【摘要】：研究背景與目的肝癌(Hepatocellular Carcinoma,HCC)是世界范圍內(nèi)第六大常見惡性腫瘤,居全球惡性腫瘤死亡原因的第二位。在我國,慢性乙型肝炎(chronic hepatitisB,CHB)是導(dǎo)致肝癌發(fā)生的主要原因。甲胎蛋白是目前臨床上診斷原發(fā)性肝癌時(shí)最為常用的血清學(xué)腫瘤標(biāo)志物,但由于其準(zhǔn)確率受腫瘤大小和數(shù)量等因素的影響,仍然存在較高的假陽性和假陰性率。為了提高早期肝癌的診斷率,我們亟需尋找甲胎蛋白之外的有效的腫瘤學(xué)標(biāo)志物。SOX11是一種轉(zhuǎn)錄因子,在調(diào)節(jié)細(xì)胞增殖、分化和多個(gè)關(guān)鍵生存環(huán)節(jié)中發(fā)揮重要的調(diào)控作用。另外有研究表明SOX11基因啟動(dòng)子區(qū)的異常甲基化在腫瘤的發(fā)生與發(fā)展中起重要作用。目前學(xué)者們已經(jīng)在多種類型的惡性腫瘤發(fā)現(xiàn)了SOX11基因的異常甲基化,如胃癌、造血系統(tǒng)惡性腫瘤和鼻咽癌。然而,S0X11啟動(dòng)子在肝癌中的甲基化狀態(tài)還未見報(bào)道。本研究旨在探究SOX11基因啟動(dòng)子甲基化在乙肝相關(guān)性肝細(xì)胞癌中的潛在診斷價(jià)值,從而為肝癌的早期診斷提供依據(jù)。研究方法在我們的回顧性隊(duì)列研究中,共納入205例研究對(duì)象,其中包括111例HCC患者,66例CHB患者,和28例健康志愿者為正常對(duì)照(heal thy control s,HCs)。通過甲基化特異性聚合酶鏈?zhǔn)椒磻?yīng)(methylation specific PCR,MSP)檢測(cè)SOX11基因啟動(dòng)子的甲基化狀態(tài)。所得數(shù)據(jù)采用SPSS22.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析,數(shù)據(jù)資料用數(shù)字或者中位數(shù)表示,組間差異采用卡方檢驗(yàn)或獨(dú)立樣本t檢驗(yàn)進(jìn)行分析。P0.05時(shí)視為具有顯著的統(tǒng)計(jì)學(xué)差異。結(jié)果1..HCC組患者血清SOX11基因啟動(dòng)子甲基化率(69.4%,77/111)顯著高于CHB 組患者(13.6%,9/66:χ2=51.467,P0.001)和正常對(duì)照組人群(10.7%,3/27;χ2=31.489,P0.001),而CHB組患者與正常對(duì)照組人群之間無統(tǒng)計(jì)學(xué)差異(χ2=0.007,P=0.934)。2.存在血管侵襲的肝癌患者其SOX11啟動(dòng)子甲基化頻率(49/58)明顯高于未發(fā)生血管侵襲肝癌患者的SOX11啟動(dòng)子甲基化頻率(28/53),兩組之間甲基化頻率存在顯著的差異(χ 2=13.058,P0.001)。3.血清SOX11啟動(dòng)子甲基化在HCC診斷中的敏感性為69%明顯高于血清AFP的敏感性(57%)。SOX11啟動(dòng)子甲基化和血清甲胎蛋白(AFP)聯(lián)合應(yīng)用檢測(cè)HCC的敏感性高達(dá)85%優(yōu)于兩者單獨(dú)使用的敏感性。結(jié)論SOX11基因啟動(dòng)子在HCC患者中的甲基化頻率顯著高于慢乙肝組及健康對(duì)照組,AFP和SOX11啟動(dòng)子甲基化聯(lián)合應(yīng)用檢測(cè)肝癌可以大大提高肝癌診斷的敏感性,表明SOX11啟動(dòng)子甲基化可能成為診斷肝癌的有效的非侵入性的生物標(biāo)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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.7

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