本文選題：大腸管狀腺瘤　切入點(diǎn)：癌變　出處：《河北醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：目的:大腸癌是常見的消化道惡性腫瘤之一,其發(fā)病率呈上升趨勢(shì)。大腸腺瘤與大腸癌關(guān)系密切,約80%大腸癌由大腸腺瘤演變而來,其形成及癌變機(jī)制錯(cuò)綜復(fù)雜,目前尚不明確。脂類代謝異常在腫瘤發(fā)生發(fā)展中的作用日益受到關(guān)注。脂質(zhì)代謝改變尤其是脂肪酸合成顯著增加是腫瘤細(xì)胞快速增殖的一個(gè)重要標(biāo)志,不同于正常細(xì)胞直接利用循環(huán)中的脂肪酸,惡性腫瘤細(xì)胞生長(zhǎng)增殖所需的脂肪酸主要來源于從頭合成途徑。固醇調(diào)節(jié)原件結(jié)合蛋白1(isterol regulatory element-binding proteins-1,SREBP-1)是調(diào)控脂肪酸從頭合成途徑(DNL)中的關(guān)鍵因子,直接影響脂肪酸從頭合成途徑中關(guān)鍵酶脂肪合酶(fatty acid synthase,FASN)的生成。FASN是SREBP-1的下游靶基因,二者合稱為代謝原癌基因。研究發(fā)現(xiàn)在不同類型腫瘤的相對(duì)早期階段,脂肪酸合成通路就已開始上調(diào)并且SREBP-1在肺癌、乳腺癌、卵巢癌等腫瘤細(xì)胞中呈高表達(dá),但在大腸癌中的相關(guān)研究鮮見報(bào)道。SREBP-1的活性主要受PI3K-Akt-mTOR通路調(diào)節(jié),通路中的哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin complex,mTOR)及上游刺激因子1(upstream stimulatory factors 1,USF1)對(duì)SREBP-1起重要調(diào)節(jié)作用:mTOR通過增加TSC1/2的表達(dá)及促進(jìn)Akt在S473位點(diǎn)的磷酸化而上調(diào)SREBP-1表達(dá);USF1其基本HLH結(jié)構(gòu)域直接與SREBP-1的N-末端區(qū)域的HLH結(jié)構(gòu)域相互作用,從而也對(duì)SREBP-1的表達(dá)起到促進(jìn)作用。為探討脂肪酸的從頭合成途徑是否在散發(fā)性大腸管狀腺瘤癌變過程中發(fā)揮作用,本研究采用免疫組化方法檢測(cè)脂肪酸從頭合成途徑中的關(guān)鍵蛋白SREBP-1、p-mTOR、FASN及USF1的表達(dá)情況并對(duì)結(jié)果進(jìn)行相關(guān)性分析,進(jìn)一步揭示其在大腸腺瘤癌變中的意義,為大腸腺瘤癌變預(yù)防和臨床治療及預(yù)后提供理論依據(jù)。方法:1采用免疫組織化學(xué)SP法檢測(cè)SREBP-1及內(nèi)源性脂肪酸合成相關(guān)因子(p-mtor、USF1、fasn)在40例正常大腸黏膜、112例不同程度異型增生大腸管狀腺瘤以及100例大腸管狀腺瘤癌變組織中的表達(dá),分析其與臨床病理特征的關(guān)系,并進(jìn)一步進(jìn)行相關(guān)性分析。2用spss21.0軟件對(duì)實(shí)驗(yàn)數(shù)據(jù)進(jìn)行分析,應(yīng)用χ2檢驗(yàn)、wilcoxon符號(hào)秩和檢驗(yàn)和spearman相關(guān)性分析,p0.05代表有統(tǒng)計(jì)學(xué)意義。結(jié)果:1免疫組織化學(xué)結(jié)果1.1SREBP-1在散發(fā)性大腸管狀腺瘤癌變過程中的表達(dá)情況SREBP-1蛋白在正常大腸黏膜組、異型增生組和瘤癌變組中的陽性表達(dá)率分別為7.5%、37.5%、77.0%,其中腺瘤組和癌變組明顯高于正常粘膜組(p0.05),癌變組明顯高于腺瘤組(p0.05)。SREBP-1蛋白在上皮輕、中、重度異型增生管狀腺瘤組的陽性表達(dá)率分別為20.0%、35.0%、62.5%,依次升高(p0.05)。其中重度異型增生組高于輕、中度異型增生組(p0.05),輕度及中度異型增生組間無差異(p0.05)。1.2p-mtor在散發(fā)性大腸管狀腺瘤癌變過程中的表達(dá)情況p-mtor蛋白在正常大腸黏膜組、管狀腺瘤異型增生組和管狀腺瘤癌變組中的陽性表達(dá)率分別為5.0%、34.8%、87.0%,依次升高(p0.05),其中腺瘤組和癌變組明顯高于正常粘膜組(p0.05),癌變組明顯高于腺瘤組(p0.05)。p-mtor蛋白在上皮輕、中、重度異型增生管狀腺瘤組中的陽性表達(dá)率分別為17.7%、35.0%、59.4%,依次升高(p0.05),其中重度異型增生組高于輕、中度異型增生組(p0.05),中度異型增生組高于輕度異性增生組(p0.05)。1.3fasn在散發(fā)性大腸管狀腺瘤癌變過程中的表達(dá)情況fasn蛋白在正常大腸黏膜組、管狀腺瘤異型增生組和管狀腺瘤癌變組中的陽性表達(dá)率分別為10.0%、32.1%、85.0%,依次升高(p0.05),其中腺瘤組和癌變組明顯高于正常粘膜組(p0.05),癌變組明顯高于腺瘤組(p0.05)。fasn蛋白在上皮輕、中、重度異型增生管狀腺瘤組中的陽性表達(dá)率分別為12.5%、32.5%、56.3%,依次升高(p0.05),其中重度異型增生組明顯高于輕、中度異型增生組(p0.05),中度異型增生組高于輕度異性增生組(p0.05)。1.4USF1在散發(fā)性大腸管狀腺瘤癌變過程中的表達(dá)情況USF1蛋白在正常大腸黏膜組、異型增生管狀腺瘤組和管狀腺瘤癌變組中的陽性表達(dá)率分別為20.0%、47.3%、65.0%,依次升高(p0.05),其中腺瘤組和癌變組明顯高于正常粘膜組(p0.05),癌變組高于腺瘤組(p0.05)。USF1蛋白陽性表達(dá)率在上皮輕、中、重度異型增生管狀腺瘤組依次升高(分別為20.0%、42.5%、87.5%),其中重度異型增生組明顯高于輕、中度異型增生組(p0.05),中度異型增生組明顯高于輕度異型增生組(p0.05)。2SREBP-1及內(nèi)源性脂肪酸合成相關(guān)蛋白(p-mtor、fasn及USF1)與臨床病理特征關(guān)系2.1SREBP-1蛋白的表達(dá)與臨床病理特征關(guān)系管狀腺瘤癌變組中SREBP-1蛋白陽性表達(dá)率與腫瘤分化程度相關(guān),隨著分化程度的降低,SREBP-1蛋白陽性表達(dá)率依次升高(χ2=18.368,p0.05);與性別、年齡、腫瘤發(fā)生部位、淋巴結(jié)轉(zhuǎn)移、dukes分期以及浸潤深度無相關(guān)性(p0.05)。2.2p-mtor蛋白的表達(dá)與臨床病理特征關(guān)系癌變組中p-mtor蛋白陽性表達(dá)率與腫瘤分化程度、浸潤深度相關(guān),隨著分化程度降低、浸潤深度增加,p-mtor蛋白陽性表達(dá)率增高(χ2=6.917、χ2=7.078,均p0.05);而與性別、年齡、腫瘤發(fā)生部位、淋巴結(jié)轉(zhuǎn)移及dukes分期無相關(guān)性(p0.05)。2.3fasn蛋白的表達(dá)與臨床病理特征關(guān)系癌變組中fasn蛋白異常表達(dá)率與分化程度,隨著分化程度降低,fasn蛋白異常表達(dá)率增高(χ2=10.080,p0.05);與性別、年齡、腫瘤發(fā)生部位、dukes分期、浸潤深度和淋巴結(jié)轉(zhuǎn)移無相關(guān)性(p0.05)。2.4USF1蛋白的表達(dá)與臨床病理特征關(guān)系癌變組中USF1蛋白陽性表達(dá)率與分化程度,隨著分化程度降低,USF1蛋白陽性表達(dá)率增高(χ2=8.487,p0.05);而與性別、年齡、腫瘤發(fā)生部位、dukes分期、浸潤深度和淋巴結(jié)轉(zhuǎn)移無相關(guān)性(p0.05)。3SREBP-1與內(nèi)源性脂肪酸合成相關(guān)蛋白(p-mtor、fasn及USF1)的相關(guān)性分析結(jié)果顯示腺瘤組SREBP-1與p-mtor、fasn、USF1呈正相關(guān)(r=0.247,r=0.494,r=0.397,p0.05);癌變組SREBP-1與p-mtor、FASN、USF1呈正相關(guān)(r=0.213,r=0.702,r=0.247,P0.05)。結(jié)論:1 SREBP-1蛋白表達(dá)隨著腺瘤異型增生程度的增高及癌變的出現(xiàn),其陽性表達(dá)率明顯增高,并且與大腸癌分化程度有關(guān),提示SREBP-1可能參與了散發(fā)性大腸管狀腺瘤癌變的發(fā)生發(fā)展。2脂肪酸從頭合成相關(guān)因子(p-mTOR、FASN、USF1)在正常大腸粘膜、不同程度異型增生管狀腺瘤組和腺瘤癌變組中表達(dá)均依次升高,提示可能與大腸癌的發(fā)生發(fā)展有關(guān)。3 SREBP-1與脂肪酸從頭合成相關(guān)因子呈正相關(guān),提示SREBP-1與脂肪酸從頭合成相關(guān)因子(p-mTOR、FASN、USF1)可能在散發(fā)性大腸管狀腺瘤癌變過程中發(fā)揮協(xié)同作用。
[Abstract]:Objective: colorectal cancer is one of the most common malignant tumor of digestive tract. Its incidence is rising. The relationship between colorectal adenoma and colorectal cancer closely, about 80% colorectal adenoma by evolution, the formation and mechanism of carcinogenesis perplexing, it is not clear. The abnormal lipid metabolism in the development of tumors in the role of increasingly attention. Altered lipid metabolism especially fatty acid synthesis increased significantly is an important sign of the rapid proliferation of tumor cells, unlike normal cells directly using fatty acid cycle, fatty acid the main source of malignant tumor cell growth and proliferation required in de novo synthesis of sterol regulatory element binding protein 1. (isterol regulatory element-binding proteins-1. SREBP-1) is the regulation of fatty acid biosynthesis pathway (DNL) in the key factor, directly affect the key enzyme of fatty fatty acid biosynthesis pathway (fatty synthase ACI D synthase, FASN) generation.FASN is a downstream target gene of SREBP-1, two of them are called metabolic gene. The study found in the relatively early stage of different tumor types, fatty acid synthesis pathway has been up-regulated and SREBP-1 in lung cancer, breast cancer, ovarian cancer and other tumor cells showed high expression, but in in colorectal cancer related research reported the activity of.SREBP-1 is mainly affected by the PI3K-Akt-mTOR pathway, mTOR pathway in (mammalian target of rapamycin complex, mTOR) and upstream stimulatory factor 1 (upstream stimulatory 1 factors, USF1) of SREBP-1 play an important regulatory role: mTOR by increasing the expression of TSC1/2 and Akt in promoting S473 phosphorylation and upregulation of the expression of SREBP-1 USF1 HLH; the basic domain of HLH directly with the N- terminal region of SREBP-1 interaction, and the expression of SREBP-1 to In order to investigate the role. De novo fatty acid synthesis pathway does play a role in the carcinogenesis of sporadic colorectal tubular adenoma in this study, immunohistochemical method was used to detect the fatty acid biosynthesis pathway in the expression of SREBP-1, p-mTOR, expression of FASN and USF1 and analyzed the correlation of the results further revealed in colorectal adenomas the significance of cancer, and provide a theoretical basis for the prevention and treatment of colorectal adenoma and prognosis. Methods: 1 Immunohistochemical SP method was used to detect the expression of SREBP-1 and endogenous fatty acid synthesis related factors (p-mTOR, USF1, FASN) in 40 cases of normal colorectal mucosa, the expression of 112 cases of dysplasia and 100 cases of colorectal colorectal tubular adenoma tubular adenoma carcinoma and analyze its relationship with clinical pathological characteristics, and further analyzed the.2 of the experimental data using spss21.0 software Analysis and application of 2 test analysis, Wilcoxon signed rank test and Spearman correlation was statistically significant P0.05. Results: 1 immunohistochemical results of 1.1SREBP-1 in the carcinogenesis of sporadic colorectal tubular adenoma in the expression of SREBP-1 protein in normal colorectal mucosa, the positive expression of dysplasia group and cancerous tumor group respectively 7.5%, 37.5%, 77%, one adenoma group and cancer group was significantly higher than that in normal mucosa group (P0.05), cancer group was significantly higher than that in adenoma group (P0.05) and.SREBP-1 protein in epithelial light, severe dysplasia tubular adenoma group positive expression rates were 20%, 35%, 62.5%, followed by increased (P0.05). The severe dysplasia group was higher than that of light, moderate dysplasia group (P0.05), no difference between the groups of mild and moderate dysplasia (P0.05) expression of p-mTOR protein.1.2p-mtor in sporadic colorectal tubular adenoma carcinoma during deformation In the normal colorectal mucosa, the positive expression of tubular adenoma dysplasia group and tubular adenoma with cancerous changes. The rates were 5%, 34.8%, 87%, (P0.05), which in turn increased adenoma group and cancer group was significantly higher than that in normal mucosa group (P0.05), cancer group was significantly higher than that in adenoma group (P0.05) and.P-mtor protein in epithelial light. In severe dysplasia tubular adenoma group positive expression rates were 17.7%, 35%, 59.4%, (P0.05), which were significantly higher in severe dysplasia group was higher than that of light, moderate dysplasia group (P0.05), moderate dysplasia group was higher than that of mild dysplasia group (P0.05).1.3fasn in the carcinogenesis of sporadic colorectal tubular adenoma in expression FASN protein in normal colorectal mucosa, the positive expression of tubular adenoma dysplasia group and tubular adenoma with cancerous changes. The rates were 10%, 32.1%, 85%, (P0.05), which in turn increased adenoma group and cancer group Higher than that in normal mucosa group (P0.05), cancer group was significantly higher than that in adenoma group (P0.05) and.Fasn protein in epithelial light, severe dysplasia tubular adenoma group positive expression rates were 12.5%, 32.5%, 56.3%, (P0.05), which were significantly higher in severe dysplasia group was significantly higher than that of mild, moderate dysplasia group (P0.05). Moderate dysplasia group was higher than that of mild dysplasia group (P0.05).1.4USF1 in the carcinogenesis of sporadic colorectal tubular adenoma in the expression of USF1 protein in normal colorectal mucosa, the positive expression of dysplasia tubular adenoma and tubular adenoma with cancerous changes. The rates were 20%, 47.3%, 65%, (P0.05), which in turn increased adenoma group and cancer group was significantly higher than that in normal mucosa group (P0.05), cancer group was higher than that in adenoma group (P0.05) the positive rate of.USF1 protein expression in epithelial light, severe atypical hyperplasia of tubular adenoma were increased in turn (respectively 20%, 42.5%, 87 .5%), the severe dysplasia group was significantly higher than that of mild, moderate dysplasia group (P0.05), moderate dysplasia group was significantly higher than that in mild dysplasia group (P0.05).2SREBP-1 and endogenous fatty acid synthesis related protein (p-mTOR, FASN and USF1) and SREBP-1 expression in clinical and pathological features of the relationship between 2.1SREBP-1 protein and clinicopathological features of tubular adenoma with cancerous changes. The expression rate and the degree of tumor differentiation, along with the lower degree of differentiation, the positive expression rate of SREBP-1 protein increased (x 2=18.368, P0.05); and gender, age, location of tumor, lymph node metastasis, dukes staging and invasion depth (P0.05) had no correlation relationship between.2.2p-mtor protein expression and clinicopathological features of positive the expression of p-mTOR protein in carcinoma group were related with the degree of differentiation, depth of invasion, with lower differentiation degree, infiltration depth increased, p-mTOR protein positive expression The rate increased (x 2=6.917, X 2=7.078, P0.05); and gender, age, tumor location, lymph node metastasis and Dukes stage (P0.05) there is no correlation between the abnormal expression of the relationship between.2.3fasn protein expression and clinicopathological features of FASN carcinoma group in the rate of protein and the degree of differentiation, with lower differentiation, abnormal expression of FASN the rate of protein increased (x 2=10.080, P0.05); and gender, age, location of tumor, dukes staging, depth of invasion and lymph node metastasis (P0.05) the relationship between.2.4USF1 protein expression and clinicopathological features of positive expression of USF1 protein in carcinoma group and differentiation rate, with the decrease of differentiation, the positive expression rate of USF1 protein increased (2=8.487, P0.05); and gender, age, location of tumor, dukes staging, depth of invasion and lymph node metastasis (P0.05.3SREBP-1) and endogenous fatty acid synthesis related protein (p-mTOR, FASN and USF1 ) the correlation analysis showed that SREBP-1 and p-mTOR FASN adenoma group, and USF1 was positively correlated (r=0.247, r=0.494, r=0.397, P0.05); group SREBP-1 and FASN cancer p-mTOR, USF1 was positively correlated (r=0.213, r=0.702, r=0.247, P0.05). Conclusion: the expression of SREBP-1 1 protein with higher degree of dysplasia and cancerous adenoma the positive expression rate was significantly increased, and associated with degree of differentiation, suggesting that SREBP-1 may be involved in the occurrence and development of.2 fatty acid biosynthesis related factors in carcinogenesis of sporadic colorectal tubular adenoma (p-mTOR, FASN, USF1) in normal colorectal mucosa, different dysplasia tubular adenoma group and adenoma group expression were in turn increased, suggesting that it may be related to the occurrence and development of.3 SREBP-1 and fatty acid biosynthesis related factors were positively related with colorectal cancer, suggesting that SREBP-1 and fatty acid biosynthesis related factors (p-mTOR, FASN, USF1) It may play a synergistic role in the carcinogenesis of sporadic tubular adenomas.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.34

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本文編號(hào)：1618293