本文關(guān)鍵詞： 胃癌 ATP6V1A 轉(zhuǎn)錄調(diào)控 預(yù)后生物標(biāo)志物 預(yù)后評分　出處：《南京醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：胃癌是當(dāng)今世界最常見的惡性腫瘤之一,其發(fā)病率高、易侵襲和轉(zhuǎn)移、臨床癥狀嚴(yán)重和低治愈率等特性導(dǎo)致其成為嚴(yán)重的世界健康問題。胃癌發(fā)病率排在肺癌、乳腺癌、結(jié)腸直腸癌和前列腺癌之后占居第五名。這些數(shù)據(jù)表明胃癌已對人類健康構(gòu)成重大威脅,并成為經(jīng)濟(jì)和社會發(fā)展的重大阻礙。目前,治療胃癌的主要手段是手術(shù)切除,早期胃癌患者的五年生存率超過90%。但是,大部分胃癌患者明確診斷時已處于進(jìn)展期并已經(jīng)失去了放療機(jī)會,導(dǎo)致五年生存率降至只有11-40%。因此,胃癌研究的當(dāng)務(wù)之急是提高胃癌患者的早期診斷率和開發(fā)新的分子靶向藥物來治療和預(yù)防胃癌的轉(zhuǎn)移和復(fù)發(fā)。最新研究表明胃癌(gastric cancer,GC)的侵襲和轉(zhuǎn)移與多亞基液泡H+-ATPase(V-ATPase)密切相關(guān)。本研究探討了編碼V-ATPase中催化亞基A的人類ATP6V1A基因在胃癌中的表達(dá)和作用。我們發(fā)現(xiàn),與正常組織相比,胃癌中ATP6V1A表達(dá)水平顯著增高,但ATP6V1A表達(dá)水平較高的胃癌患者預(yù)后較好。基因組分析顯示,在小部分胃癌患者中APT6V1A的拷貝數(shù)增加,并且在極少量胃癌中丟失。此外,ATP6V14的拷貝數(shù)與mRNA水平呈正相關(guān)。為了尋找ATP6V1A在胃癌基因中過度表達(dá)的額外機(jī)制,我們研究了轉(zhuǎn)錄因子YY1和ATP6V1A之間的關(guān)系,并發(fā)現(xiàn)YY1的mRNA表達(dá)與ATP6V1A表達(dá)密切相關(guān)。為了證明YY1能轉(zhuǎn)錄調(diào)節(jié)ATP6Y1A我們發(fā)現(xiàn)ATP6V1A的核心啟動子區(qū)域內(nèi)包含三個YY1結(jié)合位點,在胃癌細(xì)胞中由RNAi介導(dǎo)的YY1沉默會顯著減少ATP6V1A的mRNA和蛋白質(zhì)表達(dá),而YY1過度表達(dá)則會增加ATP6V1A的表達(dá)水平。并通過一系列的實驗證實了 YY1與ATP6V1A啟動子區(qū)中YY1結(jié)合位點的相互作用。總之,YY1可能在與胃癌潛在機(jī)制和臨床意義相關(guān)的ATP6V14表達(dá)中起著重要的調(diào)節(jié)作用,且較高的ATP6V1A表達(dá)水平有利于胃癌的良好預(yù)后。為了進(jìn)一步開發(fā)胃癌預(yù)后相關(guān)的基因生物標(biāo)志,我們利用基因表達(dá)模式分析幫助確定一組基因生物標(biāo)志物以預(yù)測臨床結(jié)果,并發(fā)現(xiàn)潛在的治療新靶點。本研究采用了多步驟生物信息學(xué)分析方法,以建立新的胃癌預(yù)后評分體系。我們首先確認(rèn)了 276個在正常和胃癌組織中表達(dá)有顯著差異的基因,通過單一變量Cox回歸分析,發(fā)現(xiàn)其中249個基因與總生存期(Overall Survival,OS)顯著相關(guān)。這249個基因的生物學(xué)功能涉及到細(xì)胞周期、RNA/非編碼RNA加工、乙�；图�(xì)胞外基質(zhì)組成。在265個胃癌基因中,建立了 249個基因表達(dá)相關(guān)模型網(wǎng)絡(luò)。我們采用典型判別分析法確定了一組由53個基因組成的胃癌預(yù)后生物標(biāo)志物,并根據(jù)53個基因的典型判別函數(shù)建立了預(yù)后評分體系。預(yù)后評分能準(zhǔn)確預(yù)測胃癌患者的總生存期情況。最后,我們對53個基因中的FHOD1基因在胃癌中的功能和作用進(jìn)行了研究。發(fā)現(xiàn)FHOD1的表達(dá)對胃癌細(xì)胞的增殖、侵襲和轉(zhuǎn)移、凋亡有顯著的影響�？傊�,本研究發(fā)現(xiàn)的胃癌預(yù)后生物標(biāo)志物揭示了個體腫瘤的生物學(xué)特性,可更準(zhǔn)確的預(yù)測該腫瘤的行為。建立的預(yù)后評分體系可為胃癌精準(zhǔn)醫(yī)療開辟廣闊的前景。
[Abstract]:Gastric cancer is one of the world's most common malignant tumor, its incidence rate is high, easy invasion and metastasis, clinical symptoms are severe and the low cure rate and other characteristics of the world lead to serious health problems. The incidence of gastric cancer in lung cancer, breast cancer, colorectal cancer and prostate cancer after occupying fifth. These data suggest that gastric cancer is a major threat to human health, and has become a major obstacle to economic and social development. At present, the main means for the treatment of gastric cancer is surgical resection, patients with early gastric cancer five years survival rate is more than 90%., but the majority of cancer patients diagnosed is in progress and has lost the opportunity to radiotherapy five year survival rate. To only 11-40%. therefore, a pressing matter of the moment of the research is to improve gastric cancer metastasis and recurrence rate of early diagnosis and the development of new molecular targeted drugs for the treatment and prevention of gastric cancer in patients with gastric cancer. New research shows that gastric cancer (gastric cancer, GC) in the invasion and metastasis of H+-ATPase (V-ATPase) and Doyaki vacuoles are closely related. This study investigated the expression and function of human ATP6V1A gene encoding V-ATPase catalytic subunit A in gastric carcinoma. We found that, compared with the normal tissues, the expression level of ATP6V1A in gastric cancer was significantly increased, but the expression of ATP6V1A in patients with gastric cancer prognosis better. Higher levels of genome analysis showed that the copy number of APT6V1A in a small part of the increase in gastric cancer patients, and lost in the very small amount of gastric cancer. In addition, the copy number of ATP6V14 and mRNA levels were positively correlated. In order to find additional mechanisms of overexpression of ATP6V1A in gastric cancer genes, we studied the relationship between the between the transcription factor YY1 and ATP6V1A, and found that YY1 mRNA expression is closely related with the expression of ATP6V1A. In order to prove that YY1 can regulate transcription of ATP6Y1A we found that the ATP6V1A core promoter The sub region contains three YY1 binding sites, mediated by RNAi in human gastric cancer cells YY1 silencing can significantly reduce the expression of mRNA and protein ATP6V1A, whereas overexpression of YY1 could increase the expression of ATP6V1A. And confirmed the interaction between YY1 and ATP6V1A in the promoter region of YY1 binding sites through a series of experiments. In short, YY1 in gastric cancer and the potential mechanism and clinical significance of the expression of ATP6V14 plays an important role in the regulation of the high expression level of ATP6V1A and a good prognosis for gastric cancer. In order to further the development of gastric cancer related genes have marker gene expression pattern analysis, we use a group of genes that help determine biomarkers in order to predict the clinical outcome, and find new therapeutic target potential. This study adopts multi-step bioinformatics analysis methods to establish a new scoring system. Firstly, the prognosis of gastric cancer Confirmation of the 276 gene expression were significantly different in normal and cancer tissues by single variable Cox regression analysis found that 249 genes and overall survival (Overall, Survival, OS) was significantly correlated. The biological function of these 249 genes involved in cell cycle, non encoding RNA processing RNA/, acetylation and the extracellular matrix composition. In 265 gastric cancer genes, established 249 gene expression related to model network. We use the canonical discriminant analysis method to determine the prognosis of gastric cancer biological group consists of 53 gene markers, and discriminant function established prognostic scoring system according to the typical 53 genes can accurately predict the prognosis score. Overall survival of patients with gastric cancer. Finally, we studied the function of FHOD1 gene in 53 genes in gastric carcinoma. The expression of FHOD1 on gastric cancer cell proliferation, invasion and metastasis. Death has a significant impact. In conclusion, the biomarker of gastric cancer revealed by this study reveals the biological characteristics of individual tumors, and can predict the behavior of tumors more accurately. The established scoring system of prognosis has broad prospects for precision medical treatment of gastric cancer.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R735.2

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本文編號：1503826