SREBF-1单核苷酸多态性与子宫内膜样腺癌高风险相关性分析

发布时间：2019-03-21 10:03

【摘要】：研究目的：子宫内膜癌(endometrial carcinoma, EC)是女性生殖器官常见的三大恶性肿瘤之一,在发达国家发病率位居妇科肿瘤首位,在我国发病率仅次于宫颈癌,其发病近年来呈上升趋势。恶性肿瘤的生物学行为与其特殊的物质和能量代谢密切相关,早在50多年前已发现肿瘤组织能以类似于胚胎组织的方式合成脂类,脂肪酸合成的显著增加是肿瘤细胞迅速增殖的重要标志,且肿瘤细胞自身从头合成90%以上的脂肪酸,且不受正常细胞对脂肪酸合成调节的影响。固醇调节元件结合蛋白(Sterol Regulatory Element Binding Protein, SREBP)由SREBF-1基因编码,是脂质生成基因的主要调节因子,通过结合于脂质合酶基因的启动子/增强子的固醇调节元件,激活其靶基因转录,调控胆固醇和脂质的合成代谢。研究已证实SREBP-1在子宫内膜癌中过度表达,并且与肿瘤组织分化程度的高低相关,SREBP-1shRNA可显著降低子宫内膜癌细胞的增殖、侵袭和集落形成能力,诱导子宫内膜癌细胞凋亡,并抑制裸鼠移植瘤形成和生长能力,表明内源性SREBP-1参与子宫内膜癌的发生和发展。肥胖和糖尿病是公认的子宫内膜样腺癌危险因素,研究表明SREBF-1基因多态性与肥胖和Ⅱ型糖尿病密切相关。因此,我们推测SREBF-1基因多态性可能与子宫内膜样腺癌高风险相关。研究方法：通过高通量测序检测对比无相关性的30例病人的子宫内膜样腺癌组织及6例正常人子宫内膜组织的SREBF-1基因序列。基于上述研究所得结果,选择与子宫内膜样腺癌发生高度相关的SNP(rs2297508)位点进行了一项临床病例对照研究,该研究包含122例子宫内膜腺癌病人和129例良性对照,所用组织标本均经过组织病理验证,然后用DNA提取试剂盒提取总DNA,行RT-PCR检测分析该位点的核苷酸。研究结果： (1)通过基因序列分析发现SREBF-1基因中存在10个与子宫内膜样腺癌可能相关的SNP位点,包括3个新发现的SNP位点。10个位点中SNP(rs2297508)位点与子宫内膜样腺癌关系最为密切。 (2)15.1%子宫内膜样腺癌病人在rs2297508位点为C等位基因,而在良性对照组织中该位点为C的仅有7.8%(P=0.017,OR=2.131)。C等位基因与子宫内膜样腺癌的分级(P0.05)和肌层浸润深度(P0.05)相关。研究结论： (1) SREBF-1基因中存在10个可能与子宫内膜样腺癌发生、发展相关的SNP位点,通过扩大样本进一步研究或可为子宫内膜样腺癌的分子靶向治疗提供了—定的理论基础； (2) SREBF-1基因中SNP(rs2297508)位点C等位基因增加子宫内膜样腺癌的发病风险,且可增加子宫内膜样腺癌患者的组织学分级及肌层浸润深度,表明SREBF-1基因中SNP(rs2297508)位点可作为子宫内膜样腺癌发生、发展的遗传标记物,通过筛查该位点的等位基因有助于子宫内膜样腺癌的早期检测。
[Abstract]:Objective: endometrial carcinoma (endometrial carcinoma, EC) is one of the three most common malignant tumors in female reproductive organs. In developed countries, the incidence of endometrial cancer is the first in gynecological tumors, and the incidence of endometrial cancer is second only to cervical cancer in China. The incidence of the disease has been increasing in recent years. The biological behavior of malignant tumor is closely related to its special material and energy metabolism. It has been discovered more than 50 years ago that tumor tissue can synthesize lipids in a manner similar to embryonic tissue. The significant increase in fatty acid synthesis is an important marker for the rapid proliferation of tumor cells, and the tumor cells themselves synthesize more than 90% of the fatty acids from scratch, and are not affected by the regulation of fatty acid synthesis by normal cells. The sterol regulatory element binding protein (Sterol Regulatory Element Binding Protein, SREBP), encoded by the SREBF-1 gene, is the main regulator of the lipid-producing gene by binding to the sterol regulatory element of the promoter / enhancer of the lipase gene. Activation of its target gene transcription, regulation of cholesterol and lipid synthesis and metabolism. It has been proved that SREBP-1 is overexpressed in endometrial carcinoma and correlated with the degree of tumor differentiation. SREBP-1shRNA can significantly reduce the proliferation, invasion and colony-forming ability of endometrial cancer cells. Apoptosis of endometrial carcinoma cells and inhibition of tumor formation and growth in nude mice showed that endogenous SREBP-1 was involved in the genesis and development of endometrial carcinoma. Obesity and diabetes are recognized risk factors for endometrioid adenocarcinoma. Studies have shown that SREBF-1 gene polymorphism is closely associated with obesity and type 2 diabetes. Therefore, we speculate that SREBF-1 gene polymorphism may be associated with a high risk of endometrioid adenocarcinoma. Methods: high-throughput sequencing was used to detect and compare the SREBF-1 gene sequences in 30 cases of endometrioid adenocarcinoma and 6 cases of normal endometrium. Based on the results of the above study, a clinical case-control study was conducted on the SNP (rs2297508) site, which is highly related to the occurrence of endometrioid adenocarcinoma. The study included 122 patients with endometrial adenocarcinoma and 129 benign controls. The total DNA, was extracted by DNA extraction kit and the nucleotide of the site was detected by RT-PCR. Results: (1) there were 10 SNP sites in SREBF-1 gene which may be associated with endometrioid adenocarcinoma. Among the 10 loci, SNP (rs2297508) was the most closely related to endometrioid adenocarcinoma. (2) in 15.1% of patients with endometrioid adenocarcinoma, C allele was found in rs2297508 locus, but only 7.8% in benign control tissues (P < 0.017, P < 0.01). OR=2.131). C allele was associated with the grade of endometrioid adenocarcinoma (P0.05) and the depth of myometrial invasion (P0.05). Conclusion: (1) there are 10 SNP sites in SREBF-1 gene which may be related to the development and development of endometrioid adenocarcinoma. Further study by expanding samples may provide a theoretical basis for molecular targeted therapy of endometrioid adenocarcinoma. (2) the C allele of SNP (rs2297508) locus in the SREBF-1 gene increased the risk of endometrioid adenocarcinoma, and increased the histological grade and the depth of myometrial invasion in patients with endometrioid adenocarcinoma. It is suggested that the SNP (rs2297508) site in the SREBF-1 gene can be used as a genetic marker for the development of endometrioid adenocarcinoma. Screening the alleles of the locus may be helpful for the early detection of endometrioid adenocarcinoma.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.33

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