肝癌复发转移相关标志蛋白的研究
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摘要
[背景和目的]原发性肝癌是恶性程度高、死亡率高的消化系统肿瘤。肝细胞性肝癌占原发性肝恶性肿瘤90%,转移和复发是影响其生存率的主要因素。目前,除AFP外仍没有一种得到公认可作为临床常规检查的有效的肿瘤标志物。因而,寻找肝癌转移复发相关标志蛋白,探讨其分子机制已经成为肝癌相关转化医学研究的重点。外周血血浆包含丰富的蛋白质,肝脏局部的组织病理改变也可以表现在血浆蛋白质成分和数量的改变,此类特征性变化有可能作为实时监测指标,对于肿瘤诊治有重要意义。本研究采用一个新的研究方法鉴定肿瘤组织释放到血液中的游离蛋白,以此寻找肝癌的候选肿瘤标志物,并且进行了临床标本验证。
[方法]采用本实验室前期工作构建的体液中肿瘤相关蛋白研究体系,收集了12例肝细胞性肝癌患者的肿瘤组织和癌旁肝组织样品,采用上皮细胞专用无血清培养基建立了体外原代培养并收集其条件培养基；其中6例(对)条件培养基所含总蛋白经过透析浓缩除盐后,以10%聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,随后进行质谱分析,以此构建肝细胞性肝癌相关游离蛋白数据库,对数据库中蛋白利用DAVID Bioinformatics Resources (http://david.abcc.ncifcrf.gov/ home. jsp)进行了生物信息学分析。结合目前已发表的肝癌转移、复发相关基因表达谱及蛋白标志数据库信息,选定候选肝癌复发转移蛋白标志。将首选候选肝癌复发转移蛋白标志MMP1和MMP7进行回顾性验证。回顾性复习肝癌病例69例,将其中治疗后2年后无瘤生存者定义为“极好组”,治疗后1年内复发转移/2年内死亡者定义为“极差组”；针对极好组(34例)与极差组(35例)患者的肿瘤组织进行免疫组化检测。同时,通过ELISA的方法,分析候选蛋白MMP1、MMP7以及NID1在126例肝细胞肝癌病例和104例正常人群血浆中的蛋白水平差异。
[结果]本研究从肝癌和癌旁组织原代培养的6对条件培养基样品中共鉴定出1365个高可信度蛋白,初步建立了肝细胞肝癌相关游离蛋白数据库。其中细胞外(分泌)蛋白占16%,膜蛋白占3%,胞浆蛋白占21%。免疫组化分析结果显示,MMP1在癌旁肝组织的阳性表达与预后分组、肝被膜浸润存在显著性相关；而MMP7蛋白在癌旁肝组织的表达水平显著性高于癌组织。ELISA结果显示,MMP1、MMP7和NID1肝癌病人血浆的蛋白水平显著高于正常人群对照组。NIDl与肝被膜浸润、肝炎肝病背景存在显著性负相关。MMP7与肿瘤卫星灶、肿瘤个数、肝炎肝病背景存在显著性正相关。MMP1、NID1和AFP联合检测诊断肝癌的敏感性和特异性分别为：67.7%,92.2%,高于其中任何一个单独指标。
[结论]本研究初步建立了肝细胞肝癌相关游离蛋白数据库,为肝癌肿瘤标志物等相关研究奠定了基础；MMP1、MMP7和NID1与肝细胞肝癌转移复发相关；MMP1、NID1和AFP这3种蛋白联合检测并结合肝癌预后相关临床指标,可以提高肝癌诊断及判断预后的准确性。
[Background and aims] Primary liver cancer is a kind of high malignant and high mortality digestive system tumor. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer; and metastasis and recurrence are the main factors affecting pateints'survival. Discovering the protein markers associated with tumor metastasis and recurrence of HCC and exploring the molecular mechanism have been the focus of the translational study for HCC. Besides alpha-fetoprotein (AFP), there is lack of effective tumor marker in clinical routine examination for liver cancers. Peripheral blood plasma contains large abundant proteins, and the pathological changes of tumor in liver can be reflected by the changes about type and/or quantity of proteins in the blood. Such characteristic changes may serve as indicators of real-time monitoring for development of the disease, so they are important for diagnosis and therapy. In this study, a novel approach was applied to discover the proteins released into the blood by solid tumors, and the resulting candidate protein markers were then validated with the tumor tissues and the blood samples derived from the patients with HCC.
[Methods] We selected HCC tiussue for Primary organ cultures were estalished with the tumor and the adjacent tissues from 12 HCC patients with the epithelial cells specific serum-free medium, and then the conditional media (CM) were collected. The total proteins in 6 pairs of CM samples were separated by one-dimensional polyacrylamide gel electrophoresis, and analyzed with liquid chromatography-tandem mass spectrometry. DAVID bioinformatics resources (http://david.abcc.ncifcrf.gov/ home.jsp) were used for bioinformatics analysis to establish the HCC-related protein database. The interesting proteins from the database were selected for validation. Expression status of MMP1 and MMP7 was analyzed by immunohistochemical staining, with 71 paraffin-embedded tumor tissues from HCC patients. The circulating plasma protein levels of NID1, MMP1 and MMP7 were analyzed by enzyme-linked immunosorbent assay (ELISA), with a series of 230 blood samples, including 126 HCC patients, and 104 normal controls.
[Results] Combining data of the CM samples from the tumor tissues and the adjacent tissues,1365 proteins were identified and a HCC-derived proteome database was generated. By subcellular location analysis, among these CM proteins,16% were annotated as extracellular or secreted proteins,3% were membrane associated proteins, 21% were cytoplasmic proteins. Immunohistochemistry resluts showed that MMP1 expresion in the surrounding nontumoral liver tissue were highly correlated with infiltration of liver capsule and survival of the patients. The protein expression of MMP7 in adjacent liver tissues was significantly higher than that in the tumor tissues. ELISA results indicated that the plasma protein levels of MMP1, MMP7 and NID1 were elevated in HCC patients compared to that of healthy subjects. The plasma levels of NID1 in HCC patients were significant negative correlated with infiltration of the liver capsule and background of hepatitis. The plasma levels of MMP7 in HCC patients were positive correlated with satellite tumor, number of tumors, and hepatitis. The preliminary results showed that combination of MMP1, NID1, and AFP had a higher sensitivity and specificity than any single marker.
[Conclusions] The HCC-derived'secretory/released proteome'generated in this study provides a credible repertoire of potential biomarkers in blood for guiding both detection and prognosis of HCC. The plasma protein levels of MMP1, MMP7, and NID1 are correlated with the tumor metastasis and recurrence of hepatocellular carcinoma. A tumor marker panel (MMP1, NID1 and AFP) combind with clinical factors can improve the accuracy of diagnosis and prognosis.
[方法]采用本实验室前期工作构建的体液中肿瘤相关蛋白研究体系,收集了12例肝细胞性肝癌患者的肿瘤组织和癌旁肝组织样品,采用上皮细胞专用无血清培养基建立了体外原代培养并收集其条件培养基；其中6例(对)条件培养基所含总蛋白经过透析浓缩除盐后,以10%聚丙烯酰胺凝胶电泳(SDS-PAGE)分离,随后进行质谱分析,以此构建肝细胞性肝癌相关游离蛋白数据库,对数据库中蛋白利用DAVID Bioinformatics Resources (http://david.abcc.ncifcrf.gov/ home. jsp)进行了生物信息学分析。结合目前已发表的肝癌转移、复发相关基因表达谱及蛋白标志数据库信息,选定候选肝癌复发转移蛋白标志。将首选候选肝癌复发转移蛋白标志MMP1和MMP7进行回顾性验证。回顾性复习肝癌病例69例,将其中治疗后2年后无瘤生存者定义为“极好组”,治疗后1年内复发转移/2年内死亡者定义为“极差组”；针对极好组(34例)与极差组(35例)患者的肿瘤组织进行免疫组化检测。同时,通过ELISA的方法,分析候选蛋白MMP1、MMP7以及NID1在126例肝细胞肝癌病例和104例正常人群血浆中的蛋白水平差异。
[结果]本研究从肝癌和癌旁组织原代培养的6对条件培养基样品中共鉴定出1365个高可信度蛋白,初步建立了肝细胞肝癌相关游离蛋白数据库。其中细胞外(分泌)蛋白占16%,膜蛋白占3%,胞浆蛋白占21%。免疫组化分析结果显示,MMP1在癌旁肝组织的阳性表达与预后分组、肝被膜浸润存在显著性相关；而MMP7蛋白在癌旁肝组织的表达水平显著性高于癌组织。ELISA结果显示,MMP1、MMP7和NID1肝癌病人血浆的蛋白水平显著高于正常人群对照组。NIDl与肝被膜浸润、肝炎肝病背景存在显著性负相关。MMP7与肿瘤卫星灶、肿瘤个数、肝炎肝病背景存在显著性正相关。MMP1、NID1和AFP联合检测诊断肝癌的敏感性和特异性分别为：67.7%,92.2%,高于其中任何一个单独指标。
[结论]本研究初步建立了肝细胞肝癌相关游离蛋白数据库,为肝癌肿瘤标志物等相关研究奠定了基础；MMP1、MMP7和NID1与肝细胞肝癌转移复发相关；MMP1、NID1和AFP这3种蛋白联合检测并结合肝癌预后相关临床指标,可以提高肝癌诊断及判断预后的准确性。
[Background and aims] Primary liver cancer is a kind of high malignant and high mortality digestive system tumor. Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer; and metastasis and recurrence are the main factors affecting pateints'survival. Discovering the protein markers associated with tumor metastasis and recurrence of HCC and exploring the molecular mechanism have been the focus of the translational study for HCC. Besides alpha-fetoprotein (AFP), there is lack of effective tumor marker in clinical routine examination for liver cancers. Peripheral blood plasma contains large abundant proteins, and the pathological changes of tumor in liver can be reflected by the changes about type and/or quantity of proteins in the blood. Such characteristic changes may serve as indicators of real-time monitoring for development of the disease, so they are important for diagnosis and therapy. In this study, a novel approach was applied to discover the proteins released into the blood by solid tumors, and the resulting candidate protein markers were then validated with the tumor tissues and the blood samples derived from the patients with HCC.
[Methods] We selected HCC tiussue for Primary organ cultures were estalished with the tumor and the adjacent tissues from 12 HCC patients with the epithelial cells specific serum-free medium, and then the conditional media (CM) were collected. The total proteins in 6 pairs of CM samples were separated by one-dimensional polyacrylamide gel electrophoresis, and analyzed with liquid chromatography-tandem mass spectrometry. DAVID bioinformatics resources (http://david.abcc.ncifcrf.gov/ home.jsp) were used for bioinformatics analysis to establish the HCC-related protein database. The interesting proteins from the database were selected for validation. Expression status of MMP1 and MMP7 was analyzed by immunohistochemical staining, with 71 paraffin-embedded tumor tissues from HCC patients. The circulating plasma protein levels of NID1, MMP1 and MMP7 were analyzed by enzyme-linked immunosorbent assay (ELISA), with a series of 230 blood samples, including 126 HCC patients, and 104 normal controls.
[Results] Combining data of the CM samples from the tumor tissues and the adjacent tissues,1365 proteins were identified and a HCC-derived proteome database was generated. By subcellular location analysis, among these CM proteins,16% were annotated as extracellular or secreted proteins,3% were membrane associated proteins, 21% were cytoplasmic proteins. Immunohistochemistry resluts showed that MMP1 expresion in the surrounding nontumoral liver tissue were highly correlated with infiltration of liver capsule and survival of the patients. The protein expression of MMP7 in adjacent liver tissues was significantly higher than that in the tumor tissues. ELISA results indicated that the plasma protein levels of MMP1, MMP7 and NID1 were elevated in HCC patients compared to that of healthy subjects. The plasma levels of NID1 in HCC patients were significant negative correlated with infiltration of the liver capsule and background of hepatitis. The plasma levels of MMP7 in HCC patients were positive correlated with satellite tumor, number of tumors, and hepatitis. The preliminary results showed that combination of MMP1, NID1, and AFP had a higher sensitivity and specificity than any single marker.
[Conclusions] The HCC-derived'secretory/released proteome'generated in this study provides a credible repertoire of potential biomarkers in blood for guiding both detection and prognosis of HCC. The plasma protein levels of MMP1, MMP7, and NID1 are correlated with the tumor metastasis and recurrence of hepatocellular carcinoma. A tumor marker panel (MMP1, NID1 and AFP) combind with clinical factors can improve the accuracy of diagnosis and prognosis.
引文
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