本文選題：SLFN11 + 甲基化　； 參考：《中國人民解放軍醫(yī)學(xué)院》2017年博士論文

【摘要】：背景:結(jié)直腸癌是常見的惡性腫瘤,在世界范圍內(nèi)發(fā)病率排第三位,因癌致死率排第四位。結(jié)直腸癌在年輕人中少見,50歲以后發(fā)病率明顯增高,在發(fā)達(dá)國家中位發(fā)病年齡為70歲。在中國,隨著人們生活方式和飲食結(jié)構(gòu)的改變,結(jié)直腸癌的發(fā)病率在逐年增高。大多數(shù)散發(fā)的結(jié)直腸癌病例(約85%)有染色體不穩(wěn)定,包括染色體的等位基因失衡、染色體擴(kuò)增和易位。DNA損傷修復(fù)和檢查點調(diào)控機(jī)制缺陷是造成基因突變和染色體不穩(wěn)定的重要機(jī)制。遺傳性結(jié)直腸癌主要包括家族性腺瘤性息肉病和Lynch綜合征,是由DNA錯配修復(fù)基因突變引起的,小于結(jié)直腸癌發(fā)病率的5%。DNA損傷修復(fù)基因異常甲基化是結(jié)直腸癌的重要病因之一。在1998年,Schlafen ( SLFN )基因家族首先由Steven Hedrick等發(fā)現(xiàn)。到目前為止,已有10個鼠源性和6個人源性家族成員被鑒定。SLFN家族蛋白被報道參與一系列細(xì)胞生物學(xué)功能,包括增殖、分化和免疫功能。SLFN11基因是SLFN基因家族成員之一,被報道能夠增加DNA損傷類藥物的敏感性。到目前為止,SLFN11基因在人結(jié)直腸癌中的表觀遺傳學(xué)調(diào)控機(jī)制仍不清楚,需要進(jìn)一步研究。目的:研究SLFN11基因在人結(jié)直腸癌中的表觀遺傳學(xué)改變和對化療藥物敏感性的研究。材料和方法:本研究在6種結(jié)腸癌細(xì)胞和128例人結(jié)直腸癌標(biāo)本中進(jìn)行了研究。在結(jié)腸癌細(xì)胞系中,采用RT-PCR、甲基化特異的PCR和硫化測序等方法研究了SLFN11受甲基化調(diào)控的機(jī)制。采用甲基化特異的PCR研究了人結(jié)直腸癌標(biāo)本中SLFN1甲基化情況。采用MTT、克隆形成、流式細(xì)胞術(shù)和蛋白印跡法研究了 SLFN11對結(jié)腸癌細(xì)胞增殖的影響。采用裸鼠成瘤模型探討了在體內(nèi)SLFN11對結(jié)腸癌細(xì)胞增殖的影響。在結(jié)腸癌細(xì)胞中,采用MTT、流式細(xì)胞術(shù)對SLFN11與順鉑的敏感性進(jìn)行了研究。結(jié)果:SLFN11啟動子區(qū)附近在結(jié)直腸癌中經(jīng)常發(fā)生甲基化(55.47%, 71/128)。SLFN11基因的表達(dá)受到甲基化調(diào)控。SLFN11基因甲基化與年齡、5年生存率和5年腫瘤復(fù)發(fā)時間相關(guān)。SLFN11在體內(nèi)和體外都能抑制結(jié)腸癌細(xì)胞的增殖。SLFN11能夠增強(qiáng)結(jié)腸癌細(xì)胞對順鉑的敏感性。
[Abstract]:Background: colorectal cancer is a common malignant tumor. The incidence of colorectal cancer increased significantly after 50 years of age in young people, with a median onset age of 70 years in developed countries. In China, the incidence of colorectal cancer increases year by year as people's lifestyle and diet change. Most sporadic cases of colorectal cancer (about 85) have chromosomal instability, including allelic imbalances in chromosomes, Chromosome amplification and translocation. DNA damage repair and checkpoint regulatory defects are the important mechanisms of gene mutation and chromosome instability. Hereditary colorectal cancer mainly includes familial adenomatous polyposis and Lynch syndrome, which is caused by mutation of DNA mismatch repair gene. Abnormal methylation of DNA damage repair gene is one of the important causes of colorectal cancer. In 1998, the Schlafen (SLFN) gene family was first discovered by Steven Hedrick et al. So far, 10 murine and 6 individual origin family members have been identified as involved in a series of cellular biological functions, including proliferation, differentiation and immune function. SLFN11 gene is a member of the SLFN gene family. It has been reported to increase the sensitivity of DNA damage drugs. Up to now, the epigenetic regulation mechanism of SLFN11 gene in human colorectal cancer is still unclear and needs further study. Aim: to study the epigenetic changes and chemosensitivity of SLFN11 gene in human colorectal cancer. Materials and methods: six kinds of colon cancer cells and 128 human colorectal cancer specimens were studied. In colon cancer cell line RT-PCR, methylation specific PCR and vulcanization sequencing were used to study the mechanism of SLFN11 methylation. The methylation of SLFN1 in human colorectal cancer was studied by methylation specific PCR. The effects of SLFN11 on the proliferation of colon cancer cells were studied by MTT, clone formation, flow cytometry and Western blotting. The effects of SLFN11 on the proliferation of colon cancer cells were studied in nude mice. MTT and flow cytometry were used to study the sensitivity of SLFN11 and cisplatin in colon cancer cells. Results 55.47 methylation occurs frequently in colorectal cancer near the 1: SLFN11 promoter region. The expression of 71 / 128U. SLFN11 gene is regulated by methylation. The methylation of SLFN11 gene is related to age, 5-year survival rate and 5-year recurrence time. SLFN11 can be expressed in vivo and in vitro. Inhibition of the proliferation of colon cancer cells. SLFN 11 can enhance the sensitivity of colon cancer cells to cisplatin.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R735.34

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 閆文姬;郭明洲;;表觀遺傳組學(xué)——腫瘤精準(zhǔn)治療的新靶標(biāo)[J];胃腸病學(xué)和肝病學(xué)雜志;2015年05期

，

本文編號：2037640