本文選題：人鼻咽癌 + 生物標志物��； 參考：《華中科技大學》2012年博士論文

【摘要】：鼻咽癌是具有地域特性的惡性腫瘤疾病，高發(fā)于我國廣東，因此又稱“廣東瘤”。由于其發(fā)生部位較小且隱蔽，又與重要器官相鄰，所以癥狀多變或不明顯，導致漏診誤診，常拖至晚期才被診斷出，而晚期的治療效果差，5年存活率極低，嚴重的影響到人類健康。因此迫切需要尋找新的鼻咽癌生物標志物，進而針對該生物標志物進行相應(yīng)的靶向診療研究。生物相容性好及靶向性高的仿生納米載體是實現(xiàn)特異性地殺傷腫瘤而避免其它正常組織不受藥物毒害的有效手段之一。為了更好地對鼻咽癌進行研究，需要迫切地建立起可視化鼻咽癌動物模型，能實時動態(tài)地監(jiān)測鼻咽癌的發(fā)生發(fā)展和轉(zhuǎn)移，進而有效地評估鼻咽癌的診療效果。 本文旨在尋找出鼻咽癌潛在的生物標志物，建立高信噪比的可視化鼻咽癌動物模型，進而借由高密度脂蛋白仿生納米載體對鼻咽癌進行有效的靶向診療。得出以下結(jié)果： （1）發(fā)現(xiàn)在鼻咽癌細胞和鼻咽癌患者病理組織中均高表達跨膜蛋白B類1型清道夫受體（SR-B1），故將SR-B1定義為鼻咽癌潛在的生物標志物。研究發(fā)現(xiàn)高表達SR-B1的鼻咽癌細胞，側(cè)向遷移能力增強，而縱向侵襲能力受抑制。SR-B1的表達量與癌細胞的生長速度和成瘤性無關(guān)。 （2）發(fā)現(xiàn)仿高密度脂蛋白納米顆粒（HPPS）能夠特異性地識別SR-B1高表達的鼻咽腫瘤，通過抑制腫瘤細胞的側(cè)向遷移能力和克隆形成率，進而顯著性地延緩鼻咽癌在活動物體內(nèi)的生長速度。 （3）嘗試將攜帶chol-si-bmi1的HPPS用于鼻咽癌的靶向基因治療，細胞水平實驗結(jié)果表明，可以有效地抑制鼻咽癌的側(cè)向遷移能力和克隆形成率，然而動物水平的實驗未獲得明顯的腫瘤生長抑制效果。 （4）建立了一系列熒光蛋白標記的可視化鼻咽癌實驗動物模型，為鼻咽癌的活體光學成像和靶向治療提供了良好的動物模型。其中獲得了超亮遠紅熒光蛋白mLumin標記的鼻咽癌5-8F細胞，具有良好的皮下成瘤性和轉(zhuǎn)移性。同時，還獲得了一株不成瘤的遠紅熒光蛋白Katushka S158A標記鼻咽癌細胞株5-8F-KattushkaS158A。研究證實，，這些細胞株的成瘤性與其側(cè)群細胞比率密切相關(guān)。 （5）建立了基于皰疹病毒1胸苷激酶(TK)、遠紅熒光蛋白（mLumin）和螢火蟲熒光素酶（Fluc）的三融合報告基因的可視化鼻咽癌實驗動物模型，可同時用于熒光成像、生物發(fā)光成像和microPET成像。由于將遠紅熒光蛋白引入到三融合報告基因中，明顯提升了活體熒光成像的檢測能力，從而為腫瘤的多模式成像研究提供了良好的多標記動物模型。 本文發(fā)現(xiàn)了SR-B1為鼻咽癌的新型潛在生物標志物，為鼻咽癌的靶向診療提供了有效的新型膜蛋白運輸靶點。證明仿高密度脂蛋白納米顆粒HPPS能有效的延緩鼻咽癌生長，且能有效的攜帶siRNA對鼻咽癌細胞進行胞漿釋放進而達到基因治療的效果。該研究建立的一系列可視化鼻咽癌動物模型，為動態(tài)監(jiān)測鼻咽癌的發(fā)生發(fā)展和轉(zhuǎn)移，有效的藥效評估和直觀的評判診療手段提供了便利。
[Abstract]:Nasopharyngeal carcinoma (NPC) is a malignant tumor with regional characteristics, which is often called "Guangdong tumor" in Guangdong. Therefore, it is also called "Guangdong tumor". Because of its small and hidden location and adjacent to important organs, the symptoms are changeable or inconspicuous, resulting in misdiagnosis and misdiagnosis. The late treatment is poor and the survival rate of 5 years is very low, and the survival rate is very low and serious. Therefore, it is urgent to find a new biomarker for nasopharyngeal carcinoma and to study the biomarker for the target diagnosis and treatment. The biomimetic nanoscale carrier with good biocompatibility and high targeting is one of the effective means to kill the tumor specifically and avoid the drug toxicity of other normal tissues. In order to study nasopharyngeal carcinoma better, it is necessary to establish an animal model of visual nasopharyngeal carcinoma urgently. It can monitor the occurrence, development and metastasis of nasopharyngeal carcinoma in real time and dynamically, and then effectively evaluate the diagnosis and treatment effect of nasopharyngeal carcinoma.
This paper aims to find out the potential biomarkers of nasopharyngeal carcinoma and establish a visual nasopharyngeal carcinoma model with high signal-to-noise ratio, and then the effective target diagnosis and treatment of nasopharyngeal carcinoma by high density lipoprotein biomimetic nanoscale carrier. The following results are obtained:
(1) the high expression of transmembrane protein B 1 scavenger receptor (SR-B1) was found in nasopharyngeal and nasopharyngeal carcinoma patients, so SR-B1 was defined as a potential biomarker of nasopharyngeal carcinoma. The study found that nasopharyngeal carcinoma cells with high expression of SR-B1 increased the lateral migration ability and the longitudinal invasion ability was inhibited by the expression of.SR-B1 and cancer cells. The growth rate has nothing to do with the tumorigenicity.
(2) it is found that the imitated high density lipoprotein nanoparticles (HPPS) can specifically identify the high expression of SR-B1 in nasopharyngeal tumors. By inhibiting the lateral migration ability and the clone formation rate of tumor cells, the growth rate of nasopharyngeal carcinoma in active objects can be slowed down significantly.
(3) chol-si-bmi1 HPPS was used as a target gene therapy for nasopharyngeal carcinoma. The results of cell level experiment showed that the lateral migration ability and the clone formation rate of nasopharyngeal carcinoma could be effectively suppressed. However, the experiment of animal level did not obtain the obvious inhibitory effect on tumor growth.
(4) a series of fluorescent protein labeled nasopharyngeal carcinoma experimental animal models were set up to provide a good animal model for the living optical imaging and targeting therapy of nasopharyngeal carcinoma. The 5-8F cells of nasopharyngeal carcinoma labeled with ultra bright red fluorescent protein mLumin were obtained, and a good subcutaneous tumorigenicity and metastasis were obtained. The study of nasopharyngeal carcinoma cell line 5-8F-KattushkaS158A. by Katushka S158A labeled nasopharyngeal carcinoma cell line, which was not a tumor, confirmed that the tumorigenicity of these cell lines was closely related to the ratio of side group cells.
(5) a visual nasopharyngeal carcinoma experimental animal model based on the three fusion reporter of herpes virus 1 thymidine kinase (TK), far red fluorescent protein (mLumin) and firefly luciferase (Fluc), which can be used for fluorescence imaging, bioluminescence imaging and microPET imaging, is also used for the introduction of far erythrofic protein into the three fusion reporter gene. It enhances the detection ability of live fluorescence imaging, thus providing a good multi label animal model for tumor multimode imaging research.
In this paper, SR-B1 is a new potential biomarker for nasopharyngeal carcinoma, which provides a new target for transport of membrane protein for nasopharyngeal carcinoma. It is proved that HPPS can effectively delay the growth of nasopharyngeal carcinoma and can effectively carry siRNA to the cytoplasm release of nasopharyngeal carcinoma cells to achieve gene therapy. A series of visualized animal models of nasopharyngeal carcinoma have been established to facilitate the dynamic monitoring of the occurrence, development and metastasis of nasopharyngeal carcinoma, effective drug effectiveness evaluation and intuitionistic evaluation of diagnosis and treatment.

【學位授予單位】：華中科技大學
【學位級別】：博士
【學位授予年份】：2012
【分類號】：R739.63

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相關(guān)期刊論文 前2條

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本文編號：1812028