡位次中肝癌仅次于胃癌、食道癌,居第三位。从世界范围来看,慢性乙型肝炎是肝癌最重要的病因之一。慢性乙型肝炎的分布区域与肝癌的高发区高度重合。尽管近年来早期诊断、手术切除及药物治疗等方面的发展,肝癌患者的5年生存率仍然很低,全世界范围内每年大约有600000肝癌病人死亡。肝癌预后差,一个很重要的原因就是人们对肝癌发生、发展的具体机制目前仍然所知甚少。已报道的研究多半集中于肝癌组织中单个差异表达基因的功能(多数为编码蛋白的基因)及其参与的信号途径调控。然而在肝癌发生、发展过程中复杂的调控网络改变绝不仅仅局限于此。表观遗传学调控方式在慢性乙型肝炎相关肝癌的发生、发展过程充当了重要的调控角色。功能性非编码RNA及蛋白的翻译后修饰等表观遗传遗传调控方式越来越受到研究者的重视。功能性非编码RNA在基因表达中发挥重要的作用,按照它们的大小可分为长链非编码RNA和短链非编码RNA。长链非编码RNA或在基因簇以至于整个染色体水平发挥顺式调节作用,或改变直接相互作用蛋白分子的分子结构而发挥作用,或影响相关编码蛋白基因的剪切、翻译等过程。短链RNA对基因表达进行调控,其可介导mRNA的降解,诱导染色质结构的改变,决定着细胞的分化命运。
本研究中采用蛋白质组学、基因表达谱芯片等高通量筛选技术辅以经典分子生物学技术、生物信息学分析等手段对慢性乙型肝炎向肝癌进展的过程以及肝癌发生后非编码RNA的调控功能及蛋白翻译后修饰进行了广泛而深入的研究,取得了如下结果:
第一、发现与慢性乙型肝炎疾病进展及肝癌预后相关的新分子,可做疾病诊断、预后判断的新指标。近年来,人们一直热衷于诊断新标志物的寻找,在肝癌组织中以及病人外周血中一些新诊断标志物的提出,结合着传统指标可以一定程度上提高肝癌早期诊断的灵敏性和准确性。我们的研究结果显示在肝癌组织中上调表达的长链非编码RNA lncRNA-HEIH与肝癌复发概率密切相关,该长链非编码RNA在肝癌组织中的表达量与病人的术后生存时间显著关联,肝癌组织中lncRNA-HEIH表达量越高则预示着病人的术后生存时间可能越短;同时我们的研究结果也表明在肝癌组织中特异性表达的长链非编码RNA谱可以将癌组织和癌旁组织进行准确判别。因此,检测肝癌组织中长链非编码RNA lncRNA-HEIH的表达量结合现有一些指标或者是联合检测若干个长链非编码RNA的表达情况可用于手术病人预后判断的参考指标,帮助临床医生进行决策。根据雌、雄两性别转基因鼠肝脏蛋白质组学的研究结果,我们发现在男、女两性别的慢性乙型肝炎患者血清中Apo A-I氧化修饰的程度存在着明显的差别,可能与不同性别的患者体内抗氧化应激损伤的能力大小有关,可用于慢性乙型肝炎疾病进展程度的监测指标。
第二、发现一些新分子或者是新的调控方式参与了慢性乙型肝炎相关肝癌的发生、发展过程,可成为肝癌新治疗策略的作用靶点。肝癌之所以治疗效果差,病人预后不理想,很重要的一个原因就是肝癌具有侵袭性,经常出现远处或者是肝脏内的转移。在哺乳细胞的转录产物中除了众人所熟知的编码蛋白RNA,其实包含了更多的具有信号调节功能的非编码RNA,如现在正研究地如火如荼的miRNA。在我们的研究中利用荧光差异蛋白质组学的方法,发现在肝癌组织中上调表达的miRNA-17-5p可以通过激活MAPK p38途径增加HSP27的磷酸化修饰水平而增强肝癌细胞的迁移能力,且这条信号调控通路在临床肝癌样本中也得到验证,为转移性肝癌的判别和治疗提供了新的研究靶点。近年来的文献报道表明一些长度大于200nt的非编码RNA也具有非常复杂的调控功能。我们的研究表明在肝癌组织中上调表达的长链非编码RNA lncRNA-HEIH可以和EZH2相互作用,引导PRC2复合物在基因组中的定位而调控细胞周期相关基因的表达。以往的大部分研究均在事先建立假设的基础上对某一单个的分子或者信号通路进行研究,缺乏整体、全面的手段对慢性乙型肝炎相关肝癌的发生机制进行研究。近年来各种“组学”技术的出现和发展为这一研究领域提供了新的手段。我们运用蛋白质组学的方法对HBV转基因鼠肝脏组织进行了全面、系统的研究,发现了HBV抗原的表达对宿主细胞影响的两个重要方面:①HBV抗原的表达抑制了宿主细胞的抗氧化系统(如谷胱甘肽过氧化物酶1的下调),增加了宿主细胞的氧化应激损伤(血清中DNA氧化产物8-羟基脱氧鸟苷增多,Apo A-I氧化修饰的改变);②HBV抗原的表达扰乱了宿主细胞的脂质代谢。一些脂肪酸的转运蛋白(如脂肪酸结合蛋白5,酰基辅酶A结合蛋白)及Apo A-I在HBV转基因鼠肝脏中的表达或者是修饰发生了明显的异常,为进一步深入的机制研究奠定了基础。
总之,本研究应用基因芯片、蛋白质组学等手段对参与慢性乙型肝炎相关肝癌发生、发展过程中的功能性非编码RNA调控机制及蛋白翻译后修饰等表观遗传调控方式进行深入而广泛的探讨,为进一步理解该过程中纷繁复杂的信号通路提供了新的视角,为肝癌的早期诊断及治疗提供了新的研究靶点。
Hepatocellular carcinoma (HCC) is one of the most common human cancer worldwide, particularly in Southeast Asia and Africa. Unfortunately, the 5-year survival rate of HCC patient remains poor and ~600 000 HCC patients die each year despite recent advances in surgical techniques and medical treatment. Although previous studies identified many aberrantly expressed protein-coding genes in HCC, the novel molecular markers that can help to early diagnosis and risk assessment are still urgently needed. It is also paramount important to understand the relationships between clinical symptoms and molecular changes in HCC for developing new diagnosis and treatment of HCC and improving the prognosis of diagnosed patients.
In this study, we used hybridization-based microarrays and two-dimensional electrophoresis proteomic approach to investigate the roles of protein, miRNAs and long non-coding RNAs (lncRNAs) in HCC. Our research has achieved the following results:
First, we found some novel prognostic biomarkers of chronic hepatitis B (CHB) or HCC in this study. In recent years, identifying the molecular markers correlating with the survival of cancer patients attracts much attention. For HCC, deregulated expression of both protein-coding genes and miRNAs has been suggested to have considerable potential in predicting the prognosis of HCC patients. Using a microarray platform, we identified a long non-coding RNA (termed lncRNA-HEIH), a novel mRNA-like noncoding RNA, as one of the up-regulated genes in HCC. We found that patients with lncRNA-HEIH high expression tumors had an increasing risk of recurrence and significantly reduced overall postoperative survival. Furthermore, univariate and multivariate analyses revealed that lncRNA-HEIH expression was a powerful independent prognostic factor for both recurrence and survival of HCC patients, which is consistent with the results from cell culture and with the notion that lncRNA-HEIH expression may be used as a novel prognostic biomarker of HCC. Apo A-I expression is down-regulated in male and female HBV-transgenic (HBV-Tg) mouse liver and that there is a disordered expression pattern of Apo A-I isoforms in male HBV-Tg mouse liver. We also verified this finding in CHB patient serum. Furthermore, we identified overoxidized Apo A-I mainly resides in basic isoform (isoform 3). Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, the selectively modified Apo A-I isoforms may be considered to be a pathological hallmark that could extend our knowledge of the molecular pathogenesis of CHB. Development of antibodies that specifically recognize the isoforms of Apo A-I may prove to be useful, in combination with other traditional markers, as a more efficient way to evaluate the prognosis of CHB.
Second, our study increased understanding the relationships between clinical symptoms and molecular changes in HCC. Our findings suggest that the p38 MAPK pathway plays a crucial role in miR-17-5p-induced phosphorylation of heat shock protein 27 (HSP27) and, as a consequence, phosphorylated HSP27 enhances the migration of HCC cells. Our data highlight an important role of miR-17-5p in the proliferation and migration of HCC cells and support the potential application of miR-17-5p in HCC therapy. We also identified non-overlapping signatures of a small number of lncRNAs that are aberrantly expressed in human HCC compared with paired peritumoral tissues. Then we used real-time PCR to validate five lncRNAs whose expression was altered in HCC compared with paired peritumoral tissues. Using loss-of-function and gain-of-function approaches, we found that lncRNA-HEIH plays a key role in cell cycle regulation. We further demonstrated that lncRNA-HEIH bound to enhancer of zeste homolog 2 (EZH2) and that this interaction was required for the repression of EZH2 target genes. These results reveal insights into the molecular regulation mechanisms of HCC cell cycle regulation and lead us to propose that lncRNAs may serve as key regulatory hubs in cancer biology. The present study also provides new insights into the pathogenesis of hepatitis B virus infection, which might not be obtained by studying a specific individual molecule. In addition to a close connection between glutathione peroxidase 1and oxidative stress, our integrated approach highlighted the fact that fatty acid binding 5, Acyl-CoA binding protein and apo A-I could be the key points of lipid metabolism derangement in HBV-Tg mice. Our study also shed light on the physiological difference between HBV-Tg and wild-type mice, which may pave the way for further use of HBV-Tg mice for the study of pathogenesis of hepatitis B virus infection.
Overall, our finds have diagnostic and therapeutic implications. Understanding the precise molecular mechanisms in HCC will be critical for exploring these potential new strategies for early diagnosis and therapy of HCC.
本研究中采用蛋白质组学、基因表达谱芯片等高通量筛选技术辅以经典分子生物学技术、生物信息学分析等手段对慢性乙型肝炎向肝癌进展的过程以及肝癌发生后非编码RNA的调控功能及蛋白翻译后修饰进行了广泛而深入的研究,取得了如下结果:
第一、发现与慢性乙型肝炎疾病进展及肝癌预后相关的新分子,可做疾病诊断、预后判断的新指标。近年来,人们一直热衷于诊断新标志物的寻找,在肝癌组织中以及病人外周血中一些新诊断标志物的提出,结合着传统指标可以一定程度上提高肝癌早期诊断的灵敏性和准确性。我们的研究结果显示在肝癌组织中上调表达的长链非编码RNA lncRNA-HEIH与肝癌复发概率密切相关,该长链非编码RNA在肝癌组织中的表达量与病人的术后生存时间显著关联,肝癌组织中lncRNA-HEIH表达量越高则预示着病人的术后生存时间可能越短;同时我们的研究结果也表明在肝癌组织中特异性表达的长链非编码RNA谱可以将癌组织和癌旁组织进行准确判别。因此,检测肝癌组织中长链非编码RNA lncRNA-HEIH的表达量结合现有一些指标或者是联合检测若干个长链非编码RNA的表达情况可用于手术病人预后判断的参考指标,帮助临床医生进行决策。根据雌、雄两性别转基因鼠肝脏蛋白质组学的研究结果,我们发现在男、女两性别的慢性乙型肝炎患者血清中Apo A-I氧化修饰的程度存在着明显的差别,可能与不同性别的患者体内抗氧化应激损伤的能力大小有关,可用于慢性乙型肝炎疾病进展程度的监测指标。
第二、发现一些新分子或者是新的调控方式参与了慢性乙型肝炎相关肝癌的发生、发展过程,可成为肝癌新治疗策略的作用靶点。肝癌之所以治疗效果差,病人预后不理想,很重要的一个原因就是肝癌具有侵袭性,经常出现远处或者是肝脏内的转移。在哺乳细胞的转录产物中除了众人所熟知的编码蛋白RNA,其实包含了更多的具有信号调节功能的非编码RNA,如现在正研究地如火如荼的miRNA。在我们的研究中利用荧光差异蛋白质组学的方法,发现在肝癌组织中上调表达的miRNA-17-5p可以通过激活MAPK p38途径增加HSP27的磷酸化修饰水平而增强肝癌细胞的迁移能力,且这条信号调控通路在临床肝癌样本中也得到验证,为转移性肝癌的判别和治疗提供了新的研究靶点。近年来的文献报道表明一些长度大于200nt的非编码RNA也具有非常复杂的调控功能。我们的研究表明在肝癌组织中上调表达的长链非编码RNA lncRNA-HEIH可以和EZH2相互作用,引导PRC2复合物在基因组中的定位而调控细胞周期相关基因的表达。以往的大部分研究均在事先建立假设的基础上对某一单个的分子或者信号通路进行研究,缺乏整体、全面的手段对慢性乙型肝炎相关肝癌的发生机制进行研究。近年来各种“组学”技术的出现和发展为这一研究领域提供了新的手段。我们运用蛋白质组学的方法对HBV转基因鼠肝脏组织进行了全面、系统的研究,发现了HBV抗原的表达对宿主细胞影响的两个重要方面:①HBV抗原的表达抑制了宿主细胞的抗氧化系统(如谷胱甘肽过氧化物酶1的下调),增加了宿主细胞的氧化应激损伤(血清中DNA氧化产物8-羟基脱氧鸟苷增多,Apo A-I氧化修饰的改变);②HBV抗原的表达扰乱了宿主细胞的脂质代谢。一些脂肪酸的转运蛋白(如脂肪酸结合蛋白5,酰基辅酶A结合蛋白)及Apo A-I在HBV转基因鼠肝脏中的表达或者是修饰发生了明显的异常,为进一步深入的机制研究奠定了基础。
总之,本研究应用基因芯片、蛋白质组学等手段对参与慢性乙型肝炎相关肝癌发生、发展过程中的功能性非编码RNA调控机制及蛋白翻译后修饰等表观遗传调控方式进行深入而广泛的探讨,为进一步理解该过程中纷繁复杂的信号通路提供了新的视角,为肝癌的早期诊断及治疗提供了新的研究靶点。
Hepatocellular carcinoma (HCC) is one of the most common human cancer worldwide, particularly in Southeast Asia and Africa. Unfortunately, the 5-year survival rate of HCC patient remains poor and ~600 000 HCC patients die each year despite recent advances in surgical techniques and medical treatment. Although previous studies identified many aberrantly expressed protein-coding genes in HCC, the novel molecular markers that can help to early diagnosis and risk assessment are still urgently needed. It is also paramount important to understand the relationships between clinical symptoms and molecular changes in HCC for developing new diagnosis and treatment of HCC and improving the prognosis of diagnosed patients.
In this study, we used hybridization-based microarrays and two-dimensional electrophoresis proteomic approach to investigate the roles of protein, miRNAs and long non-coding RNAs (lncRNAs) in HCC. Our research has achieved the following results:
First, we found some novel prognostic biomarkers of chronic hepatitis B (CHB) or HCC in this study. In recent years, identifying the molecular markers correlating with the survival of cancer patients attracts much attention. For HCC, deregulated expression of both protein-coding genes and miRNAs has been suggested to have considerable potential in predicting the prognosis of HCC patients. Using a microarray platform, we identified a long non-coding RNA (termed lncRNA-HEIH), a novel mRNA-like noncoding RNA, as one of the up-regulated genes in HCC. We found that patients with lncRNA-HEIH high expression tumors had an increasing risk of recurrence and significantly reduced overall postoperative survival. Furthermore, univariate and multivariate analyses revealed that lncRNA-HEIH expression was a powerful independent prognostic factor for both recurrence and survival of HCC patients, which is consistent with the results from cell culture and with the notion that lncRNA-HEIH expression may be used as a novel prognostic biomarker of HCC. Apo A-I expression is down-regulated in male and female HBV-transgenic (HBV-Tg) mouse liver and that there is a disordered expression pattern of Apo A-I isoforms in male HBV-Tg mouse liver. We also verified this finding in CHB patient serum. Furthermore, we identified overoxidized Apo A-I mainly resides in basic isoform (isoform 3). Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, the selectively modified Apo A-I isoforms may be considered to be a pathological hallmark that could extend our knowledge of the molecular pathogenesis of CHB. Development of antibodies that specifically recognize the isoforms of Apo A-I may prove to be useful, in combination with other traditional markers, as a more efficient way to evaluate the prognosis of CHB.
Second, our study increased understanding the relationships between clinical symptoms and molecular changes in HCC. Our findings suggest that the p38 MAPK pathway plays a crucial role in miR-17-5p-induced phosphorylation of heat shock protein 27 (HSP27) and, as a consequence, phosphorylated HSP27 enhances the migration of HCC cells. Our data highlight an important role of miR-17-5p in the proliferation and migration of HCC cells and support the potential application of miR-17-5p in HCC therapy. We also identified non-overlapping signatures of a small number of lncRNAs that are aberrantly expressed in human HCC compared with paired peritumoral tissues. Then we used real-time PCR to validate five lncRNAs whose expression was altered in HCC compared with paired peritumoral tissues. Using loss-of-function and gain-of-function approaches, we found that lncRNA-HEIH plays a key role in cell cycle regulation. We further demonstrated that lncRNA-HEIH bound to enhancer of zeste homolog 2 (EZH2) and that this interaction was required for the repression of EZH2 target genes. These results reveal insights into the molecular regulation mechanisms of HCC cell cycle regulation and lead us to propose that lncRNAs may serve as key regulatory hubs in cancer biology. The present study also provides new insights into the pathogenesis of hepatitis B virus infection, which might not be obtained by studying a specific individual molecule. In addition to a close connection between glutathione peroxidase 1and oxidative stress, our integrated approach highlighted the fact that fatty acid binding 5, Acyl-CoA binding protein and apo A-I could be the key points of lipid metabolism derangement in HBV-Tg mice. Our study also shed light on the physiological difference between HBV-Tg and wild-type mice, which may pave the way for further use of HBV-Tg mice for the study of pathogenesis of hepatitis B virus infection.
Overall, our finds have diagnostic and therapeutic implications. Understanding the precise molecular mechanisms in HCC will be critical for exploring these potential new strategies for early diagnosis and therapy of HCC.
引文
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