长链非编码RNA MT1JP在胃癌发生发展中的作用及其机制研究
发布时间：2018-07-27 19:57
【摘要】：胃癌(gastric cancer, GC)是最常见的恶性肿瘤之一,世界范围内死亡率高居肿瘤相关死亡的第三位。在中国胃癌的发病率和死亡率均为消化系统肿瘤前列,每年新发病例数约40多万。由于早期胃癌多无症状或仅有轻微症状,当临床症状明显时,病变已属晚期,且缺乏早期诊断的生物标志物,所以胃癌患者确诊时大多已经处于中晚期,错过最佳治疗时机。目前,手术切除和放化疗是胃癌最主要的治疗方法,但由于胃癌复发率高,尤其是远处转移和化疗耐药的频繁发生,使胃癌5年存活率为仅为40%左右。因此,胃癌不仅给患者健康带来严重损害,同时也让社会家庭背负沉重的精神及经济负担。目前已有诸多研究探讨胃癌的生物学特性,但在胃癌的临床疗效改善上发挥的作用却微乎其微。缺乏早期诊断的生物标志物、预后指标以及有效的治疗靶点使得胃癌治疗始终存在瓶颈。因此,关于胃癌发生、发展的生物学机制研究具有积极的意义,发现更多的具有诊断潜力或评估疗效的生物标志物分子以更好的改善胃癌患者的生存质量。胃癌的发生是环境因素和遗传因素共同作用的结果。环境危险因素主要包括饮食因素诸如盐和硝酸盐的高剂量摄入、职业暴露、幽门螺杆菌感染及吸烟饮酒等。然而在接触相同的环境因素的情况下仅有少数人最终发展为胃癌,表明个体对环境暴露因素的反应不尽相同,提示遗传因素参与其中。研究表明遗传因素在胃癌发生、发展中起着重要作用,这些研究主要集中在关键蛋白编码基因上,即关键基因的突变导致其编码的蛋白发生改变从而引起生物学功能的异常。然而,随着分子遗传机制研究的深入,人们发现表观遗传学在胃癌的发生发展中同样起着重要的作用。表观遗传学机制主要包括：组蛋白修饰、染色质重塑、DNA甲基化和非编码RNA (non-coding RNAs, ncRNAs)。基因组测序发现蛋白编码基因仅占总转录基因的2%,大多数基因被转录为非编码RNA。非编码RNA根据转录本长度不同又分为两类,一类是长度小于200个核苷酸的短链非编码RNA,包括微小RNA (miRNAs)、、干扰RNA (siRNAs)和Piwi相关RNA (piRNAs)。另一类长度超过200核苷酸称为长链非编码RNA (long non-coding RNA, 1ncRNA),其最初被视为“转录噪声”,不具备生物学功能,但越来越多的证据表明1ncRNA可以在转录水平、转录后水平以及表观遗传学层面调控基因的表达,从而参与人体的多种生理和病理过程,包括癌症转移、侵袭、细胞分化及凋亡等。随着对1ncRNA的研究增多,越来越多的1ncRNA在多种肿瘤中被发现,然而目前在胃癌中1ncRNA的研究仍处于起步阶段,在胃癌发生发展中作用机制尚不明确,有待进一步阐释。本研究采用高通量检测和qRT-PCR验证筛选的策略,寻找在胃癌中异常表达的1ncRNA,并在细胞和动物水平开展一系列分子生物学实验,结合人群样本验证,揭示lncRNA在胃癌中异常表达的临床意义以及生物学功能,并进一步阐明1ncRNA在胃癌发生过程中可能的分子机制,为评价1ncRNA作为胃癌早期诊断、预后评估以及治疗靶标的生物标志物提供理论依据。第一部分长链非编码RNAMT1JP在胃癌中异常表达的筛选、验证及其临床意义研究背景：胃癌是危害人类健康的常见肿瘤之一,在中国,胃癌的发病率及死亡率均居第二位,是危害我国国民健康的主要致死性肿瘤之一。胃癌的发生发展是一个多阶段、多因素的过程。近年来研究表明,长链非编码RNA与肿瘤的发生发展密切相关,其能够在转录、转录后以及翻译等水平调控肿瘤相关基因的表达。目前己有研究发现胃癌组织中存在异常表达1ncRNA,且这些异常表达1ncRNA在胃癌发生发展发挥重要的作用。然而,关于1ncRNA在胃癌中的具体作用机制尚未完全阐明,有待进一步探讨。方法及结果：我们对5对胃癌及癌旁组织进行了IncRNA表达谱芯片检测并整合GEO中胃癌GSE53137 lncRNA表达谱芯片数据,发现IncRNA MT1JP在胃癌组织中显著低表达；采用RT-PCR技术在75例胃癌及癌旁组织中验证以及TCGA胃癌公共数据中验证筛选结果,证实IncRNA MT1JP在胃癌组织中显著下调：分析IncRNA MT1JP表达水平与75例胃癌患者临床表型的关联性,发现其表达水平与胃癌分期、淋巴结转移有显著相关性：通过核质分离实验检测1ncRNA MT1JP亚细胞定位,发现IncRNA MT1JP细胞质中高丰度表达；我们采用RT-PCR方法检测308例胃癌组织中1ncRNA MT1JP表达水平,以表达量中位数为标准将病例分IncRNA MT1JP高低表达组,进一步采用Kaplan-Meier方法分析并绘制生存曲线,结果发现低表达IncRNA MT1JP的胃癌患者较高表达组患者的死亡风险提高了33%,Log-Rank P=0.03, HR=1.33 (95% CI:1.015-1.758)。结论：本研究发现lncRNA MT1JP在胃癌组织中显著低表达,其表达水平与胃癌的分期、淋巴结转移具有显著相关性且高表达的lncRNA MT1JP对胃癌患者的预后有保护的作用,为lncRNA MT1JP作为评价胃癌病程进展以及评估预后判断潜在生物标志物提供重要参考,也为进一步深入研究lncRNA MT1JP在胃癌中的作用及其机制提供依据。第二部分长链非编码RNA MT1JP在胃癌中生物学功能及其分子机制研究研究背景：长期以来,长链非编码RNA被认为是不具蛋白编码能力的无功能序列,一直未受到重视。然而近年来,越来越多研究发现1ncRNA能够在转录、转录后和翻译等水平调控基因表达从而发挥生物学功能,影响肿瘤细胞增殖、凋亡、浸润和转移等生物学行为。竞争性内源RNA(competing endogenous RNA, ceRNA)理论认为IncRNA、mRNA、假基因等转录产物可以通过竞争性与miRNA结合,行使“分子海绵(sponge)”功能,使与mRNA结合的miRNA数量减少,在转录后水平调控miRNA下游靶基因的表达。方法及结果：我们构建1ncRNA MT1JP过表达质粒,转染胃癌细胞后通过一系列细胞恶性表型实验,包括CCK-8, Transwell及流式细胞检测等方法,观察1ncRNA MT1JP对胃癌细胞恶性表型的影响,结果发现1ncRNA MT1JP可以显著的抑制胃癌细胞的增殖、侵袭和迁移能力并且促进胃癌细胞的凋亡；采用裸鼠成瘤实验研究1ncRNA MT1JP对胃癌细胞体内成瘤能力的影响,结果发现1ncRNA MT1JP可以明显抑制胃癌细胞体内成瘤的能力。为探讨1ncRNA MT1JP对细胞表型的影响具体分子机制,我们以ceRNA调控理论为依据,通过报告基因、细胞过表达、干扰以及Western blot等细胞分子生物学实验,结果发现1ncRNA MT1JP可能通过竞争性结合miR-92a-3p抑制抑癌基因FBXW7表达参与胃癌发生发展。结论：本研究发现1ncRNA MT1JP抑制胃癌细胞增殖、侵袭及转移的能力并促进胃癌细胞的凋亡,1ncRNA MT1JP这种抑癌基因样作用可能与其通过竞争性结合miRNA-92a-3p对抑癌基因FBXW7调控作用有关。不仅阐释了1ncRNA在胃癌发生发展中的作用,同时也为1ncRNA MT1JP临床应用价值的实现提供理论支撑。
[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.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.2
本文编号：2148966
[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.
【学位授予单位】：南京医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R735.2
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