本文選題：食管癌　切入點(diǎn)：表觀遺傳　出處：《天津醫(yī)科大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：食管癌是人類常見(jiàn)的惡性腫瘤,位居全球六大致死性腫瘤之列。2011年國(guó)際癌癥研究機(jī)構(gòu)(IARC)最新統(tǒng)計(jì),每年全世界有近50萬(wàn)食管癌新發(fā)患者,死亡人數(shù)約40萬(wàn)。我國(guó)是食管癌最高發(fā)的國(guó)家,發(fā)病率及死亡率均居世界首位:發(fā)病率占全球54%,以河北磁縣、河南林縣、山西陽(yáng)城為代表的華北太行山高發(fā)區(qū)發(fā)病率可高達(dá)110/10萬(wàn)以上;而我國(guó)每年因食管癌死亡人數(shù)也占據(jù)世界食管癌年死亡人數(shù)52%,死亡率在我國(guó)惡性腫瘤中位居第4位。制約食管癌療效主要有如下幾方面原因:第一,食管癌的早期篩查尚無(wú)明確的方法,尚未發(fā)現(xiàn)明確的腫瘤標(biāo)志物,由于發(fā)現(xiàn)不及時(shí)而錯(cuò)過(guò)治療最佳時(shí)機(jī);第二,術(shù)后的復(fù)發(fā)和轉(zhuǎn)移,是食管癌患者治療失敗和死亡的主要原因,該機(jī)理尚不十分清楚,也無(wú)有效的抑制手段;第三,國(guó)內(nèi)外尚未報(bào)道任何針對(duì)食管癌特異性的治療靶點(diǎn)及藥物。另外,我國(guó)食管癌的發(fā)病相對(duì)歐美國(guó)家有其獨(dú)特性,以鱗癌為主,而非國(guó)外報(bào)道較多的腺癌,因此不能只依賴于國(guó)際報(bào)道的數(shù)據(jù),而應(yīng)針對(duì)中國(guó)食管癌發(fā)病特點(diǎn)來(lái)展開(kāi)研究。SMYD3與許多惡性腫瘤的發(fā)生發(fā)展關(guān)系密切,能夠影響腫瘤細(xì)胞的增殖、凋亡、遷移及粘附等生物學(xué)行為,如結(jié)直腸癌、肝細(xì)胞癌、胰腺癌、前列腺癌、多發(fā)性骨髓瘤、肺癌、乳腺癌、腦瘤、胃癌等。本研究前期已應(yīng)用免疫組化方法在15例人食管鱗癌及癌旁組織樣本檢測(cè)了SMYD3蛋白表達(dá)情況,發(fā)現(xiàn)其表達(dá)呈漿染且在癌組織中表達(dá)水平明顯增高,并發(fā)現(xiàn)SMYD3對(duì)抑癌基因RIZ1具有調(diào)控作用,下調(diào)SMYD3表達(dá)后RIZ1表達(dá)增高,腫瘤增殖受到抑制。本研究進(jìn)一步針對(duì)143例臨床大樣本病例中SMYD3的表達(dá)情況進(jìn)行檢測(cè),試圖明確其表達(dá)水平與臨床病理參數(shù)關(guān)系,如腫瘤大小、病變長(zhǎng)度、腫瘤分化、發(fā)生部位、有無(wú)淋巴結(jié)轉(zhuǎn)移、TNM分期等。另一方面,試圖明確SMYD3的表達(dá)水平是否與食管鱗癌患者的生存情況相關(guān),是否具有指示預(yù)后的作用。研究結(jié)果顯示,SMYD3表達(dá)水平與中位總生存期以及中位無(wú)進(jìn)展生存期均獨(dú)立相關(guān),是食管鱗癌獨(dú)立的預(yù)后指標(biāo),SMYD3高表達(dá)患者較低表達(dá)患者具有較差的預(yù)后。SMYD3在癌組織高表達(dá)進(jìn)一步被證實(shí),隨腫瘤TNM分期的從低到高,漿染逐漸加強(qiáng),但并未發(fā)現(xiàn)轉(zhuǎn)移淋巴結(jié)中SMYD3表達(dá)與癌組織之間的差異。另外,在對(duì)其表達(dá)水平與臨床病理參數(shù)相關(guān)性分析中也未有陽(yáng)性發(fā)現(xiàn),差異無(wú)統(tǒng)計(jì)學(xué)意義。因此,SMYD3是食管鱗癌重要的預(yù)后因子,其對(duì)癌癥發(fā)生和進(jìn)展臨床意義重大。前期研究通過(guò)shrna敲降smyd3后riz1表達(dá)水平提升,抑癌活性恢復(fù),腫瘤增殖受到抑制。本次應(yīng)用sirna及構(gòu)建shrna表達(dá)載體轉(zhuǎn)染細(xì)胞的方法在食管鱗癌細(xì)胞系中下調(diào)和上調(diào)smyd3表達(dá),檢測(cè)riz1表達(dá)水平,驗(yàn)證前期結(jié)果并評(píng)價(jià)riz1表達(dá)是否隨smyd3過(guò)表達(dá)而減低?另外,通過(guò)borden小室法檢測(cè)癌細(xì)胞侵襲能力變化情況;通過(guò)流式細(xì)胞儀檢測(cè)細(xì)胞凋亡的改變以及細(xì)胞周期的變化。結(jié)果我們發(fā)現(xiàn),當(dāng)應(yīng)用sirna下調(diào)smyd3表達(dá)后,riz1的mrna和蛋白表達(dá)明顯提升,癌細(xì)胞的侵襲力減弱,細(xì)胞凋亡增加,細(xì)胞周期s期細(xì)胞含量增加,而g2/m期細(xì)胞含量相對(duì)減少,g0/g1期無(wú)明顯變化,提示抑制smyd3后細(xì)胞增殖下降的原因可能是由于細(xì)胞阻滯于s期。相反,當(dāng)過(guò)表達(dá)smyd3后riz1的表達(dá)并未發(fā)生減低,也未發(fā)現(xiàn)腫瘤侵襲力的增加。針對(duì)前兩部分內(nèi)容及前期研究結(jié)果,smyd3作為抑癌基因riz1的上游調(diào)控基因,究竟是通過(guò)哪些因素的改變而調(diào)控了riz1的表達(dá),又是通過(guò)哪些因素引起食管鱗癌細(xì)胞生物學(xué)行為變化呢?smyd3作為組蛋白甲基化酶,可以介導(dǎo)h3k4甲基化修飾的改變,而組蛋白甲基化改變已被證明與多種腫瘤的發(fā)生、進(jìn)展、復(fù)發(fā)、耐藥等方面密切相關(guān)。因此本研究的第三部分就smyd3-riz1在食管鱗癌中具體調(diào)控機(jī)制展開(kāi)研究,首先應(yīng)用elisa的方法對(duì)15例小樣本h3k4一甲基化、二甲基化、三甲基化進(jìn)行檢測(cè),經(jīng)統(tǒng)計(jì)發(fā)現(xiàn)組蛋白甲基化水平在癌組織中均高于癌旁組織。之后在食管鱗癌細(xì)胞株te13敲低和過(guò)表達(dá)smyd3,檢測(cè)以上甲基化的修飾變化,結(jié)果發(fā)現(xiàn)當(dāng)smyd3下調(diào)時(shí)h3k4二甲基化和三甲基化減低,一甲基化未發(fā)生改變,而過(guò)表達(dá)smyd3時(shí),三種甲基化水平均無(wú)變化。由于前期已證明riz1表達(dá)減低與dna啟動(dòng)子高甲基化有關(guān),因此我們對(duì)smyd3敲低后的riz1啟動(dòng)子甲基化再一次進(jìn)行了檢測(cè),發(fā)現(xiàn)其水平較對(duì)照發(fā)生了部分逆轉(zhuǎn)。由此揭示了食管鱗癌中smyd3調(diào)控riz1的兩種表觀遺傳機(jī)制。第一,是通過(guò)介導(dǎo)h3k4二甲基化和三甲基化的增加;第二,是使riz1的dna啟動(dòng)子區(qū)發(fā)生高甲基化。前三部分通過(guò)實(shí)驗(yàn)證明了smyd3與riz1的關(guān)聯(lián)和可能存在的表觀調(diào)控機(jī)制。組蛋白甲基化、dna甲基化都是動(dòng)態(tài)存在的,它們受到組蛋白甲基化酶與去甲基化酶、dna甲基化酶與去甲基化酶間相互作用的影響,處于某種動(dòng)態(tài)平衡之中,一旦平衡被打破就可能激活相關(guān)信號(hào)通路,導(dǎo)致腫瘤發(fā)生。本研究的第四部分試圖對(duì)此展開(kāi)初步探索,首先以上述15例食管鱗癌臨床標(biāo)本為研究對(duì)象,針對(duì)組蛋白賴氨酸特異性去甲基化酶lsd1和jarid1的酶活性進(jìn)行了檢測(cè),發(fā)現(xiàn)癌組織中LSD1的酶活性明顯高于癌旁組織,而JARID1酶活性并未發(fā)現(xiàn)區(qū)別。當(dāng)應(yīng)用5-aza-CdR逆轉(zhuǎn)DNA甲基化后,H3K4一甲基化和二甲基化水平明顯減低,在1μM時(shí)最為顯著,H3K4三甲基化未見(jiàn)明顯改變;LSD1和JARID1酶活性隨用藥濃度變化也產(chǎn)生了不同的改變,LSD1活性隨用藥濃度增加逐漸減低,而JARID1的酶活性較對(duì)照呈現(xiàn)先低后高的走勢(shì)。以上說(shuō)明了組蛋白去甲基化酶在食管鱗癌的發(fā)生過(guò)程中也起重要作用;DNA的甲基化可以影響H3K4甲基化修飾改變,同時(shí)也影響組蛋白去甲基化酶LSD1和JARID1的活性,具體機(jī)制還有待進(jìn)一步探明。
[Abstract]:Esophageal cancer is a common malignant tumor, among the world's six most deadly cancer among.2011 years of the international agency for research on cancer (IARC) to the latest statistics, the whole world has nearly 500 thousand new cases of esophageal cancer each year, about 400 thousand deaths. China is the highest incidence of esophageal cancer, incidence rate and mortality rate in the the first in the world: the incidence accounted for 54% of the world, in Hebei, Cixian, Henan, Lin County, Shanxi Yangcheng as the representative of the high incidence area of North Taihang Mountain the incidence rate can be as high as 110/10 million; and China each year due to esophageal cancer deaths also occupy the world of esophageal cancer deaths in 52%, mortality ranked fourth in malignant tumors in China control effect of esophageal cancer. There are several reasons: first, there is no clear method for early screening of esophageal cancer, has not found a clear tumor marker, because it is not timely and miss the best time for treatment; second, postoperative rehabilitation Primary and metastatic esophageal cancer patients, is the main cause of treatment failure and death, the mechanism is not very clear, no inhibition of effective means; third, have not been reported for any esophageal cancer specific therapeutic targets and drugs at home and abroad. In addition, the incidence of esophageal cancer in China which is unique to Europe and the United States the country, mainly squamous cell carcinoma, but not reported more adenocarcinoma, it is not only dependent on the reported data, and should be closely related to the development of Chinese for incidence of esophageal cancer of.SMYD3 and many malignant tumors, can affect tumor cell proliferation, apoptosis, migration and adhesion of biological behavior. Such as colorectal cancer, hepatocellular carcinoma, pancreatic cancer, prostate cancer, multiple myeloma, lung cancer, breast cancer, brain cancer, gastric cancer. This study previously by immunohistochemical method in 15 cases of esophageal squamous cell carcinoma and paracancerous tissue samples The expression of SMYD3 protein, we found that the expression of a pulp and the expression level increased significantly, and found that SMYD3 has a role in the regulation of tumor suppressor gene RIZ1 and down-regulation of SMYD3 expression after the increased expression of RIZ1 in tumor proliferation. This study further for the expression of SMYD3 in 143 cases was detected in large sample cases, trying to clear the relationship between its expression and clinical pathological parameters, such as tumor size, tumor length, tumor differentiation, location, lymph node metastasis and TNM stage. On the other hand, trying to clear the SMYD3 expression level is associated with the survival of patients with esophageal squamous cell carcinoma, whether can indicate the prognosis. Results showed that the expression level of SMYD3 and the median overall survival and median progression free survival were independent prognostic indicators of esophageal squamous cell carcinoma, is independent of the high expression of SMYD3 in patients with low expression in patients with Have a poor prognosis of.SMYD3 in cancer tissues of high expression was further confirmed, with the tumor TNM stage from low to high, the pulp gradually strengthened, but did not find a difference between the expression of SMYD3 in lymph node metastasis and cancer. In addition, the expression level and clinicopathological correlation analysis also found no positive parameters on it the difference was not statistically significant. Therefore, SMYD3 is an important prognostic factor in esophageal squamous cell carcinoma, the cancer occurrence and development is of great clinical significance. Previous research by shRNA on the expression level of RIZ1 stable after SMYD3 tumor suppressor activity recovery, tumor proliferation was inhibited. The application of siRNA and the way to construct shRNA expression vector transfected cells in esophageal squamous cell carcinoma cell lines downregulated and upregulated expression of SMYD3 to detect the expression level of RIZ1, to validate the result and evaluate whether the expression of RIZ1 with overexpression of SMYD3 decreased? In addition, detected by Borden assay. Cancer cell invasion ability changes; changes by flow cytometry to detect apoptosis and the change of cell cycle. Results we found that when siRNA was used to downregulate SMYD3 expression, protein expression of mRNA and RIZ1 significantly, decreased cancer cell invasion, cell apoptosis, increase of cells in the S phase of the cell cycle, and the cells in g2/m phase decreased, g0/g1 phase did not change significantly, suggesting that inhibition of SMYD3 cell proliferation after the cause of the decline may be due to cell cycle arrest in S phase. On the contrary, when after overexpression of SMYD3 RIZ1 expression was not impaired, also found no increased invasiveness of tumors. In the first two parts and the previous research results. SMYD3 as the upstream regulatory genes of tumor suppressor gene RIZ1, whether through which factors change and regulation of the expression of RIZ1, and by what factors caused by esophageal squamous cell carcinoma cell behavior changes SMYD3? As a histone methyltransferase, mediated by H3K4 methylation modification, and group change of histone methylation has been shown with a variety of tumor occurrence, progression, recurrence, closely related to resistance and so on. So the third part of the study of smyd3-riz1 in esophageal squamous cell carcinoma specific regulatory mechanism research methods the first application of ELISA in 15 cases of small sample H3K4 two methylation, methylation, methylation was detected by statistics found that histone methylation levels were higher than the adjacent tissues in cancer tissues. After knockdown and overexpression of SMYD3 in esophageal squamous cell carcinoma cell line te13, detection of the methylation modification. The results showed that when the SMYD3 cut H3K4 two methylation and methylation reduced methylation is not changed, and the expression of SMYD3, no change in three methylation level. Because of the early RIZ1 has been shown to reduce expression of DNA promoter Hypermethylation, so we SMYD3 knockdown of RIZ1 promoter methylation were detected again, found the levels than the control has been partially reversed. This reveals two epigenetic mechanisms of SMYD3 in esophageal squamous cell carcinoma and the regulation of RIZ1. First, the two is to increase the methylation and trimethyl mediated by H3K4; second, is to make RIZ1 DNA hypermethylation of the promoter region. The three part is proved through experiments on regulation mechanism of SMYD3 is associated with RIZ1 and possible. Histone methylation and DNA methylation are dynamic, they are histone methyltransferase and demethylase, DNA methylase and to influence the interaction between methylation enzyme, in a dynamic balance. Once the balance is broken can activate signaling pathways leading to tumorigenesis. The fourth part of this study attempts to launch the preliminary exploration, First of all the 15 cases of esophageal squamous cell carcinoma clinical samples as the research object, the enzyme activity of histone lysine specific demethylase LSD1 and jarid1 were detected, found that the enzyme activity of LSD1 in cancer tissues was significantly higher than that of adjacent tissues, and the enzyme activity of JARID1 did not find a difference. When using 5-aza-CdR reverse DNA methylation after a two H3K4 methylation and methylation level was significantly decreased in 1 M was the most significant, H3K4 trimethylation had no obvious change; LSD1 and JARID1 activity changes with the drug concentration had different changes, the activity of LSD1 increased with the drug concentration gradually decreased, while the enzyme activity of JARID1 compared with the control show the trend of low to high. The above described histone demethylase also plays an important role in carcinogenesis of esophageal squamous cell carcinoma; DNA methylation can affect H3K4 methylation changes also affect histone methylation enzyme The activity of LSD1 and JARID1 and the specific mechanism still need to be further explored.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.1

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