肝细胞肝癌的新非编码基因及病毒相关性研究
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摘要
研究背景
肝细胞肝癌(肝癌)是一种高度异质的恶性肿瘤,严重危害中国人民的健康,其发生发展是一种多基因、多环境因素协同作用的过程,需要经历多个病理阶段,涉及多种分子事件。近几年对于肝癌非编码RNA (ncRNA)的有限研究虽然得到了一些有提示意义的数据,但是尚未达到大规模转录组学水平,特别是small ncRNA和mRNA-like ncRNA在肝癌中差异表达的报道几乎为空白。本研究拟通过用芯片研究新ncRNA在肝癌中的差异表达,填补肝癌相关ncRNA高通量研究的空白,首次建立肝细胞特定长度范围的ncRNA高通量测序模型,成为国际领先的研究领域。
另一方面,中国的肝癌绝大多数发生于慢性乙型肝炎(乙肝)、肝硬化的基础之上。虽然乙肝在中国无论是绝对数量还是相对比例在世界上都居前列,但是由于慢性乙肝的并发症通常要几十年才能观察到,大陆地区颇具说服力的大宗前瞻性队列研究乙肝与肝癌相关的报告稀缺,尚缺乏直接针对临床转归结果的长期随访研究证据。
目的
发现肝癌特异表达的新非编码基因。
发现肝癌早期诊断标记物。
探索肝癌发生机制,辅助肝癌基因分型、治疗方案选择和预后预测。
探索乙型肝炎病毒感染状态与肝癌发生的相关性。
方法
研究一：计算处理构建大型ncRNA数据库。收集不同分化程度的HCC及相应癌旁组织标本,系统性记录患者的临床病理特征,构建特异性ncRNA文库。用新发现的small ncRNA和：mRNA-like ncRNA制备芯片,通过与芯片杂交,寻找肝癌中差异表达的靶基因,并用RT-PCR和Northern印迹验证。整合已有芯片数据,建立肝癌相关ncRNA数据库。
研究二：回顾性分析北京协和医院和佑安医院收治的接受肝切除术、并经病理确诊的乙肝相关性肝癌患者的病历资料,以及协和医院体检中心的乙肝相关检查结果。
结果
研究一构建了4个大型ncRNA数据库：NONCODE, antiCODE, HPtaa和HPtam。在肝癌标本中识别出30条差异表达的新ncRNA,选择其中6条进行并获得Northern印迹验证。
研究二共纳入371名乙肝相关性肝癌患者,男／女：317／54；中位年龄53岁；ALT中位值41 U／L,48.5%在诊断时ALT水平正常；HBsAg携带者87.6%,乙肝大三阳15.9%,小三阳65.5%,HBsAg血清清除12.4%。与普通人群相比,乙肝相关性肝癌患者的大小三阳之比无显著性差异(P=0.1460)。139人检测了HBV DNA水平,拷贝数<103／mL、103-104／mL以及>104／mL的比例分别为51.1%、8.6%和40.3%。体检结果中HBsAg携带率为2.74%(3,548／129,568)。单位组织体检者(136／810)和个人体检者(283／1,333)大小三阳之比存在显著性差异(P=0.0383)。
结论
研究一表明,肝癌中存在诸多特异性表达的新非编码RNA,它们在肝癌相关领域的研究中颇具希望。需要进一步探索其功能；分析它们与临床病理特征之间的关系,用于肝癌诊治及分型；构建肝癌转录调控网络,理解肝癌发生发展机制；并可探索新的靶向治疗基因来帮助阻止癌变。
研究二提示,乙肝小三阳患者发生肝癌的风险可能与大三阳患者相似；HBVDNA拷贝数低于103／mL者依然可能有较高的肝癌发生风险。目前亟需汇集各主要医疗机构和流行病监控机构的资料,进行大规模临床调查,为真正意义上的乙肝一级、二级和三级预防提供依据。
Background
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy which is seriously jeopardizing the health of Chinese people. The carcinogenic process of HCC involves synergetic effects of multiple genes and environmental factors, requires various pathologic stages and engages a number of molecular events. Although the information obtained from limited studies on HCC-related noncoding RNAs (ncRNAs) in recent years can be suggestive, they have not yet reached the level of large-scale transcriptome research; particularly, there are currently few reports on the differential expression of small ncRNA and mRNA-like ncRNA in HCC. With microarray analysis of novel small ncRNAs and mRNA-like ncRNAs in HCCs, this study will be complementary to high throughput researches on HCC-related ncRNAs. It will for the first time establish a high throughput model of hepatocyte-specific ncRNA sequencing and pilot the related field.
On the other hand, HCCs in China mainly develop on the basis of chronic hepatitis B and cirrhosis. Although either the absolute number or the relative ratio of hepatitis B in China is among the highest in the world, there are few persuasive reports of large-scale prospective cohort studies on the relationship of hepatitis B and HCC, and sufficient evidence from long-term follow-ups which directly focus on the clinical consequences of chronic hepatitis B is still lacking, as it may take years for them to develop.
Objective
To identify novel HCC-specific noncoding genes.
To identify novel biomarkers for early diagnosis of HCC.
To investigate the carcinogenic mechanism of HCC, to facilitate the classification of HCC genes, choice of treatment regime, and prediction of prognosis.
To investigate the relationship of hepatitis B virus (HBV) infection status and HCC development.
Methods
In Part I, large-scale ncRNA databases were established by in silico computing. A specimen collection which includes various differentiated HCCs and their matched noncancerous tissues were established, patients'clinicopathological characteristics were systematically recorded, and a liver-specific ncRNA library was constructed. By hybridizing with gene chips containing novelly identified small ncRNAs and mRNA-like ncRNAs, microarray analysis was applied to search for target genes that differentially expressed in HCC, which were then verified by RT-PCR and Northern blot. A HCC-related ncRN A database will be established by integrating results of this study with available data of other ncRNA chips.
In Part II, the medical records of patients who were admitted into Peking Union Medical College Hospital (PUMCH) and Youan Hospital, and underwent hepatectomy followed with a pathologically confirmed diagnosis of HBV-related HCC, and the results of HBV-related tests in PUMCH Health Checkup Center were retrospectively analyzed.
Results
In PartⅠ, four large-scale ncRNA databases were established, i.e. NONCODE, antiCODE, HPtaa, and HPtam.30 differentially expressed novel ncRNAs were identified in HCC specimens.6 of them were selected and verified by Northern blot.
In PartⅡ, a total of 371 patients with HBV-related HCC were enrolled, male/female: 317/54; median age:53 yrs; median ALT:41 U/L,48.5% were with a normal ALT level at HCC diagonosis; patients who were HBsAg carriers, HBsAg-positive/HBeAg-positive, HBsAg-positive/HBeAg-negative, and HBsAg-seronegative were 87.6%,15.9%,65.5% and 12.4% respectively. Compared with the data from regular health checkups, the ratio of HBeAg-positive patients with HBV-related HCC to HBeAg-negative ones was not significantly different (P=0.1460). HBV DNA levels were determined in a total of 139 patients with HBV-related HCC. Among them, the rates of HBV DNA<103,103-104, and>104 copies/mL were 51.1%,8.6% and 40.3% respectively. According to the data from regular health checkups, HBsAg carrier rate was 2.74% (3,548/129,568). The ratio of HBeAg-positive to HBeAg-negative patients in company-organized participants was significantly different from that in individual ones (136/810 vs 283/1,333,P=0.0383).
Conclusions
PartⅠreveals that there are a large number of novel ncRNAs which specifically express in HCCs, suggesting the promise of these ncRNAs in HCC-related field. It is warranted to further investigate their functions, to analyze their relationship with clinicopathological features for the diagnosis, treatment and classification of HCC, to construct the transcription modulation network in HCC to understand its carcinogenic mechanisms, and to explore novel target genes to prevent HCC development.
PartⅡindicates that the risk of HCC development in HBsAg-positive, HBeAg-negative patients seems to be similar to that in HBsAg-positive, HBeAg-positive ones; patients with a HBV DNA level<103 copies/mL are still at a higher risk of HCC. At present, collecting data from major medical institutes and disease control centers and conducting large-scale clinical investigations are warranted to provide supports for the primary, secondary and third preventions against hepatitis B.
肝细胞肝癌(肝癌)是一种高度异质的恶性肿瘤,严重危害中国人民的健康,其发生发展是一种多基因、多环境因素协同作用的过程,需要经历多个病理阶段,涉及多种分子事件。近几年对于肝癌非编码RNA (ncRNA)的有限研究虽然得到了一些有提示意义的数据,但是尚未达到大规模转录组学水平,特别是small ncRNA和mRNA-like ncRNA在肝癌中差异表达的报道几乎为空白。本研究拟通过用芯片研究新ncRNA在肝癌中的差异表达,填补肝癌相关ncRNA高通量研究的空白,首次建立肝细胞特定长度范围的ncRNA高通量测序模型,成为国际领先的研究领域。
另一方面,中国的肝癌绝大多数发生于慢性乙型肝炎(乙肝)、肝硬化的基础之上。虽然乙肝在中国无论是绝对数量还是相对比例在世界上都居前列,但是由于慢性乙肝的并发症通常要几十年才能观察到,大陆地区颇具说服力的大宗前瞻性队列研究乙肝与肝癌相关的报告稀缺,尚缺乏直接针对临床转归结果的长期随访研究证据。
目的
发现肝癌特异表达的新非编码基因。
发现肝癌早期诊断标记物。
探索肝癌发生机制,辅助肝癌基因分型、治疗方案选择和预后预测。
探索乙型肝炎病毒感染状态与肝癌发生的相关性。
方法
研究一：计算处理构建大型ncRNA数据库。收集不同分化程度的HCC及相应癌旁组织标本,系统性记录患者的临床病理特征,构建特异性ncRNA文库。用新发现的small ncRNA和：mRNA-like ncRNA制备芯片,通过与芯片杂交,寻找肝癌中差异表达的靶基因,并用RT-PCR和Northern印迹验证。整合已有芯片数据,建立肝癌相关ncRNA数据库。
研究二：回顾性分析北京协和医院和佑安医院收治的接受肝切除术、并经病理确诊的乙肝相关性肝癌患者的病历资料,以及协和医院体检中心的乙肝相关检查结果。
结果
研究一构建了4个大型ncRNA数据库：NONCODE, antiCODE, HPtaa和HPtam。在肝癌标本中识别出30条差异表达的新ncRNA,选择其中6条进行并获得Northern印迹验证。
研究二共纳入371名乙肝相关性肝癌患者,男／女：317／54；中位年龄53岁；ALT中位值41 U／L,48.5%在诊断时ALT水平正常；HBsAg携带者87.6%,乙肝大三阳15.9%,小三阳65.5%,HBsAg血清清除12.4%。与普通人群相比,乙肝相关性肝癌患者的大小三阳之比无显著性差异(P=0.1460)。139人检测了HBV DNA水平,拷贝数<103／mL、103-104／mL以及>104／mL的比例分别为51.1%、8.6%和40.3%。体检结果中HBsAg携带率为2.74%(3,548／129,568)。单位组织体检者(136／810)和个人体检者(283／1,333)大小三阳之比存在显著性差异(P=0.0383)。
结论
研究一表明,肝癌中存在诸多特异性表达的新非编码RNA,它们在肝癌相关领域的研究中颇具希望。需要进一步探索其功能；分析它们与临床病理特征之间的关系,用于肝癌诊治及分型；构建肝癌转录调控网络,理解肝癌发生发展机制；并可探索新的靶向治疗基因来帮助阻止癌变。
研究二提示,乙肝小三阳患者发生肝癌的风险可能与大三阳患者相似；HBVDNA拷贝数低于103／mL者依然可能有较高的肝癌发生风险。目前亟需汇集各主要医疗机构和流行病监控机构的资料,进行大规模临床调查,为真正意义上的乙肝一级、二级和三级预防提供依据。
Background
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy which is seriously jeopardizing the health of Chinese people. The carcinogenic process of HCC involves synergetic effects of multiple genes and environmental factors, requires various pathologic stages and engages a number of molecular events. Although the information obtained from limited studies on HCC-related noncoding RNAs (ncRNAs) in recent years can be suggestive, they have not yet reached the level of large-scale transcriptome research; particularly, there are currently few reports on the differential expression of small ncRNA and mRNA-like ncRNA in HCC. With microarray analysis of novel small ncRNAs and mRNA-like ncRNAs in HCCs, this study will be complementary to high throughput researches on HCC-related ncRNAs. It will for the first time establish a high throughput model of hepatocyte-specific ncRNA sequencing and pilot the related field.
On the other hand, HCCs in China mainly develop on the basis of chronic hepatitis B and cirrhosis. Although either the absolute number or the relative ratio of hepatitis B in China is among the highest in the world, there are few persuasive reports of large-scale prospective cohort studies on the relationship of hepatitis B and HCC, and sufficient evidence from long-term follow-ups which directly focus on the clinical consequences of chronic hepatitis B is still lacking, as it may take years for them to develop.
Objective
To identify novel HCC-specific noncoding genes.
To identify novel biomarkers for early diagnosis of HCC.
To investigate the carcinogenic mechanism of HCC, to facilitate the classification of HCC genes, choice of treatment regime, and prediction of prognosis.
To investigate the relationship of hepatitis B virus (HBV) infection status and HCC development.
Methods
In Part I, large-scale ncRNA databases were established by in silico computing. A specimen collection which includes various differentiated HCCs and their matched noncancerous tissues were established, patients'clinicopathological characteristics were systematically recorded, and a liver-specific ncRNA library was constructed. By hybridizing with gene chips containing novelly identified small ncRNAs and mRNA-like ncRNAs, microarray analysis was applied to search for target genes that differentially expressed in HCC, which were then verified by RT-PCR and Northern blot. A HCC-related ncRN A database will be established by integrating results of this study with available data of other ncRNA chips.
In Part II, the medical records of patients who were admitted into Peking Union Medical College Hospital (PUMCH) and Youan Hospital, and underwent hepatectomy followed with a pathologically confirmed diagnosis of HBV-related HCC, and the results of HBV-related tests in PUMCH Health Checkup Center were retrospectively analyzed.
Results
In PartⅠ, four large-scale ncRNA databases were established, i.e. NONCODE, antiCODE, HPtaa, and HPtam.30 differentially expressed novel ncRNAs were identified in HCC specimens.6 of them were selected and verified by Northern blot.
In PartⅡ, a total of 371 patients with HBV-related HCC were enrolled, male/female: 317/54; median age:53 yrs; median ALT:41 U/L,48.5% were with a normal ALT level at HCC diagonosis; patients who were HBsAg carriers, HBsAg-positive/HBeAg-positive, HBsAg-positive/HBeAg-negative, and HBsAg-seronegative were 87.6%,15.9%,65.5% and 12.4% respectively. Compared with the data from regular health checkups, the ratio of HBeAg-positive patients with HBV-related HCC to HBeAg-negative ones was not significantly different (P=0.1460). HBV DNA levels were determined in a total of 139 patients with HBV-related HCC. Among them, the rates of HBV DNA<103,103-104, and>104 copies/mL were 51.1%,8.6% and 40.3% respectively. According to the data from regular health checkups, HBsAg carrier rate was 2.74% (3,548/129,568). The ratio of HBeAg-positive to HBeAg-negative patients in company-organized participants was significantly different from that in individual ones (136/810 vs 283/1,333,P=0.0383).
Conclusions
PartⅠreveals that there are a large number of novel ncRNAs which specifically express in HCCs, suggesting the promise of these ncRNAs in HCC-related field. It is warranted to further investigate their functions, to analyze their relationship with clinicopathological features for the diagnosis, treatment and classification of HCC, to construct the transcription modulation network in HCC to understand its carcinogenic mechanisms, and to explore novel target genes to prevent HCC development.
PartⅡindicates that the risk of HCC development in HBsAg-positive, HBeAg-negative patients seems to be similar to that in HBsAg-positive, HBeAg-positive ones; patients with a HBV DNA level<103 copies/mL are still at a higher risk of HCC. At present, collecting data from major medical institutes and disease control centers and conducting large-scale clinical investigations are warranted to provide supports for the primary, secondary and third preventions against hepatitis B.
引文
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