本文選題：結(jié)直腸癌 + 小分子抑制劑4EGI-1��； 參考：《山西醫(yī)科大學(xué)》2017年碩士論文

【摘要】：結(jié)直腸癌(colorectal cancer,CRC)是常見的消化系統(tǒng)惡性腫瘤之一。據(jù)估計(jì)全世界范圍內(nèi)每年大約有新增病例1,360,000例,其中死亡達(dá)694,000例。2015年中國癌癥中心統(tǒng)計(jì)數(shù)據(jù)報(bào)導(dǎo),結(jié)直腸癌的發(fā)病率以及致死率在所有惡性腫瘤中高居第五位。傳統(tǒng)結(jié)直腸癌治療手段,如放療與化療,對結(jié)直腸癌中晚期患者治療療效差,后期產(chǎn)生耐藥性且會對患者機(jī)體免疫系統(tǒng)造成傷害,給患者身心帶來痛苦。真核細(xì)胞翻譯起始因子4E(eukaryotic translation initiation factor 4E,e IF4E)是真核生物帽狀依賴性蛋白質(zhì)翻譯起始階段的限速分子與翻譯調(diào)控的核心成分,e IF4E與真核細(xì)胞翻譯起始因子4G(eukaryotic translation initiation factor 4G,e IF4G)、ATP依賴的RNA解旋酶e IF4A組裝形成的復(fù)合物e IF4F對與腫瘤細(xì)胞生長、增殖相關(guān)基因的表達(dá)起著關(guān)鍵的調(diào)控作用。e IF4E結(jié)合蛋白1(e IF4E-binding protein 1,4EBP1)通過與e IF4G競爭性結(jié)合e IF4E而負(fù)調(diào)控e IF4F的組裝。由于癌細(xì)胞依靠新生蛋白來維持快速生長,因此,靶向蛋白合成機(jī)制治療癌癥策略已引起廣泛關(guān)注。小分子抑制劑4EGI-1因阻礙e IF4E與e IF4G的結(jié)合,同時(shí)促進(jìn)4EBP1與e IF4E的結(jié)合,阻礙蛋白質(zhì)翻譯進(jìn)程進(jìn)而起到顯著的抗腫瘤效果。目前,4EGI-1已經(jīng)在乳腺癌、慢性淋巴細(xì)胞白血病、鼻咽癌、神經(jīng)膠質(zhì)瘤等不同的腫瘤細(xì)胞中均被證實(shí)有抗腫瘤作用,而4EGI-1對結(jié)直腸癌的影響則鮮有報(bào)道,故本研究采用小分子抑制劑4EGI-1作用于結(jié)直腸癌細(xì)胞,探討了4EGI-1對結(jié)直腸癌細(xì)胞增殖、凋亡的影響及其作用的分子機(jī)制,以期為結(jié)直腸癌的靶向治療提供科學(xué)依據(jù)。方法:1.用不同濃度的4EGI-1處理結(jié)直腸癌細(xì)胞,采用MTT、流式細(xì)胞術(shù)以及western blot技術(shù)檢測4EGI-1對結(jié)直腸癌細(xì)胞增殖,凋亡的影響。2.用不同濃度的4EGI-1處理結(jié)直腸癌細(xì)胞,采用Western blot技術(shù)檢測腫瘤凋亡相關(guān)蛋白cleaved-PARP,caspase-3,Bcl-2,Puma以及Noxa等蛋白的表達(dá)。3.免疫共沉淀(Co-Immunoprecipitation,Co-IP)的方法檢測4EGI-1對e IF4E與e IF4G表達(dá)的影響。結(jié)果:1.4EGI-1抑制結(jié)直腸癌細(xì)胞增殖。2.4EGI-1增強(qiáng)cleaved-Caspase3和cleaved-PARP的表達(dá),誘導(dǎo)結(jié)直腸癌細(xì)胞凋亡。3.4EGI-1通過降低Bcl-2的表達(dá)而誘導(dǎo)結(jié)直腸癌細(xì)胞凋亡。4.4EGI-1可能降低了結(jié)直腸癌細(xì)胞e IF4G的表達(dá)。結(jié)論:小分子抑制劑4EGI-1可以抑制結(jié)直腸癌細(xì)胞的生長,促進(jìn)結(jié)腸癌細(xì)胞的凋亡。其作用機(jī)制可能是通過下調(diào)抗凋亡蛋白Bcl-2的表達(dá)。
[Abstract]:Colorectal cancer CRC is one of the most common malignant tumors of digestive system. It is estimated that there are about 1360000 new cases every year worldwide, including 694000 deaths. In 2015, the China Cancer Center reported that the incidence and mortality of colorectal cancer ranked fifth among all malignant tumors. Traditional methods of treatment for colorectal cancer, such as radiotherapy and chemotherapy, have poor therapeutic effect on patients with advanced colorectal cancer, and will cause harm to the immune system of patients and bring pain to the patients' body and mind. Eukaryotic translation initiation factor 4E(eukaryotic translation initiation factor 4E e IF4E is the rate-limiting molecule and the core component of translation regulation in eukaryote capsiform dependent protein translation initiation stage and the eukaryotic cell translation initiation factor 4G(eukaryotic translation initiation factor 4GN e IF4G tasp. Lyme RNA helicase e IF4A assembles the complex e IF4F pair with tumor cell growth. The expression of proliferation-related genes plays a key role in regulating the assembly of e IF4F by competitive binding of e IF4E with e IF4G. As cancer cells rely on new proteins to maintain rapid growth, targeted protein synthesis mechanisms for cancer treatment have attracted widespread attention. 4EGI-1, a small molecule inhibitor, inhibits the binding of e IF4E to e IF4G and promotes the binding of 4EBP1 to e IF4E, which hinders the process of protein translation and thus plays a significant role in the anti-tumor effect. At present, EGI-1 has been proved to have anti-tumor effect in breast cancer, chronic lymphoblastic leukemia, nasopharyngeal carcinoma, glioma and other tumor cells, but the effect of 4EGI-1 on colorectal cancer is rarely reported. In order to provide scientific basis for the targeted therapy of colorectal cancer, the effect of 4EGI-1 on the proliferation and apoptosis of colorectal cancer cells and its molecular mechanism were studied by using small molecule inhibitor 4EGI-1. Method 1: 1. Colorectal cancer cells were treated with different concentrations of 4EGI-1. The effects of 4EGI-1 on proliferation and apoptosis of colorectal cancer cells were detected by MTT, flow cytometry and western blot techniques. Colorectal cancer cells were treated with different concentrations of 4EGI-1. The expression of cleaved-PARPncaspase-3, Bcl-2Puma and Noxa were detected by Western blot technique. Co-immunoprecipitation Co-IP) was used to detect the effect of 4EGI-1 on the expression of e IF4E and e IF4G. Results: 1. 1. 4 EGI-1 inhibited the proliferation of colorectal cancer cells. 2.4EGI-1 enhanced the expression of cleaved-Caspase3 and cleaved-PARP, and induced apoptosis of colorectal cancer cells. 3.4EGI-1 induced apoptosis of colorectal cancer cells by decreasing the expression of Bcl-2. 4.4EGI-1 may decrease the expression of e IF4G in colorectal cancer cells. Conclusion: small molecule inhibitor 4EGI-1 can inhibit the growth of colorectal cancer cells and promote the apoptosis of colon cancer cells. Its mechanism may be by down-regulating the expression of anti-apoptotic protein Bcl-2.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R735.34

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