不同转移潜能癌症细胞系的脂组学研究

发布时间：2018-03-17 15:13

本文选题：癌症转移　切入点：胃癌　出处：《广西医科大学》2017年硕士论文　论文类型：学位论文

【摘要】：癌症是严重危害人类生命健康和造成人类死亡的主要疾病。胃癌、乳腺癌、肺癌和结直肠癌都是世界范围内最常见的恶性肿瘤,有很高的发病率和死亡率。其中,肺癌和乳腺癌的癌症发病率和死亡率在男性和女性中分别位居第一,胃癌和结直肠癌在男性和女性中的癌症发病率均居前五位。转移是以上四种癌症的重要特征和导致患者死亡的主要原因。然而,各癌症发生发展和转移的分子机制仍然不是很清楚。因此,阐明与各癌症转移相关的分子机制、寻找各癌症转移的特异生物分子和干预癌症转移的靶向治疗分子是当前癌症基础研究领域的重点和亟待解决的问题。随着脂组学理论和技术的不断完善,大量研究证据表明脂质代谢异常与癌症的发生发展及侵袭转移有关,基于脂质代谢异常与癌症发生机制的研究也越来越受到重视。为了阐明与胃癌、乳腺癌、肺癌和结直肠癌转移相关的脂质轮廓变化,我们分别以遗传背景相似而转移潜能不同的3个胃癌细胞系、3个乳腺癌细胞系、2个肺癌细胞系、2个结直肠癌细胞系构建了胃癌转移细胞模型、乳腺癌转移细胞模型、肺癌转移细胞模型和结直肠癌转移细胞模型,四个癌症转移模型间的细胞由于组织起源不同而遗传背景有差异。运用非靶向鸟枪脂组学方法对10个细胞系中的三大类脂质,包括鞘脂类、甘油磷脂类和甘油酯类,分别在正离子和负离子模式下用子离子扫描和中性丢失扫描进行全面的脂质轮廓分析。所得数据经归一化后,用单变量分析和多元统计分析方法进行比较脂组学分析。最后,10个细胞系共鉴定到2217个脂质分子。对四种不同组织起源的癌症细胞系进行比较脂组学分析,得到433个差异脂质分子,分层聚类分析(hca)结果显示四种不同组织起源的癌症细胞系明显分类聚集。此外,脂质种类和脂肪酸侧链的相对定量结果显示两个肺癌细胞系a549和nci-h1299的pe含量明显低于胃、乳腺和结直肠癌细胞系以及有c22:6(dha)脂肪酸侧链的缺失表达。分别对各个癌症转移细胞模型中不同转移潜能的癌症细胞系进行比较脂组学分析,在胃癌转移细胞模型、乳腺癌转移细胞模型、肺癌转移细胞模型和结直肠癌转移细胞模型中分别鉴定到105种、110种、144种和73种与癌症细胞系转移潜能相关的差异脂质分子。分层聚类分析(hca)、主成分分析(pca)和偏最小二乘法-判别分析(pls-da)结果显示除了三个不同转移潜能的乳腺癌细胞系有部分重叠外,其余模型中不同转移潜能的癌症细胞系都能明显分开。与各癌症转移潜能增加有关的主要鞘脂代谢异常包括cerp水平在胃癌中降低,hexcer水平在乳腺癌和肺癌中升高而在结直肠癌中降低,cer水平在肺癌中升高。主要的甘油磷脂代谢异常包括胃癌中pe、pa、pi水平升高和lpc水平降低,结直肠癌中大多数甘油磷脂水平都降低。主要脂肪酸代谢异常包括c16:0和c18:1水平在乳腺癌和结直肠癌中都降低,c16:1水平在胃癌中升高,多不饱和脂肪酸水平在胃癌和结直肠癌中逐渐减少,在乳腺癌和肺癌中逐渐升高。本研究表明:1.不同组织起源的癌症细胞系的脂质组成有很大的差异,这对研究疾病在不同组织器官中的发病机理有重要意义,鉴定到的差异脂质分子还可以作为潜在的组织细胞特异性标志分子。2.来源于同一原生组织但转移潜能不同的癌症细胞,其脂质轮廓组成和脂质水平随着癌症细胞转移潜能的增加而发生明显变化,而且各个癌症的脂质代谢变化是多样化的。鉴定到的与癌症转移相关的差异分子可以作为癌症转移的潜在生物标志物,为进一步筛选临床生物标志物提供依据。脂质代谢水平的变化可以为进一步研究与癌症转移相关的脂质代谢通路和寻找癌症治疗靶点提供思路。
[Abstract]:Cancer is a serious health hazard to human life and death cause of major human diseases. Gastric cancer, breast cancer, lung cancer and colorectal cancer is the most common malignant tumors in the world, there is a high incidence and mortality. Among them, lung cancer and breast cancer incidence and mortality in men and women were among the first, gastric cancer and colorectal cancer incidence in men and women were ranked in the top five. Metastasis is an important feature of these four kinds of cancer and the leading cause of death in patients. However, the molecular mechanism of the tumorigenesis and metastasis is still unclear. Therefore, to elucidate the molecular mechanisms associated with the cancer transfer, looking for specific biological molecules and intervention of cancer metastasis of cancer metastasis to the target molecule is the current treatment of basic research in the field of cancer and the key problems to be solved. With the theory and technology of fat group With continuous improvement, a lot of research evidence of abnormal lipid metabolism, tumorigenesis and metastasis of cancer, abnormal lipid metabolism and cancer pathogenesis has been paid more and more attention. In order to clarify and based on gastric cancer, breast cancer, lung cancer and colorectal cancer metastasis and serum lipid profile changes associated with similar genetic background, we were 3 a gastric cancer cell line and different metastatic potential, 3 breast cancer cell lines, 2 lung cancer cell lines, 2 colorectal cancer cell lines constructed the cell model of metastasis of gastric cancer cells, model of metastatic breast cancer, metastasis of lung cancer cell model and metastasis of colorectal carcinoma cell model, four cancer metastasis model between cells due to tissue origin different genetic background differences. The use of non targeted shotgun lipidomics methods for three kinds of lipid in 10 cell lines, including phospholipids and sphingolipids, glycerol glycerol esters, divided Don't use sub ion scan and neutral in positive and negative ion mode of lipid profile of comprehensive analysis of the data missing scan. After normalization, comparative lipidomics analysis using univariate analysis and multivariate statistical analysis method. Finally, 10 cell lines were identified to 2217 cancer cell lines of lipid molecules. Four kinds of different tissue origins comparative lipidomics analysis, 433 different lipid molecules, hierarchical cluster analysis (HCA) results showed that four kinds of cancer cell lines of different tissue origins were clustered. In addition, the relative quantitative results of lipid classes and fatty acid side chain showed two A549 and human lung cancer cell line NCI-H1299 the content of PE was significantly lower than that in gastric, breast and colorectal cancer cell lines and c22:6 (DHA) expression of fatty acid side chain. The cancer metastasis of cancer cell lines with different metastatic potential in the cell model Comparative lipidomics analysis in the metastasis of gastric cancer cell model, cell model of breast cancer metastasis, metastasis of lung cancer cell model and cell model of colorectal cancer metastasis were identified in 105, 110, 144 and 73 kinds of potential differences related to lipid molecules with cancer metastasis cell line. A hierarchical clustering analysis (HCA), the main component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) results show that except for the three different metastatic potential of breast cancer cell lines overlap, all cancer cell lines with different metastatic potential in other models can significantly increase the main part. The sphingolipid metabolic abnormalities including reduced levels of CERP in gastric carcinoma and the cancer metastasis, the level of hexcer in breast cancer and lung cancer increased in colorectal cancer, elevated levels of CER in lung cancer. The main exceptions include glycerol phospholipid metabolism in gastric cancer PE, PA, PI level increased And the lower the level of LPC, the majority of glycerophospholipids in colorectal cancer are decreased. The level of main fatty acid metabolism including c16:0 and C18:1 levels are lower in breast cancer and colorectal cancer, elevated levels of c16:1 in gastric cancer, polyunsaturated fatty acid levels decreased in gastric cancer and colorectal cancer, increased in breast cancer and lung cancer. This study shows that: lipid 1. cancer cell lines of different tissue origins. There is a big difference, it has important significance for the study of pathogenesis of disease in different tissues, different lipid molecules can also be identified as potential tissue cell specific marker.2. derived from the same original organization but different metastatic potential of cancer cells, the lipid composition and lipid profile levels increase with the metastatic potential of cancer cells and changed obviously, and the change of lipid metabolism in various cancers Is diverse. Potential biomarkers identified in cancer metastasis and related molecular differences can be used as a cancer metastasis, for further screening clinical biomarkers. Provide the basis for changes in lipid metabolism level can transfer pathways associated with lipid metabolism and find cancer therapeutic targets to provide ideas for further research and cancer.

【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R73-37

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