本文選題：胰腺癌 + Fyn��； 參考：《第三軍醫(yī)大學(xué)》2016年博士論文

【摘要】：一、研究背景胰腺癌是一種致死率極高的消化道惡性疾病,發(fā)病早期腫瘤細(xì)胞即發(fā)生局部侵襲與遠(yuǎn)處轉(zhuǎn)移。胰腺癌的主要臨床病理特征之一就是腫瘤細(xì)胞周圍存在著大量的纖維組織以及豐富的細(xì)胞外基質(zhì)成分(extracellular matrix,ECM)。這些特殊的ECM成分能夠通過激活腫瘤細(xì)胞表面整合素Integrin及其胞內(nèi)信號分子的相互作用調(diào)控胰腺癌的侵襲與轉(zhuǎn)移。因而,深入理解胰腺癌中Integrin及其胞內(nèi)信號分子之間的這種相互調(diào)控作用能夠為理解胰腺癌的轉(zhuǎn)移提供新的理論依據(jù)。選擇性剪接修飾是基因轉(zhuǎn)錄后調(diào)控的一種重要的分子機制。其異常變化往往會導(dǎo)致腫瘤的發(fā)生與發(fā)展。因而,解析腫瘤細(xì)胞中基因選擇性剪接的分子調(diào)控機制能夠為腫瘤的臨床診治提供潛在的干預(yù)靶點。前期研究發(fā)現(xiàn)非受體酪氨酸激酶Fyn及Integrinβ1在胰腺癌的轉(zhuǎn)移過程中發(fā)揮了十分重要的作用。抑制Fyn的活性能夠上調(diào)胰腺癌細(xì)胞中核內(nèi)不均一蛋白hnRNP E1以及integrinβ1C剪接體的的表達。由于hn RNP E1具有調(diào)控基因選擇性剪接的功能,因而我們推測:胰腺癌中Fyn的活性能夠通過影響hnRNP E1的表達與功能從而調(diào)控integrinβ1基因的選擇性剪接,并最終影響胰腺癌的轉(zhuǎn)移。本課題主要研究胰腺癌中hnRNP E1剪接子功能復(fù)合物調(diào)控integrinβ1基因選擇性剪接的分子機制。二、研究方案1.我們首先檢測了本研究所收集的76例胰腺癌臨床標(biāo)本中hnRNP E1和integrinβ1剪接體的表達,并將檢測結(jié)果與胰腺癌病人的臨床資料進行了相關(guān)性分析;2.我們利用BxPC3和Panc-1胰腺癌細(xì)胞分析了抑制Fyn活性對細(xì)胞中hnRNP E1和integrinβ1剪接體表達的影響;3.我們通過干預(yù)hnRNP E1的表達分析了hnRNP E1對BxPC3和Panc-1胰腺癌細(xì)胞中integrinβ1基因選擇性剪接的影響;4.我們利用RNA免疫共沉淀、蛋白質(zhì)免疫共沉淀、質(zhì)譜分析、RNA干擾實驗分析了胰腺癌細(xì)胞中hnRNP E1剪接子功能復(fù)合物對integrinβ1基因選擇性剪接的調(diào)控機制;5.我們利用在體與離體的實驗方法分析了Fyn通過hnRNP E1調(diào)控胰腺癌細(xì)胞運動與轉(zhuǎn)移的能力;三、研究結(jié)果1.胰腺癌組織中hn RNP E1蛋白的胞漿分布以及integrinβ1A剪接體的表達與胰腺癌的TNM分期、淋巴結(jié)轉(zhuǎn)移及肝轉(zhuǎn)移具有顯著的相關(guān)性并且hn RNP E1蛋白的胞漿分布與integrinβ1A剪接體的表達具有顯著的正相關(guān)性;2.胰腺癌細(xì)胞中Fyn的活性通過PAK1調(diào)控hn RNP E1的磷酸化水平及其細(xì)胞內(nèi)分布;并通過調(diào)節(jié)細(xì)胞核內(nèi)hnRNP E1剪接子功能復(fù)合物中hnRNP A1和SF2/ASF的組成比例,調(diào)控integrinβ1基因的選擇性剪接;3.Fyn通過hnRNP E1調(diào)控了胰腺癌細(xì)胞的遷移、侵襲與轉(zhuǎn)移能力;四、研究結(jié)論胰腺癌中Fyn的活性通過PAK1調(diào)控hn RNP E1的磷酸化水平及其細(xì)胞內(nèi)分布;并通過調(diào)節(jié)細(xì)胞核內(nèi)hn RNP E1剪接子功能復(fù)合物中hn RNP A1和SF2/ASF的組成比例,調(diào)控integrinβ1基因的選擇性剪接,并最終影響胰腺癌的侵襲與轉(zhuǎn)移。
[Abstract]:Background Pancreatic carcinoma is a malignant digestive tract disease with high mortality. Local invasion and distant metastasis of tumor cells occur in the early stage of pancreatic cancer.One of the main clinicopathological features of pancreatic cancer is the presence of a large number of fibrous tissues and abundant extracellular matrix components around the tumor cells.These special ECM components can regulate the invasion and metastasis of pancreatic cancer by activating the interaction of integrin Integrin and its intracellular signaling molecules.Therefore, an in-depth understanding of the interaction between Integrin and its intracellular signaling molecules in pancreatic cancer may provide a new theoretical basis for understanding the metastasis of pancreatic cancer.Selective splicing modification is an important molecular mechanism of gene posttranscriptional regulation.Its abnormal changes often lead to the occurrence and development of tumors.Therefore, the molecular regulation mechanism of gene selective splicing in tumor cells can provide potential intervention targets for the clinical diagnosis and treatment of tumor.Previous studies have found that non-receptor tyrosine kinase Fyn and Integrin 尾 1 play an important role in the metastasis of pancreatic cancer.Inhibition of Fyn activity could up-regulate the expression of hnRNP E1 and integrin 尾 1C splicing proteins in the nucleus of pancreatic cancer cells.Because hn RNP E1 has the function of regulating gene selective splicing, we speculate that the activity of Fyn in pancreatic cancer can regulate the selective splicing of integrin 尾 1 gene by affecting the expression and function of hnRNP E1, and ultimately affect the metastasis of pancreatic cancer.The aim of this study was to investigate the molecular mechanism of hnRNP E1 splicing complex regulating selective splicing of integrin 尾 1 gene in pancreatic cancer.Second, research programme 1.We first detected the expression of hnRNP E1 and integrin 尾 1 splicing bodies in 76 cases of pancreatic cancer, and analyzed the correlation between the results and the clinical data of pancreatic cancer patients.We used BxPC3 and Panc-1 pancreatic cancer cells to analyze the effect of inhibition of Fyn activity on the expression of hnRNP E1 and integrin 尾 1 splicing bodies.We analyzed the effect of hnRNP E1 on the selective splicing of integrin 尾 1 gene in BxPC3 and Panc-1 pancreatic cancer cells by interfering with the expression of hnRNP E1.We used RNA immunoprecipitation, protein immunoprecipitation and mass spectrometry to analyze the regulation mechanism of hnRNP E1 splicing functional complex on integrin 尾 1 gene selective splicing in pancreatic cancer cells.We used in vivo and in vitro experiments to analyze the ability of Fyn to regulate the movement and metastasis of pancreatic cancer cells through hnRNP E1.The cytoplasmic distribution of hn RNP E1 protein, the expression of integrin 尾 1A splice and the TNM stage of pancreatic carcinoma.There was significant correlation between lymph node metastasis and liver metastasis, and there was a significant positive correlation between the cytoplasmic distribution of hn RNP E1 protein and the expression of integrin 尾 1A splice.The activity of Fyn in pancreatic cancer cells regulated the phosphorylation level of hn RNP E1 and its intracellular distribution through PAK1, and the composition of hnRNP A1 and SF2/ASF in hnRNP E1 splicing functional complex.3. Fyn regulates the migration, invasion and metastasis of pancreatic cancer cells through hnRNP E1. 4. Conclusion the activity of Fyn in pancreatic cancer regulates the phosphorylation level of hn RNP E1 and its intracellular distribution through PAK1.The selective splicing of integrin 尾 1 gene was regulated by regulating the composition of hn RNP A1 and SF2/ASF in the functional complex of hn RNP E1 splice, and the invasion and metastasis of pancreatic cancer were also affected.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R735.9

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