【摘要】：研究背景:胃癌是常見(jiàn)的消化道惡性腫瘤,發(fā)病率與死亡率均較高。目前對(duì)胃癌化學(xué)預(yù)防的研究主要集中在根除幽門螺桿菌、抗氧化劑、葉酸、選擇性環(huán)氧合酶抑制劑上。由于幽門螺桿菌耐藥能力的增強(qiáng),除菌藥的效率降低。因此,開(kāi)發(fā)新藥、尋找藥物靶點(diǎn)尤為重要。甘草次酸是甘草的主要活性成分之一,具有多種生理活性,包括抗炎、抗?jié)�、抗病毒、抗腫瘤及調(diào)節(jié)免疫功能等。甘草次酸在體內(nèi)外實(shí)驗(yàn)中具有潛在抑制腫瘤的作用,因此有可能成為新型胃癌化學(xué)預(yù)防的藥物。轉(zhuǎn)基因胃腫瘤鼠模型K19-C2m E能夠在胃近端自發(fā)的出現(xiàn)隆起型腫瘤,且其所生長(zhǎng)的胃腫瘤形態(tài)特征與人自發(fā)的腫瘤很相似,可作為理想的胃癌模型供實(shí)驗(yàn)研究。Micro RNA是一類長(zhǎng)約20-22個(gè)核苷酸的非編碼單鏈RNA。這類RNA能夠調(diào)節(jié)癌基因或抑癌基因的表達(dá),將來(lái)癌基因mi RNA抑制劑或抑癌基因mi RNA的替代品將可能成為腫瘤治療的新手段。目的:探討甘草次酸能否降低K19-C2m E轉(zhuǎn)基因鼠胃腫瘤的發(fā)病率,是否影響轉(zhuǎn)基因鼠胃腫瘤中的mi RNAs表達(dá)。并進(jìn)一步研究相關(guān)mi RNA對(duì)人胃癌細(xì)胞增殖、凋亡和細(xì)胞周期的影響。方法:建立K19-C2m E轉(zhuǎn)基因胃腫瘤小鼠模型。設(shè)立對(duì)照組和甘草次酸投藥組。對(duì)小鼠胃癌組織進(jìn)行mi RNA芯片分析,同時(shí)用甘草次酸處理胃癌細(xì)胞系MKN-1和BGC-823分析相關(guān)mi RNA的表達(dá),并通過(guò)細(xì)胞轉(zhuǎn)染改變相關(guān)mi RNA的表達(dá)對(duì)胃癌細(xì)胞的影響。利用統(tǒng)計(jì)學(xué)分析軟件,分析甘草次酸組和對(duì)照組轉(zhuǎn)基因小鼠胃癌組織和胃癌細(xì)胞中mi RNA的變化。結(jié)果:18β-甘草次酸能顯著降低胃腫瘤的發(fā)生率(P=0.002),其中對(duì)照組小鼠腫瘤發(fā)生率是77.8%(28/36),甘草次酸組小鼠胃腫瘤發(fā)生率為33.3%(13/39);mi RNA芯片分析發(fā)現(xiàn)甘草次酸處理后小鼠腫瘤中的38種mi RNAs的表達(dá)發(fā)生改變(fd≥2或fd≤0.5,P0.01);其中變化差異最大的是mi R-149-3P,與對(duì)照組相比其表達(dá)量上調(diào)了3.8倍;甘草次酸處理胃癌細(xì)胞系BGC-823和MKN-1后可使mi R-149-3p上調(diào),并呈濃度和時(shí)間依賴性;mi R-149-3p能夠抑制胃癌細(xì)胞系MKN-1和BGC-823增殖,促進(jìn)細(xì)胞凋亡。
[Abstract]:Background: gastric cancer is a common malignant tumor of digestive tract with high morbidity and mortality. Current studies on chemical prevention of gastric cancer have focused on the eradication of Helicobacter pylori, antioxidants, folic acid and selective cyclooxygenase inhibitors. Because of the enhancement of drug resistance of Helicobacter pylori, the efficiency of sterilizing agents was decreased. Therefore, it is very important to develop new drugs and find drug targets. Glycyrrhetinic acid is one of the main active components of licorice. It has many physiological activities, including anti-inflammation, anti-ulcer, anti-virus, anti-tumor and regulating immune function. Glycyrrhetinic acid has the potential to inhibit tumor in vitro and in vivo, so it may become a new chemoprevention drug for gastric cancer. K19-C2m E, a transgenic gastric tumor model, was able to spontaneously present protruding tumors at the proximal end of the stomach, and the morphological characteristics of the gastric tumors were similar to those of human spontaneous tumors. It can be used as an ideal gastric cancer model for experimental research. Micro RNA is a class of uncoded single-stranded RNA. with about 20-22 nucleotides in length. This kind of RNA can regulate the expression of oncogene or tumor suppressor gene. In the future, mi RNA inhibitor or mi RNA replacement of oncogene may become a new method of tumor therapy. Aim: to investigate whether glycyrrhetinic acid can reduce the incidence of gastric neoplasms in K19-C2m E transgenic mice and whether it affects the expression of mi RNAs in gastric neoplasms of transgenic mice. Furthermore, the effects of mi RNA on proliferation, apoptosis and cell cycle of human gastric cancer cells were studied. Methods: K19-C2m E transgenic gastric tumor model was established in mice. Control group and glycyrrhetinic acid group were established. The expression of related mi RNA in gastric cancer cell line MKN-1 and BGC-823 was analyzed by mi RNA microarray, and the expression of related mi RNA was changed by cell transfection. The changes of mi RNA in gastric cancer tissues and gastric cancer cells of Glycyrrhetinic acid group and control group were analyzed by statistical analysis software. Results 1: 18 尾 -glycyrrhetinic acid could significantly reduce the incidence of gastric neoplasms (P0. 002). The incidence of gastric neoplasms in the control group was 77.8% (28 / 36), and the incidence of gastric tumors in the glycyrrhetinic acid group was 33. 3% (13 / 39). The results of RNA microarray analysis showed that 38 of the tumors were treated with glycyrrhetinic acid. The expression of mi RNAs was changed (fd 鈮，

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