本文選題：Bapx1 + 胃癌��； 參考：《南方醫(yī)科大學》2017年博士論文

【摘要】：背景:胃癌仍然是威脅人類健康的一大類疾病,并有著相當高的至死率。胃癌的高死亡率與其較易發(fā)生轉(zhuǎn)移的特性相關(guān)。上皮間質(zhì)轉(zhuǎn)化(Epithelia-mesenchymal transition,EMT)是以非運動的、有極性的、細胞連接緊密的上皮細胞,轉(zhuǎn)化成為具有侵襲性的、非極性的、細胞連接松散的間質(zhì)細胞為特點,在腫瘤的轉(zhuǎn)移中起重要作用。同源結(jié)構(gòu)域家族在胚胎發(fā)育的調(diào)控過程中占據(jù)著絕對重要的頂層地位,越來越多的證據(jù)表明它們在多種腫瘤中表達異常,并使腫瘤獲得各種轉(zhuǎn)移、侵襲、增殖等特性。同源結(jié)構(gòu)域蛋白Bapx1(又名NKX3.2)是胃十二指腸形態(tài)發(fā)生中的重要調(diào)節(jié)蛋白。但對于其在腫瘤中作用的研究甚少,最近有報道顯示Bapx1在卵巢癌中的高表達與遠處轉(zhuǎn)移和化療抵抗有關(guān),對于其機制也并沒有進行深入研究。目前尚沒有關(guān)于其在胃癌中的研究報道。轉(zhuǎn)化生長因子β(transforming growth factor-β,TGF-β)被認為是在發(fā)育過程、癌癥以及其他病理狀態(tài)下誘導EMT最重要的因子,已被證明能促進多種腫瘤細胞的轉(zhuǎn)移。Bapx1在胚胎樣的細胞中被證明做為TGF-β和BMP(bone morphogenetic proteins)的下游而進一步發(fā)揮作用。NF-κB是參與腫瘤細胞侵襲轉(zhuǎn)移的重要信號通路,已有報道顯示,NF-κB參與了 TGF-β介導的EMT。而在軟骨細胞中的研究顯示,Bapx1可激活NF-κB,促進NF-κB的入核。本研究的目的是探索Bapx1在胃癌中的作用及其可能的機制。方法:免疫組化和Western-Blot法來研究Bapx1在胃癌和其對應(yīng)的癌旁組織以及胃癌細胞株與胃永生化上皮細胞株中的表達;在BGC823和MGC803細胞中瞬時轉(zhuǎn)染沉默Bapx1后進一步觀察其遷移侵襲功能并用Western-Blot來驗證EMT相關(guān)蛋白的表達;在BGC823和MGC803細胞中加入TGF-β刺激,進一步探究Bapx1對TGF-β誘導的EMT的作用;其后進一步研究Bapx1對EMT影響的可能下游機制。統(tǒng)計學檢驗使用SPSS軟件。T檢驗或ANOVA來比較差異的顯著性。Spearman相關(guān)性分析Bapx1表達量與各臨床指標間的相關(guān)性。應(yīng)用Kaplan-Meier方法評估各臨床指標及Bapx1免疫組化評分對胃癌患者預(yù)后的影響。結(jié)果:Bapx1的表達在胃癌組織中遠高于其相鄰的癌旁組織。Bapx1在胃癌細胞株中的表達高于胃永生化上皮細胞株的表達。且它的表達與TNM分期,淋巴和遠處轉(zhuǎn)移以及死亡率呈正相關(guān)。而在BGC823和MGC803胃癌細胞株中沉默Bapx1,可減弱胃癌細胞的侵襲和遷移能力,同時減少胃癌細胞間質(zhì)表型,增加胃癌細胞上皮表型。TGF-β刺激可誘導BGC823和MGC803細胞株的EMT,同時Bapx1的表達增加,但當下調(diào)Bapx1的表達后,可以逆轉(zhuǎn)TGF-β誘導的侵襲、遷移和形態(tài)學變化以及EMT的表型變化。進一步的研究顯示,在胃癌細胞中沉默Bapx1可減少NF-κB的核定位表達,提示胃癌細胞中Bapx1的高表達至少部分地參與了 NF-κB的激活。結(jié)論:該研究提示,Bapx1在胃癌中的高表達與胃癌的淋巴、遠處轉(zhuǎn)移及不良預(yù)后有關(guān),在體外實驗中證實Bapx1可通過介導TGF-β誘導的EMT進而促進胃癌的侵襲和轉(zhuǎn)移,并進一步推測Bapx1有可能通過激活NF-κB通路而參與介導TGF-β誘導的EMT。
[Abstract]:Background: gastric cancer is still a major disease that threatens human health and has a fairly high death rate. The high mortality rate of gastric cancer is related to the characteristics that are easier to metastasize. Epithelia-mesenchymal transition (EMT) is a non athletic, polar, cell connected epithelial cell that is transformed into an invasion. Sexual, nonpolar, loosely connected stromal cells, which play an important role in the metastasis of a tumor. The family of homologous domains occupies an absolutely important position in the regulation of embryonic development. More and more evidence shows that they are abnormal in a variety of tumors and make the tumor a variety of metastasis, invasion, and proliferation. Homologous domain protein Bapx1 (also known as NKX3.2) is an important regulatory protein in the formation of gastroduodenal morphogenesis. However, few studies have been made on its role in the tumor. Recently, it has been reported that the high expression of Bapx1 in ovarian cancer is related to distant metastasis and chemotherapy resistance, and the mechanism has not been deeply studied. Transforming growth factor- beta (TGF- beta) is considered to be the most important factor in the induction of EMT in development, cancer and other pathological conditions. It has been proved to be able to promote the transfer of.Bapx1 in a variety of tumor cells to be proved to be TGF- beta and BMP (bone m) in embryonic like cells. In the lower reaches of orphogenetic proteins,.NF- kappa B is an important signaling pathway involved in the invasion and metastasis of tumor cells. It has been reported that NF- kappa B participates in TGF- beta mediated EMT. in cartilage cells and shows that Bapx1 activates NF- kappa B and promotes the nucleation of NF- kappa. The purpose of this study is to explore the gastric cancer. Effects and possible mechanisms. Methods: immunohistochemical and Western-Blot methods were used to study the expression of Bapx1 in gastric carcinoma and its corresponding para cancer tissues, gastric cancer cell lines and gastric immortalized epithelial cells. After transient transfection of silent Bapx1 in BGC823 and MGC803 cells, the migration and invasion function was further observed and Western-Blot was used to verify EMT. The expression of related proteins; adding TGF- beta stimulation in BGC823 and MGC803 cells to further explore the effect of Bapx1 on EMT induced by TGF- beta; then further study the possible downstream mechanism of Bapx1 on EMT. Statistical tests use SPSS software.T test or ANOVA to compare the distinct.Spearman correlation analysis The correlation between clinical indicators. Kaplan-Meier method was used to evaluate the effect of various clinical indicators and Bapx1 immunohistochemical scores on the prognosis of gastric cancer patients. Results: the expression of Bapx1 in gastric carcinoma tissue is much higher than that of adjacent tissue,.Bapx1 expression in gastric cancer cell lines is higher than that of gastric immortalized epithelial cell lines. TNM staging, lymphoid and distant metastasis and mortality are positively correlated. While silencing of Bapx1 in BGC823 and MGC803 gastric cancer cell lines can weaken the invasion and migration of gastric cancer cells, reduce the phenotype of gastric cancer cells, and increase the.TGF- beta stimulation of the epithelial phenotype of gastric cancer cells to induce EMT in BGC823 and MGC803 cell lines and increase the expression of Bapx1. Addition, when the expression of Bapx1 was downregulated, it could reverse the invasion, migration and morphological changes of TGF- beta induced, and the phenotypic changes of EMT. Further studies showed that the silence of Bapx1 in gastric cancer cells could reduce the nuclear localization and expression of NF- kappa B, suggesting that the high expression of Bapx1 in gastric cancer cells was at least partly involved in the activation of NF- kappa B. Conclusion: the study It is suggested that the high expression of Bapx1 in gastric cancer is related to the lymph, distant metastasis and poor prognosis of gastric cancer. In vitro experiments have proved that Bapx1 can promote the invasion and metastasis of gastric cancer by mediating EMT induced by TGF- beta and further promoting the invasion and metastasis of gastric cancer, and further speculate that Bapx1 may be involved in the mediation of TGF- beta induced EMT. through the activation of the NF- kappa B pathway.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.2

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1 歐陽石;Bapx1在胃癌中參與轉(zhuǎn)化生長因子-β誘發(fā)的上皮間質(zhì)轉(zhuǎn)化[D];南方醫(yī)科大學;2017年

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