蛋白芯片技术在肝癌诊断和介入治疗疗效评价中的应用
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摘要
目的:
肝癌是一类常见的恶性肿瘤。在我国,肝癌的发病率和死亡率都位于恶性肿瘤的前列。肝癌的发病隐匿,在早期缺乏明显的临床症状,发展又比较迅速,这导致了大多数患者就诊时已处于癌症的中、晚期,错过了最佳的治疗时期。血清AFP检测是目前早期诊断肝癌的最佳指标,但AFP检测的灵敏度只有39%~65%,特异度也只有70%~90%。除AFP外,目前尚无更好的早期诊断肝癌的血清学指标。因此,探寻新的肝癌相关标志物将有助于更为准确的早期诊断肝癌。在肝癌的治疗方面,手术切除是首选的治疗方法,但由于很多患者确诊较晚,已错过了手术治疗的时期。对于这些已错过手术切除时期的肝癌患者,肝动脉灌注化疗栓塞术是一种很好的治疗手段。该方法具有操作简便,创伤小和副作用少的优点,目前已广泛应用于治疗中晚期肝癌患者。由于该方法需多次介入治疗,其疗效的评判对于后续的治疗有十分重要的意义,而目前除影像学方法外,尚无较好的血清学指标。表面激光解析电离飞行时间质谱技术(surface-enhanced laser desorption-ionization time-of-flight mass spectrometry, SELDI-TOF-MS)是一种新兴的蛋白组学技术,该方法具有快速,简便和高通量的优点,为肿瘤血清标志物的研究提供了崭新的技术平台。本研究旨在运用SELDI技术分析健康对照和原发性肝癌患者介入治疗前和介入治疗后的血清蛋白表达谱,找寻三者之间的差异蛋白,发现对肝癌的诊断和评价介入治疗疗效有意义的标志物。
方法:
应用表面增强激光解析电离飞行时间质谱(SELDI-TOF-MS)技术和IMAC-Cu蛋白芯片检测64例健康人和30例原发性肝癌患者介入治疗前和介入治疗后的血清,获得蛋白表达谱,用Bio-Marker Wizard软件分析图谱得到表达差异蛋白,并从中筛选出可用于肝癌诊断和疗效评价的蛋白。
结果:
健康对照组、介入治疗前和介入治疗后的肝癌患者三组间有14个蛋白表达有显著性差异(P<0.05),其中质荷比(M/Z)为3949和4276的蛋白对肝癌的诊断有较高的诊断效能,其灵敏度分别为93.30%和100%,特异度分别为81.25%和84.38%。肝癌患者介入治疗前后比较,质荷比2786.08的蛋白峰表达有显著性差异(P<0.05),介入治疗后该蛋白表达升高,但有一组患者介入治疗后该蛋白仅有略微升高,另一组患者该蛋白表达大幅度升高。前一组在术后两月肿瘤缩小率,术后总生存时间和术后两年生存率这些指标上都要高于另一组患者(P<0.05)。
结论:
SELDI-TOF-MS技术可用于筛选肝癌的特异性标志物,所发现的这14个蛋白可能参与了肝癌的发生和发展进程,其中质荷比为3949和4276的蛋白有可能是肝癌诊断的潜在标志物,质荷比为2786的蛋白对肝癌介入治疗的疗效评价有指导意义。
Objective: Hepatocellular carcinoma is a common cancer. In China, the incidence and mortality rates of hepatocellular carcinoma are in front of all cancers. Because of no obvious clinical symptoms in the early period, most patients have missed the best treatment period . In currently, detection of serum AFP is the best diagnostic biomarker of liver cancer. But the sensitivity of AFP is only 39%~65%, and the specificity is 70%~90%. In addition to AFP, there is no better diagnostic biomarker of liver cancer. If we found a new biomarker which is more sensitive and accurate than AFP, the early diagnosis and treatment of liver cancer will be great improving. In the treatment of liver cancer, surgical resection is the preferred treatment. But many patient have not diagnosed in time, they have missed the best time of operation. For these patients, transcatheter arterial chemoembolization is a good choice. This method is more simple, have less wound and fewer side effect for patients. So it has been widely used in the treatment of patients of liver cancer. Because this method requires several times intervention treatment, the evaluation of efficacy is very important for the follow-up treatment. In addition to the imaging method, there is no good serum biomarker in recently. Surface-enhanced laser desorption/ ionization time of flight mass spectrometry is a new proteomics technology. This method have the advantages of fast, simple and high-throughput. It provided a new platform for the research of biomarker of cancer. This research use the SELDI-TOF-MS technique to screen meaningful protein for diagnosis and estimating the efficacy of transcatheter arterial chemoembolization of hepatocellular carcinoma by analyzing the serum protein expression profiles of healthy people and the patients with primary liver cancer before and after interventional therapy.
Methods: SELDI-TOF-MS technique and IMAC-Cu Protein Chip were used to detect serum of 64 healthy people and 30 patients with hepatocellular carcinoma before and after transcatheter arterial chemoembolization. Proteomic spectra were analyzed by Bio-Marker Wizard software. Results: 14 proteins were significantly different among the healthy people,the patients without any treatment and the patients with intervention treatment(P<0.05).2 proteins(mass-to-charge ratio 3949Da and 4276Da) have a higher diagnostic efficacy, the sensitivity were 93.3% and 100%,specificity were 81.25% and 84.38%. One protein( M/Z2786.08) was significantly different between before and after TACE(P <0.05).The group of this protein low expressed after TACE were better than the group of this protein high expressed after TACE on tumor shrinkage rate ,survival time and survival rate after surgery(P <0.05).
Conclusion: SELDI-TOF-MS technology can be used to screen serum markers of liver cancer, 14 proteins which was found may be involved in the process of occurrence and development of liver cancer, the protein(M/Z2786.08) may be the drug targets of treatment and can be used to evaluate the efficacy of TACE.
肝癌是一类常见的恶性肿瘤。在我国,肝癌的发病率和死亡率都位于恶性肿瘤的前列。肝癌的发病隐匿,在早期缺乏明显的临床症状,发展又比较迅速,这导致了大多数患者就诊时已处于癌症的中、晚期,错过了最佳的治疗时期。血清AFP检测是目前早期诊断肝癌的最佳指标,但AFP检测的灵敏度只有39%~65%,特异度也只有70%~90%。除AFP外,目前尚无更好的早期诊断肝癌的血清学指标。因此,探寻新的肝癌相关标志物将有助于更为准确的早期诊断肝癌。在肝癌的治疗方面,手术切除是首选的治疗方法,但由于很多患者确诊较晚,已错过了手术治疗的时期。对于这些已错过手术切除时期的肝癌患者,肝动脉灌注化疗栓塞术是一种很好的治疗手段。该方法具有操作简便,创伤小和副作用少的优点,目前已广泛应用于治疗中晚期肝癌患者。由于该方法需多次介入治疗,其疗效的评判对于后续的治疗有十分重要的意义,而目前除影像学方法外,尚无较好的血清学指标。表面激光解析电离飞行时间质谱技术(surface-enhanced laser desorption-ionization time-of-flight mass spectrometry, SELDI-TOF-MS)是一种新兴的蛋白组学技术,该方法具有快速,简便和高通量的优点,为肿瘤血清标志物的研究提供了崭新的技术平台。本研究旨在运用SELDI技术分析健康对照和原发性肝癌患者介入治疗前和介入治疗后的血清蛋白表达谱,找寻三者之间的差异蛋白,发现对肝癌的诊断和评价介入治疗疗效有意义的标志物。
方法:
应用表面增强激光解析电离飞行时间质谱(SELDI-TOF-MS)技术和IMAC-Cu蛋白芯片检测64例健康人和30例原发性肝癌患者介入治疗前和介入治疗后的血清,获得蛋白表达谱,用Bio-Marker Wizard软件分析图谱得到表达差异蛋白,并从中筛选出可用于肝癌诊断和疗效评价的蛋白。
结果:
健康对照组、介入治疗前和介入治疗后的肝癌患者三组间有14个蛋白表达有显著性差异(P<0.05),其中质荷比(M/Z)为3949和4276的蛋白对肝癌的诊断有较高的诊断效能,其灵敏度分别为93.30%和100%,特异度分别为81.25%和84.38%。肝癌患者介入治疗前后比较,质荷比2786.08的蛋白峰表达有显著性差异(P<0.05),介入治疗后该蛋白表达升高,但有一组患者介入治疗后该蛋白仅有略微升高,另一组患者该蛋白表达大幅度升高。前一组在术后两月肿瘤缩小率,术后总生存时间和术后两年生存率这些指标上都要高于另一组患者(P<0.05)。
结论:
SELDI-TOF-MS技术可用于筛选肝癌的特异性标志物,所发现的这14个蛋白可能参与了肝癌的发生和发展进程,其中质荷比为3949和4276的蛋白有可能是肝癌诊断的潜在标志物,质荷比为2786的蛋白对肝癌介入治疗的疗效评价有指导意义。
Objective: Hepatocellular carcinoma is a common cancer. In China, the incidence and mortality rates of hepatocellular carcinoma are in front of all cancers. Because of no obvious clinical symptoms in the early period, most patients have missed the best treatment period . In currently, detection of serum AFP is the best diagnostic biomarker of liver cancer. But the sensitivity of AFP is only 39%~65%, and the specificity is 70%~90%. In addition to AFP, there is no better diagnostic biomarker of liver cancer. If we found a new biomarker which is more sensitive and accurate than AFP, the early diagnosis and treatment of liver cancer will be great improving. In the treatment of liver cancer, surgical resection is the preferred treatment. But many patient have not diagnosed in time, they have missed the best time of operation. For these patients, transcatheter arterial chemoembolization is a good choice. This method is more simple, have less wound and fewer side effect for patients. So it has been widely used in the treatment of patients of liver cancer. Because this method requires several times intervention treatment, the evaluation of efficacy is very important for the follow-up treatment. In addition to the imaging method, there is no good serum biomarker in recently. Surface-enhanced laser desorption/ ionization time of flight mass spectrometry is a new proteomics technology. This method have the advantages of fast, simple and high-throughput. It provided a new platform for the research of biomarker of cancer. This research use the SELDI-TOF-MS technique to screen meaningful protein for diagnosis and estimating the efficacy of transcatheter arterial chemoembolization of hepatocellular carcinoma by analyzing the serum protein expression profiles of healthy people and the patients with primary liver cancer before and after interventional therapy.
Methods: SELDI-TOF-MS technique and IMAC-Cu Protein Chip were used to detect serum of 64 healthy people and 30 patients with hepatocellular carcinoma before and after transcatheter arterial chemoembolization. Proteomic spectra were analyzed by Bio-Marker Wizard software. Results: 14 proteins were significantly different among the healthy people,the patients without any treatment and the patients with intervention treatment(P<0.05).2 proteins(mass-to-charge ratio 3949Da and 4276Da) have a higher diagnostic efficacy, the sensitivity were 93.3% and 100%,specificity were 81.25% and 84.38%. One protein( M/Z2786.08) was significantly different between before and after TACE(P <0.05).The group of this protein low expressed after TACE were better than the group of this protein high expressed after TACE on tumor shrinkage rate ,survival time and survival rate after surgery(P <0.05).
Conclusion: SELDI-TOF-MS technology can be used to screen serum markers of liver cancer, 14 proteins which was found may be involved in the process of occurrence and development of liver cancer, the protein(M/Z2786.08) may be the drug targets of treatment and can be used to evaluate the efficacy of TACE.
引文
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[2] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancerstatistics, 2002. CA Cancer J Clin 2005; 55: 74-108.
[3]吴孟超,陈汉,沈锋.原发性肝癌的外科治疗——附5524例报告[J].中华外科杂志,2001,39(1):25-28.
[4]魏学、王少斌、芮静安.原发性肝癌诊断中血清αL岩藻糖苷酶的价值.中华肿瘤杂志、2000、22:148-150.
[5] ]Yoshida S, Kurokohchik, Arimak, et al. Clinical significance of lens culinaris agglutinin-reaetive fraction of serum alpha-fetoprotein in patients with hepatocellrlar carcinoma.Int J Oncol.2002 Feb,20(2):305-309.
[6] Parasole R, Izzo F, Perrone F, et al. Prognostic value of serurn biological markers in patients with hepatocellular carcinoma .Clin Cancer Res,2001,7:3504-3509.
[7] Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907-1917
[8]Sidransky D.Emerging molecular markers of cancer.Nat Rev Cancer.2002,2(3):210-219.
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