血清SOX11基因启动子甲基化作为肝癌潜在标志物的研究
发布时间：2018-07-16 07:45
【摘要】：研究背景与目的肝癌(Hepatocellular Carcinoma,HCC)是世界范围内第六大常见恶性肿瘤,居全球恶性肿瘤死亡原因的第二位。在我国,慢性乙型肝炎(chronic hepatitisB,CHB)是导致肝癌发生的主要原因。甲胎蛋白是目前临床上诊断原发性肝癌时最为常用的血清学肿瘤标志物,但由于其准确率受肿瘤大小和数量等因素的影响,仍然存在较高的假阳性和假阴性率。为了提高早期肝癌的诊断率,我们亟需寻找甲胎蛋白之外的有效的肿瘤学标志物。SOX11是一种转录因子,在调节细胞增殖、分化和多个关键生存环节中发挥重要的调控作用。另外有研究表明SOX11基因启动子区的异常甲基化在肿瘤的发生与发展中起重要作用。目前学者们已经在多种类型的恶性肿瘤发现了SOX11基因的异常甲基化,如胃癌、造血系统恶性肿瘤和鼻咽癌。然而,S0X11启动子在肝癌中的甲基化状态还未见报道。本研究旨在探究SOX11基因启动子甲基化在乙肝相关性肝细胞癌中的潜在诊断价值,从而为肝癌的早期诊断提供依据。研究方法在我们的回顾性队列研究中,共纳入205例研究对象,其中包括111例HCC患者,66例CHB患者,和28例健康志愿者为正常对照(heal thy control s,HCs)。通过甲基化特异性聚合酶链式反应(methylation specific PCR,MSP)检测SOX11基因启动子的甲基化状态。所得数据采用SPSS22.0软件进行统计学分析,数据资料用数字或者中位数表示,组间差异采用卡方检验或独立样本t检验进行分析。P0.05时视为具有显著的统计学差异。结果1..HCC组患者血清SOX11基因启动子甲基化率(69.4%,77/111)显著高于CHB 组患者(13.6%,9/66:χ2=51.467,P0.001)和正常对照组人群(10.7%,3/27;χ2=31.489,P0.001),而CHB组患者与正常对照组人群之间无统计学差异(χ2=0.007,P=0.934)。2.存在血管侵袭的肝癌患者其SOX11启动子甲基化频率(49/58)明显高于未发生血管侵袭肝癌患者的SOX11启动子甲基化频率(28/53),两组之间甲基化频率存在显著的差异(χ 2=13.058,P0.001)。3.血清SOX11启动子甲基化在HCC诊断中的敏感性为69%明显高于血清AFP的敏感性(57%)。SOX11启动子甲基化和血清甲胎蛋白(AFP)联合应用检测HCC的敏感性高达85%优于两者单独使用的敏感性。结论SOX11基因启动子在HCC患者中的甲基化频率显著高于慢乙肝组及健康对照组,AFP和SOX11启动子甲基化联合应用检测肝癌可以大大提高肝癌诊断的敏感性,表明SOX11启动子甲基化可能成为诊断肝癌的有效的非侵入性的生物标志物。
[Abstract]:Background and objective Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world and the second leading cause of death in the world. In China, chronic hepatitis B (chronic hepatitis B) is the main cause of liver cancer. Alpha-fetoprotein is the most commonly used serological tumor marker in the diagnosis of primary liver cancer. However, due to the influence of tumor size and quantity, there are still high false positive and false negative rates. In order to improve the diagnosis rate of early hepatocellular carcinoma, we need to find an effective oncology marker. SOX11 is a transcription factor, which plays an important role in regulating cell proliferation, differentiation and many key survival links. In addition, some studies have shown that abnormal methylation of SOX11 gene promoter plays an important role in tumorigenesis and development. At present, SOX11 gene methylation has been found in many types of malignant tumors, such as gastric cancer, hematopoietic system malignant tumor and nasopharyngeal carcinoma. However, the methylation status of the S 0 X 11 promoter in HCC has not been reported. The purpose of this study was to explore the potential diagnostic value of SOX11 promoter methylation in Hepatitis B associated hepatocellular carcinoma and provide evidence for early diagnosis of liver cancer. Methods A total of 205 subjects were enrolled in our retrospective cohort study, including 111 patients with HCC, 66 patients with CHB and 28 healthy volunteers as normal controls. Methylation status of SOX11 promoter was detected by methylation specific polymerase chain reaction (methylation specific PCR). The data were analyzed by SPSS22.0 software, the data were represented by numbers or median, and the differences between groups were analyzed by chi-square test or independent sample t-test. Results 1.The methylation rate of SOX11 promoter in HCC group (69.4%) was significantly higher than that in CHB group (13.666: 51.467% P0.001) and the normal control group (10.7% 32.7%; 蠂 2 + 31.489P0.001), but there was no significant difference between CHB group and normal control group (蠂 2 0.007 P 0.934) .2.The results showed that the methylation rate of SOX11 gene promoter in HCC group (69.4%) was significantly higher than that in CHB group (13.666: 51.467% P0.001) and that in normal control group (10.7% 32.7%; 蠂 2 + 31.489P0.001). The methylation frequency of SOX11 promoter in HCC patients with vascular invasion (49 / 58) was significantly higher than that in HCC patients without vascular invasion (28 / 53). The sensitivity of serum SOX11 promoter methylation in the diagnosis of HCC was 69% significantly higher than that of serum AFP (57%). The sensitivity of serum SOX11 promoter methylation combined with serum alpha-fetoprotein (AFP) was 85% higher than that of both alone. Conclusion the methylation frequency of SOX11 gene promoter in HCC patients is significantly higher than that in chronic hepatitis B group and healthy control group. Combined use of AFP and SOX11 promoter methylation can greatly improve the sensitivity of HCC diagnosis. These results suggest that SOX11 promoter methylation may be an effective noninvasive biomarker for the diagnosis of liver cancer.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.7
[Abstract]:Background and objective Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world and the second leading cause of death in the world. In China, chronic hepatitis B (chronic hepatitis B) is the main cause of liver cancer. Alpha-fetoprotein is the most commonly used serological tumor marker in the diagnosis of primary liver cancer. However, due to the influence of tumor size and quantity, there are still high false positive and false negative rates. In order to improve the diagnosis rate of early hepatocellular carcinoma, we need to find an effective oncology marker. SOX11 is a transcription factor, which plays an important role in regulating cell proliferation, differentiation and many key survival links. In addition, some studies have shown that abnormal methylation of SOX11 gene promoter plays an important role in tumorigenesis and development. At present, SOX11 gene methylation has been found in many types of malignant tumors, such as gastric cancer, hematopoietic system malignant tumor and nasopharyngeal carcinoma. However, the methylation status of the S 0 X 11 promoter in HCC has not been reported. The purpose of this study was to explore the potential diagnostic value of SOX11 promoter methylation in Hepatitis B associated hepatocellular carcinoma and provide evidence for early diagnosis of liver cancer. Methods A total of 205 subjects were enrolled in our retrospective cohort study, including 111 patients with HCC, 66 patients with CHB and 28 healthy volunteers as normal controls. Methylation status of SOX11 promoter was detected by methylation specific polymerase chain reaction (methylation specific PCR). The data were analyzed by SPSS22.0 software, the data were represented by numbers or median, and the differences between groups were analyzed by chi-square test or independent sample t-test. Results 1.The methylation rate of SOX11 promoter in HCC group (69.4%) was significantly higher than that in CHB group (13.666: 51.467% P0.001) and the normal control group (10.7% 32.7%; 蠂 2 + 31.489P0.001), but there was no significant difference between CHB group and normal control group (蠂 2 0.007 P 0.934) .2.The results showed that the methylation rate of SOX11 gene promoter in HCC group (69.4%) was significantly higher than that in CHB group (13.666: 51.467% P0.001) and that in normal control group (10.7% 32.7%; 蠂 2 + 31.489P0.001). The methylation frequency of SOX11 promoter in HCC patients with vascular invasion (49 / 58) was significantly higher than that in HCC patients without vascular invasion (28 / 53). The sensitivity of serum SOX11 promoter methylation in the diagnosis of HCC was 69% significantly higher than that of serum AFP (57%). The sensitivity of serum SOX11 promoter methylation combined with serum alpha-fetoprotein (AFP) was 85% higher than that of both alone. Conclusion the methylation frequency of SOX11 gene promoter in HCC patients is significantly higher than that in chronic hepatitis B group and healthy control group. Combined use of AFP and SOX11 promoter methylation can greatly improve the sensitivity of HCC diagnosis. These results suggest that SOX11 promoter methylation may be an effective noninvasive biomarker for the diagnosis of liver cancer.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.7
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