本文選題：癌癥轉(zhuǎn)移　切入點(diǎn)：胃癌　出處：《廣西醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：癌癥是嚴(yán)重危害人類生命健康和造成人類死亡的主要疾病。胃癌、乳腺癌、肺癌和結(jié)直腸癌都是世界范圍內(nèi)最常見(jiàn)的惡性腫瘤,有很高的發(fā)病率和死亡率。其中,肺癌和乳腺癌的癌癥發(fā)病率和死亡率在男性和女性中分別位居第一,胃癌和結(jié)直腸癌在男性和女性中的癌癥發(fā)病率均居前五位。轉(zhuǎn)移是以上四種癌癥的重要特征和導(dǎo)致患者死亡的主要原因。然而,各癌癥發(fā)生發(fā)展和轉(zhuǎn)移的分子機(jī)制仍然不是很清楚。因此,闡明與各癌癥轉(zhuǎn)移相關(guān)的分子機(jī)制、尋找各癌癥轉(zhuǎn)移的特異生物分子和干預(yù)癌癥轉(zhuǎn)移的靶向治療分子是當(dāng)前癌癥基礎(chǔ)研究領(lǐng)域的重點(diǎn)和亟待解決的問(wèn)題。隨著脂組學(xué)理論和技術(shù)的不斷完善,大量研究證據(jù)表明脂質(zhì)代謝異常與癌癥的發(fā)生發(fā)展及侵襲轉(zhuǎn)移有關(guān),基于脂質(zhì)代謝異常與癌癥發(fā)生機(jī)制的研究也越來(lái)越受到重視。為了闡明與胃癌、乳腺癌、肺癌和結(jié)直腸癌轉(zhuǎn)移相關(guān)的脂質(zhì)輪廓變化,我們分別以遺傳背景相似而轉(zhuǎn)移潛能不同的3個(gè)胃癌細(xì)胞系、3個(gè)乳腺癌細(xì)胞系、2個(gè)肺癌細(xì)胞系、2個(gè)結(jié)直腸癌細(xì)胞系構(gòu)建了胃癌轉(zhuǎn)移細(xì)胞模型、乳腺癌轉(zhuǎn)移細(xì)胞模型、肺癌轉(zhuǎn)移細(xì)胞模型和結(jié)直腸癌轉(zhuǎn)移細(xì)胞模型,四個(gè)癌癥轉(zhuǎn)移模型間的細(xì)胞由于組織起源不同而遺傳背景有差異。運(yùn)用非靶向鳥槍脂組學(xué)方法對(duì)10個(gè)細(xì)胞系中的三大類脂質(zhì),包括鞘脂類、甘油磷脂類和甘油酯類,分別在正離子和負(fù)離子模式下用子離子掃描和中性丟失掃描進(jìn)行全面的脂質(zhì)輪廓分析。所得數(shù)據(jù)經(jīng)歸一化后,用單變量分析和多元統(tǒng)計(jì)分析方法進(jìn)行比較脂組學(xué)分析。最后,10個(gè)細(xì)胞系共鑒定到2217個(gè)脂質(zhì)分子。對(duì)四種不同組織起源的癌癥細(xì)胞系進(jìn)行比較脂組學(xué)分析,得到433個(gè)差異脂質(zhì)分子,分層聚類分析(hca)結(jié)果顯示四種不同組織起源的癌癥細(xì)胞系明顯分類聚集。此外,脂質(zhì)種類和脂肪酸側(cè)鏈的相對(duì)定量結(jié)果顯示兩個(gè)肺癌細(xì)胞系a549和nci-h1299的pe含量明顯低于胃、乳腺和結(jié)直腸癌細(xì)胞系以及有c22:6(dha)脂肪酸側(cè)鏈的缺失表達(dá)。分別對(duì)各個(gè)癌癥轉(zhuǎn)移細(xì)胞模型中不同轉(zhuǎn)移潛能的癌癥細(xì)胞系進(jìn)行比較脂組學(xué)分析,在胃癌轉(zhuǎn)移細(xì)胞模型、乳腺癌轉(zhuǎn)移細(xì)胞模型、肺癌轉(zhuǎn)移細(xì)胞模型和結(jié)直腸癌轉(zhuǎn)移細(xì)胞模型中分別鑒定到105種、110種、144種和73種與癌癥細(xì)胞系轉(zhuǎn)移潛能相關(guān)的差異脂質(zhì)分子。分層聚類分析(hca)、主成分分析(pca)和偏最小二乘法-判別分析(pls-da)結(jié)果顯示除了三個(gè)不同轉(zhuǎn)移潛能的乳腺癌細(xì)胞系有部分重疊外,其余模型中不同轉(zhuǎn)移潛能的癌癥細(xì)胞系都能明顯分開(kāi)。與各癌癥轉(zhuǎn)移潛能增加有關(guān)的主要鞘脂代謝異常包括cerp水平在胃癌中降低,hexcer水平在乳腺癌和肺癌中升高而在結(jié)直腸癌中降低,cer水平在肺癌中升高。主要的甘油磷脂代謝異常包括胃癌中pe、pa、pi水平升高和lpc水平降低,結(jié)直腸癌中大多數(shù)甘油磷脂水平都降低。主要脂肪酸代謝異常包括c16:0和c18:1水平在乳腺癌和結(jié)直腸癌中都降低,c16:1水平在胃癌中升高,多不飽和脂肪酸水平在胃癌和結(jié)直腸癌中逐漸減少,在乳腺癌和肺癌中逐漸升高。本研究表明:1.不同組織起源的癌癥細(xì)胞系的脂質(zhì)組成有很大的差異,這對(duì)研究疾病在不同組織器官中的發(fā)病機(jī)理有重要意義,鑒定到的差異脂質(zhì)分子還可以作為潛在的組織細(xì)胞特異性標(biāo)志分子。2.來(lái)源于同一原生組織但轉(zhuǎn)移潛能不同的癌癥細(xì)胞,其脂質(zhì)輪廓組成和脂質(zhì)水平隨著癌癥細(xì)胞轉(zhuǎn)移潛能的增加而發(fā)生明顯變化,而且各個(gè)癌癥的脂質(zhì)代謝變化是多樣化的。鑒定到的與癌癥轉(zhuǎn)移相關(guān)的差異分子可以作為癌癥轉(zhuǎn)移的潛在生物標(biāo)志物,為進(jìn)一步篩選臨床生物標(biāo)志物提供依據(jù)。脂質(zhì)代謝水平的變化可以為進(jìn)一步研究與癌癥轉(zhuǎn)移相關(guān)的脂質(zhì)代謝通路和尋找癌癥治療靶點(diǎn)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.

【學(xué)位授予單位】：廣西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R73-37

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本文編號(hào)：1625287