發(fā)布時間：2018-07-27 19:57

【摘要】：胃癌(gastric cancer, GC)是最常見的惡性腫瘤之一,世界范圍內(nèi)死亡率高居腫瘤相關(guān)死亡的第三位。在中國胃癌的發(fā)病率和死亡率均為消化系統(tǒng)腫瘤前列,每年新發(fā)病例數(shù)約40多萬。由于早期胃癌多無癥狀或僅有輕微癥狀,當(dāng)臨床癥狀明顯時,病變已屬晚期,且缺乏早期診斷的生物標(biāo)志物,所以胃癌患者確診時大多已經(jīng)處于中晚期,錯過最佳治療時機。目前,手術(shù)切除和放化療是胃癌最主要的治療方法,但由于胃癌復(fù)發(fā)率高,尤其是遠(yuǎn)處轉(zhuǎn)移和化療耐藥的頻繁發(fā)生,使胃癌5年存活率為僅為40%左右。因此,胃癌不僅給患者健康帶來嚴(yán)重?fù)p害,同時也讓社會家庭背負(fù)沉重的精神及經(jīng)濟負(fù)擔(dān)。目前已有諸多研究探討胃癌的生物學(xué)特性,但在胃癌的臨床療效改善上發(fā)揮的作用卻微乎其微。缺乏早期診斷的生物標(biāo)志物、預(yù)后指標(biāo)以及有效的治療靶點使得胃癌治療始終存在瓶頸。因此,關(guān)于胃癌發(fā)生、發(fā)展的生物學(xué)機制研究具有積極的意義,發(fā)現(xiàn)更多的具有診斷潛力或評估療效的生物標(biāo)志物分子以更好的改善胃癌患者的生存質(zhì)量。胃癌的發(fā)生是環(huán)境因素和遺傳因素共同作用的結(jié)果。環(huán)境危險因素主要包括飲食因素諸如鹽和硝酸鹽的高劑量攝入、職業(yè)暴露、幽門螺桿菌感染及吸煙飲酒等。然而在接觸相同的環(huán)境因素的情況下僅有少數(shù)人最終發(fā)展為胃癌,表明個體對環(huán)境暴露因素的反應(yīng)不盡相同,提示遺傳因素參與其中。研究表明遺傳因素在胃癌發(fā)生、發(fā)展中起著重要作用,這些研究主要集中在關(guān)鍵蛋白編碼基因上,即關(guān)鍵基因的突變導(dǎo)致其編碼的蛋白發(fā)生改變從而引起生物學(xué)功能的異常。然而,隨著分子遺傳機制研究的深入,人們發(fā)現(xiàn)表觀遺傳學(xué)在胃癌的發(fā)生發(fā)展中同樣起著重要的作用。表觀遺傳學(xué)機制主要包括：組蛋白修飾、染色質(zhì)重塑、DNA甲基化和非編碼RNA (non-coding RNAs, ncRNAs)�；蚪M測序發(fā)現(xiàn)蛋白編碼基因僅占總轉(zhuǎn)錄基因的2%,大多數(shù)基因被轉(zhuǎn)錄為非編碼RNA。非編碼RNA根據(jù)轉(zhuǎn)錄本長度不同又分為兩類,一類是長度小于200個核苷酸的短鏈非編碼RNA,包括微小RNA (miRNAs)、、干擾RNA (siRNAs)和Piwi相關(guān)RNA (piRNAs)。另一類長度超過200核苷酸稱為長鏈非編碼RNA (long non-coding RNA, 1ncRNA),其最初被視為“轉(zhuǎn)錄噪聲”,不具備生物學(xué)功能,但越來越多的證據(jù)表明1ncRNA可以在轉(zhuǎn)錄水平、轉(zhuǎn)錄后水平以及表觀遺傳學(xué)層面調(diào)控基因的表達,從而參與人體的多種生理和病理過程,包括癌癥轉(zhuǎn)移、侵襲、細(xì)胞分化及凋亡等。隨著對1ncRNA的研究增多,越來越多的1ncRNA在多種腫瘤中被發(fā)現(xiàn),然而目前在胃癌中1ncRNA的研究仍處于起步階段,在胃癌發(fā)生發(fā)展中作用機制尚不明確,有待進一步闡釋。本研究采用高通量檢測和qRT-PCR驗證篩選的策略,尋找在胃癌中異常表達的1ncRNA,并在細(xì)胞和動物水平開展一系列分子生物學(xué)實驗,結(jié)合人群樣本驗證,揭示lncRNA在胃癌中異常表達的臨床意義以及生物學(xué)功能,并進一步闡明1ncRNA在胃癌發(fā)生過程中可能的分子機制,為評價1ncRNA作為胃癌早期診斷、預(yù)后評估以及治療靶標(biāo)的生物標(biāo)志物提供理論依據(jù)。第一部分長鏈非編碼RNAMT1JP在胃癌中異常表達的篩選、驗證及其臨床意義研究背景：胃癌是危害人類健康的常見腫瘤之一,在中國,胃癌的發(fā)病率及死亡率均居第二位,是危害我國國民健康的主要致死性腫瘤之一。胃癌的發(fā)生發(fā)展是一個多階段、多因素的過程。近年來研究表明,長鏈非編碼RNA與腫瘤的發(fā)生發(fā)展密切相關(guān),其能夠在轉(zhuǎn)錄、轉(zhuǎn)錄后以及翻譯等水平調(diào)控腫瘤相關(guān)基因的表達。目前己有研究發(fā)現(xiàn)胃癌組織中存在異常表達1ncRNA,且這些異常表達1ncRNA在胃癌發(fā)生發(fā)展發(fā)揮重要的作用。然而,關(guān)于1ncRNA在胃癌中的具體作用機制尚未完全闡明,有待進一步探討。方法及結(jié)果：我們對5對胃癌及癌旁組織進行了IncRNA表達譜芯片檢測并整合GEO中胃癌GSE53137 lncRNA表達譜芯片數(shù)據(jù),發(fā)現(xiàn)IncRNA MT1JP在胃癌組織中顯著低表達；采用RT-PCR技術(shù)在75例胃癌及癌旁組織中驗證以及TCGA胃癌公共數(shù)據(jù)中驗證篩選結(jié)果,證實IncRNA MT1JP在胃癌組織中顯著下調(diào)：分析IncRNA MT1JP表達水平與75例胃癌患者臨床表型的關(guān)聯(lián)性,發(fā)現(xiàn)其表達水平與胃癌分期、淋巴結(jié)轉(zhuǎn)移有顯著相關(guān)性：通過核質(zhì)分離實驗檢測1ncRNA MT1JP亞細(xì)胞定位,發(fā)現(xiàn)IncRNA MT1JP細(xì)胞質(zhì)中高豐度表達；我們采用RT-PCR方法檢測308例胃癌組織中1ncRNA MT1JP表達水平,以表達量中位數(shù)為標(biāo)準(zhǔn)將病例分IncRNA MT1JP高低表達組,進一步采用Kaplan-Meier方法分析并繪制生存曲線,結(jié)果發(fā)現(xiàn)低表達IncRNA MT1JP的胃癌患者較高表達組患者的死亡風(fēng)險提高了33%,Log-Rank P=0.03, HR=1.33 (95% CI:1.015-1.758)。結(jié)論：本研究發(fā)現(xiàn)lncRNA MT1JP在胃癌組織中顯著低表達,其表達水平與胃癌的分期、淋巴結(jié)轉(zhuǎn)移具有顯著相關(guān)性且高表達的lncRNA MT1JP對胃癌患者的預(yù)后有保護的作用,為lncRNA MT1JP作為評價胃癌病程進展以及評估預(yù)后判斷潛在生物標(biāo)志物提供重要參考,也為進一步深入研究lncRNA MT1JP在胃癌中的作用及其機制提供依據(jù)。第二部分長鏈非編碼RNA MT1JP在胃癌中生物學(xué)功能及其分子機制研究研究背景：長期以來,長鏈非編碼RNA被認(rèn)為是不具蛋白編碼能力的無功能序列,一直未受到重視。然而近年來,越來越多研究發(fā)現(xiàn)1ncRNA能夠在轉(zhuǎn)錄、轉(zhuǎn)錄后和翻譯等水平調(diào)控基因表達從而發(fā)揮生物學(xué)功能,影響腫瘤細(xì)胞增殖、凋亡、浸潤和轉(zhuǎn)移等生物學(xué)行為。競爭性內(nèi)源RNA(competing endogenous RNA, ceRNA)理論認(rèn)為IncRNA、mRNA、假基因等轉(zhuǎn)錄產(chǎn)物可以通過競爭性與miRNA結(jié)合,行使“分子海綿(sponge)”功能,使與mRNA結(jié)合的miRNA數(shù)量減少,在轉(zhuǎn)錄后水平調(diào)控miRNA下游靶基因的表達。方法及結(jié)果：我們構(gòu)建1ncRNA MT1JP過表達質(zhì)粒,轉(zhuǎn)染胃癌細(xì)胞后通過一系列細(xì)胞惡性表型實驗,包括CCK-8, Transwell及流式細(xì)胞檢測等方法,觀察1ncRNA MT1JP對胃癌細(xì)胞惡性表型的影響,結(jié)果發(fā)現(xiàn)1ncRNA MT1JP可以顯著的抑制胃癌細(xì)胞的增殖、侵襲和遷移能力并且促進胃癌細(xì)胞的凋亡；采用裸鼠成瘤實驗研究1ncRNA MT1JP對胃癌細(xì)胞體內(nèi)成瘤能力的影響,結(jié)果發(fā)現(xiàn)1ncRNA MT1JP可以明顯抑制胃癌細(xì)胞體內(nèi)成瘤的能力。為探討1ncRNA MT1JP對細(xì)胞表型的影響具體分子機制,我們以ceRNA調(diào)控理論為依據(jù),通過報告基因、細(xì)胞過表達、干擾以及Western blot等細(xì)胞分子生物學(xué)實驗,結(jié)果發(fā)現(xiàn)1ncRNA MT1JP可能通過競爭性結(jié)合miR-92a-3p抑制抑癌基因FBXW7表達參與胃癌發(fā)生發(fā)展。結(jié)論：本研究發(fā)現(xiàn)1ncRNA MT1JP抑制胃癌細(xì)胞增殖、侵襲及轉(zhuǎn)移的能力并促進胃癌細(xì)胞的凋亡,1ncRNA MT1JP這種抑癌基因樣作用可能與其通過競爭性結(jié)合miRNA-92a-3p對抑癌基因FBXW7調(diào)控作用有關(guān)。不僅闡釋了1ncRNA在胃癌發(fā)生發(fā)展中的作用,同時也為1ncRNA MT1JP臨床應(yīng)用價值的實現(xiàn)提供理論支撐。
[Abstract]:Gastric cancer (GC) is one of the most common malignant tumors, and the death rate in the world is third. The incidence and mortality of gastric cancer in China are the forefront of the digestive system tumor, and the number of new cases is about about 400000 each year. The symptoms of early gastric cancer are more than symptoms or only mild symptoms, when the clinical symptoms are obvious At the time, the pathological changes are in the late stage and lack the biomarkers of early diagnosis, so most of the patients with gastric cancer are in the middle and late stages and miss the best time to treat them. At present, surgical resection and radiotherapy are the most important treatment methods for gastric cancer. However, the recurrence rate of gastric cancer is high, especially the frequent occurrence of distant metastasis and chemotherapy resistance, which makes gastric cancer 5 The annual survival rate is only about 40%. Therefore, gastric cancer not only causes serious damage to the health of the patients, but also makes social families bear heavy mental and economic burdens. Many studies have been done to explore the biological characteristics of gastric cancer, but the clinical efficacy of gastric cancer is negligible. There is always a bottleneck in the treatment of gastric cancer. Therefore, the biological mechanism research on the occurrence and development of gastric cancer is of positive significance, and more biomarker molecules with diagnostic potential or evaluation are found to better improve the quality of life of gastric cancer patients. The occurrence of gastric cancer is Environmental and genetic factors are common results. Environmental risk factors include dietary factors such as high dose of salt and nitrate, occupational exposure, Helicobacter pylori infection, and smoking and drinking. However, only a few people have developed gastric cancer at the end of contact with the same environmental factors, indicating that individuals are exposed to environmental exposure. The study shows that genetic factors play an important role in the occurrence and development of gastric cancer. These studies mainly focus on the key protein coding genes, that is, the mutation of key genes causes the changes of the encoded proteins to cause abnormal biological functions. However, with the molecular remains The mechanism of epigenetics has been found to play an important role in the development of gastric cancer. Epigenetic mechanisms include histone modification, chromatin remodeling, DNA methylation and non coded RNA (non-coding RNAs, ncRNAs). The genome sequencing found that the protein encoding gene is only 2% of the total gene. Most genes are transcribed into non coded RNA. non coded RNA, which are divided into two classes according to the length of transcriptional transcripts. One is short chain non coded RNA of less than 200 nucleotides, including small RNA (miRNAs), RNA (siRNAs) and Piwi related RNA (piRNAs). Another class of longer than 200 nucleotides is called long chain non coding RNA. 1ncRNA), initially considered as a "transcriptional noise", does not have biological functions, but more and more evidence suggests that 1ncRNA can regulate the expression of genes at the level of transcription, posttranscriptional level and epigenetic level, thus participating in a variety of physiological and pathological processes in the human body, including cancer metastasis, invasion, cell differentiation and apoptosis. More and more studies of 1ncRNA have been found in many kinds of tumors. However, the study of 1ncRNA in gastric cancer is still in its infancy. The mechanism of the action in the development of gastric cancer is still unclear. This study is to be further explained. This study uses high throughput and qRT-PCR screening strategies to find abnormal expression in gastric cancer. 1ncRNA, and carrying out a series of molecular biology experiments at the level of cell and animal, combined with the sample of the crowd to reveal the clinical significance and biological function of the abnormal expression of lncRNA in gastric cancer, and further elucidate the possible molecular mechanism of 1ncRNA in the process of gastric cancer, to evaluate the prognosis of the early diagnosis of the gastric cancer and the evaluation of the prognosis for the evaluation of the prognosis of the gastric cancer. It provides a theoretical basis for the biomarkers for the target treatment. Part 1 screening, verification and clinical significance of abnormal expression of long chain non coded RNAMT1JP in gastric cancer: gastric cancer is one of the common tumors that harm human health. In China, the incidence and mortality of gastric cancer are second, which are the main hazards to the national health of China. The occurrence and development of gastric cancer is a multistage, multi factor process. In recent years, studies have shown that long chain noncoding RNA is closely related to the development of tumor, and it can regulate the expression of tumor related genes at the level of transcription, post transcription and translation. Up to 1ncRNA, and these abnormal expressions of 1ncRNA play an important role in the development of gastric cancer. However, the specific mechanisms of action of 1ncRNA in gastric cancer have not been fully elucidated. Methods and results are still to be further explored. We have detected 5 pairs of gastric and paracancerous tissues by IncRNA expression chip and integrated the GSE53137 lncRNA in GEO. A significant low expression of IncRNA MT1JP in gastric cancer tissues was found by the expression of spectral chip data. The results were verified by RT-PCR technique in 75 cases of gastric cancer and para cancer tissue and in the public data of TCGA gastric cancer. It was proved that IncRNA MT1JP was significantly down-regulated in gastric cancer tissue: the analysis of the expression level of IncRNA MT1JP and the clinical phenotype of 75 cases of gastric cancer patients. There was a significant correlation between the expression level of the gastric carcinoma and the lymph node metastasis. The high abundance expression in the cytoplasm of the IncRNA MT1JP was detected by the detection of the 1ncRNA MT1JP subcellular location by the nuclear separation experiment. The expression of 1ncRNA MT1JP in 308 cases of gastric cancer was detected by RT-PCR, and the median of the expression was the standard of the expression. The cases were divided into IncRNA MT1JP high and low expression groups, and the survival curve was further analyzed by Kaplan-Meier method. The results showed that the mortality risk of patients with high expression of IncRNA MT1JP with low expression of MT1JP increased by 33%, Log-Rank P=0.03, HR=1.33 (95% CI:1.015-1.758). Conclusion: This study found lncRNA MT1JP in gastric cancer tissue The expression level has a significant correlation with the stage of gastric cancer and lymph node metastasis and the high expression of lncRNA MT1JP has a protective effect on the prognosis of gastric cancer patients. It provides an important reference for the evaluation of the progression of gastric cancer and the evaluation of the potential biomarkers of the prognosis of the gastric cancer and the further in-depth study of lncRNA MT1, as well as the further in-depth study of lncRNA MT1. The role of JP in gastric cancer and its mechanism provide the basis. Second the research background of the biological function and molecular mechanism of long chain non coding RNA MT1JP in gastric cancer: long chain non coding RNA has been considered to be a non functional sequence without protein coding ability and has not been paid attention to. However, more and more studies have found 1 in recent years. NcRNA can regulate gene expression at transcriptional, post transcriptional and translation levels to play biological functions, affect tumor cell proliferation, apoptosis, infiltration and metastasis. Competitive endogenous RNA (competing endogenous RNA, ceRNA) theory suggests that IncRNA, mRNA, pseudogenes, and other transcriptional products can be combined with miRNA to compete with miRNA. The function of "molecular sponge (sponge)" to reduce the number of miRNA associated with mRNA and to regulate the expression of the target gene in the downstream miRNA at post transcriptional level. Methods and results: we construct 1ncRNA MT1JP overexpressed plasmids and transfect gastric cancer cells through a series of cell malignant phenotype experiments, including CCK-8, Transwell and flow cytometry, and so on. The effects of 1ncRNA MT1JP on the malignant phenotype of gastric cancer cells were observed. The results showed that 1ncRNA MT1JP could significantly inhibit the proliferation, invasion and migration of gastric cancer cells and promote the apoptosis of gastric cancer cells. The effect of 1ncRNA MT1JP on the tumorigenicity of gastric cancer cells was studied in nude mice. The results found that 1ncRNA MT1JP was clear. The ability to inhibit tumor formation in gastric cancer cells was inhibited. In order to explore the specific molecular mechanism of the effect of 1ncRNA MT1JP on the cell phenotype, based on the ceRNA regulation theory, we found that 1ncRNA MT1JP may be inhibited by competitive binding of miR-92a-3p through the reporter gene, cell overexpression, interference and Western blot cell molecular biology experiments. The expression of tumor suppressor gene FBXW7 is involved in the development of gastric cancer. Conclusion: This study found that 1ncRNA MT1JP inhibits the proliferation, invasion and metastasis of gastric cancer cells and promotes the apoptosis of gastric cancer cells. The role of 1ncRNA MT1JP as a tumor suppressor may be related to the competitive binding of miRNA-92a-3p to the regulation of the tumor suppressor gene FBXW7. Not only does it explain the effect of miRNA-92a-3p on the regulation of cancer suppressor gene FBXW7. It also explains the role of 1ncRNA in the development of gastric cancer, and provides theoretical support for the realization of clinical value of 1ncRNA MT1JP.
【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】：2016
【分類號】：R735.2

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5 楊軍樂;寧文德;董季平;徐敏;;多層螺旋CT在胃癌診斷中的應(yīng)用研究[A];中華醫(yī)學(xué)會第十三屆全國放射學(xué)大會論文匯編（下冊）[C];2006年

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7 張麗紅;常維平;黃賢會;;螺旋CT在特殊部位胃癌診斷中的應(yīng)用[A];中國醫(yī)師協(xié)會放射醫(yī)師分會首屆會員大會暨第四屆醫(yī)學(xué)影像山東論壇、山東省第16次放射學(xué)會議暨山東省第14屆醫(yī)學(xué)影像學(xué)學(xué)術(shù)研討會論文集[C];2007年

8 陳靜;;彩色多普勒超聲檢查在胃癌的應(yīng)用[A];中國超聲醫(yī)學(xué)工程學(xué)會第七屆全國腹部超聲學(xué)術(shù)會議學(xué)術(shù)論文匯編[C];2007年

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10 吳厚賓;;腹腔鏡在胃癌診治中的應(yīng)用進展(綜述)[A];江西省第二屆胃腸外科學(xué)術(shù)會議暨江西省第十二次中西醫(yī)結(jié)合普通外科學(xué)術(shù)會議論文匯編[C];2012年

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