本文選題：結(jié)直腸癌 + ACY-1�。� 參考：《山東大學(xué)》2017年博士論文

【摘要】：背景結(jié)直腸癌為目前世界上最為常見(jiàn)的惡性腫瘤之一,其在消化道惡性腫瘤發(fā)病率中僅次于胃癌和食道癌。在我國(guó),結(jié)直腸癌的發(fā)病率在近二十年來(lái)呈逐漸上升趨勢(shì),且發(fā)病人群的年齡逐漸趨于年輕化。隨著我國(guó)居民的飲食結(jié)構(gòu)以及生活方式的改變,結(jié)直腸癌的發(fā)病率在城市居民中增高尤其明顯。結(jié)直腸癌具有高發(fā)病率、高死亡率以及高轉(zhuǎn)移率的特點(diǎn),因此對(duì)人類(lèi)生命健康構(gòu)成了巨大威脅。盡管隨著現(xiàn)代醫(yī)療技術(shù)水平的不斷發(fā)展和完善,在對(duì)結(jié)直腸癌的治療上已經(jīng)取得了突破性進(jìn)展,但結(jié)直腸癌患者生存率依然未得到明顯改善。結(jié)直腸癌患者的生存率與其診斷時(shí)所處的惡性化程度之間存在相關(guān)性,即Ⅰ期結(jié)直腸癌患者的五年生存率可高達(dá)93%,而Ⅲ期結(jié)直腸癌患者的5年生存率則僅為8%。引起結(jié)直腸癌患者死亡的大部分原因是由于腫瘤復(fù)發(fā)轉(zhuǎn)移,目前臨床上通過(guò)手術(shù)為主的綜合治療方法僅能夠使約50%的結(jié)直腸癌患者在術(shù)后三年內(nèi)無(wú)進(jìn)展生存,但約有大于40%的結(jié)直腸癌患者在術(shù)后發(fā)生復(fù)發(fā)和轉(zhuǎn)移,而且結(jié)直腸癌復(fù)發(fā)的高峰期往往集中在術(shù)后2年左右。因此,尋找與結(jié)直腸癌發(fā)生以及惡性化進(jìn)程相關(guān)的分子標(biāo)志物,同時(shí)對(duì)其相關(guān)功能及作用機(jī)制進(jìn)行深入探索是目前醫(yī)學(xué)界研究的重點(diǎn)和熱點(diǎn)內(nèi)容,對(duì)于結(jié)直腸癌患者的早期檢測(cè)、治療以及預(yù)后情況判斷具有十分重要的意義。結(jié)直腸癌的惡性化過(guò)程通常是由體內(nèi)外多種因素參與的多步驟的復(fù)雜過(guò)程,通過(guò)網(wǎng)絡(luò)性調(diào)控影響結(jié)直腸癌的生物學(xué)行為。隨著腫瘤分子生物學(xué)探索的不斷深入,越來(lái)越多的基因被證實(shí)參與了結(jié)直腸癌的發(fā)生和發(fā)展過(guò)程。氨基�；�1(aminoacylase-1,ACY-1)為一種胞質(zhì)酶,能夠使細(xì)胞內(nèi)蛋白的N末端肽鏈上的αα酰化氨基酸發(fā)生乙�；�,在此過(guò)程之后能夠使該蛋白質(zhì)的穩(wěn)定性增強(qiáng)。當(dāng)機(jī)體內(nèi)的原癌基因活化或者抑癌基因失活時(shí),細(xì)胞的生長(zhǎng)以及分化過(guò)程將發(fā)生失控,從而向癌細(xì)胞轉(zhuǎn)變。目前對(duì)于ACY-1的研究大部分集中在其具有的�；被崴饷傅幕钚宰饔梅矫�,臨床上通常將血清ACY-1作為判斷腎移植預(yù)后的指標(biāo),但依然缺少其在惡性腫瘤發(fā)生和發(fā)展過(guò)程中作用的研究。目前已有研究表明,ACY-1在多種實(shí)體惡性腫瘤組織中的表達(dá)量發(fā)生下調(diào),從而提示ACY-1可能參與了腫瘤的發(fā)生、發(fā)展。還有報(bào)道發(fā)現(xiàn),ACY-1在神經(jīng)母細(xì)胞瘤患者的血清中呈低表達(dá)狀態(tài)時(shí)往往預(yù)示著患者的預(yù)后情況較差。但目前尚未有對(duì)于ACY-1在結(jié)直腸癌中表達(dá)以及作用機(jī)制的報(bào)道。轉(zhuǎn)化生長(zhǎng)因子β(TGF-β)為一個(gè)在人體多種生理病理過(guò)程具有生物學(xué)功能的生長(zhǎng)因子超家族,主要功能是調(diào)控細(xì)胞增殖以及分化過(guò)程,同時(shí)還在胚胎發(fā)育過(guò)程中發(fā)揮重要作用。除此之外,TGF-β還具有促進(jìn)細(xì)胞外基質(zhì)的形成以及調(diào)控機(jī)體免疫反應(yīng)等功能。TGF-β共包括6種異構(gòu)體(TGF-β1～6),其中TGF-β1最為常見(jiàn),幾乎參與了生物機(jī)體內(nèi)所有的病理以及生理過(guò)程,與臨床上多種疾病的發(fā)生和發(fā)展密切相關(guān)。研究發(fā)現(xiàn),TGF-β在惡性腫瘤的發(fā)生和發(fā)展、胚胎發(fā)育、細(xì)胞外基質(zhì)的形成以及免疫調(diào)節(jié)過(guò)程中均扮演著十分重要的角色。目前已有研究證實(shí),TGF-β1在乳腺癌、胃癌、結(jié)腸癌、前列腺癌、宮頸癌以及膀胱癌等惡性腫瘤組織中呈異常高表達(dá)狀態(tài),且其表達(dá)水平與上述腫瘤的進(jìn)展以及轉(zhuǎn)移相關(guān)。細(xì)胞外信號(hào)調(diào)節(jié)激酶(extracellular regulated kinase,ERK)為絲裂原活化蛋白激酶(mitogen-activatedprotein kinase,MAPK)家族的重要成員之一。MAPK通路能夠被多種因素刺激而活化,其中包括細(xì)胞因子、神經(jīng)遞質(zhì)、生長(zhǎng)因子、激素、細(xì)胞應(yīng)激以及細(xì)胞黏附等,其下游靶基因包括多種蛋白激酶、磷脂酶和轉(zhuǎn)錄因子等。當(dāng)這些下游靶基因被活化之后能夠直接使核轉(zhuǎn)錄因子以及其他蛋白激酶等底物發(fā)生磷酸化,從而對(duì)相關(guān)基因的轉(zhuǎn)錄過(guò)程進(jìn)行調(diào)控,最終影響機(jī)體細(xì)胞的生長(zhǎng)、發(fā)育、分裂,從而維持其正常生理功能的完整性。ERK1和ERK2是MAPK/ERK信號(hào)轉(zhuǎn)導(dǎo)通路中的兩個(gè)重要成員,主要對(duì)細(xì)胞生長(zhǎng)、發(fā)育、分化、凋亡等生理過(guò)程進(jìn)行調(diào)控,同時(shí)在細(xì)胞的惡性轉(zhuǎn)化過(guò)程中亦扮演著重要角色。由ERK所介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)通路受到來(lái)自于細(xì)胞內(nèi)外多種絲裂原的刺激和應(yīng)激,從而使ERK的底物活化,最終實(shí)現(xiàn)調(diào)控細(xì)胞周期以及抑制細(xì)胞凋亡的作用,同時(shí)還能夠促進(jìn)細(xì)胞增殖、遷移以及侵襲等生理病理過(guò)程。ERK1/2在生物機(jī)體細(xì)胞內(nèi)分布產(chǎn)生變化往往預(yù)示著MAPK信號(hào)轉(zhuǎn)導(dǎo)通路的功能狀態(tài)發(fā)生改變。研究表明,在未受到刺激的細(xì)胞中,ERK1/2大部分均存在于細(xì)胞質(zhì)中;當(dāng)細(xì)胞受到刺激時(shí),部分ERK1/2向細(xì)胞核中聚集,從而形成p-ERK1/2。p-ERK1/2能夠與細(xì)胞核內(nèi)的多種轉(zhuǎn)錄因子發(fā)生相互作用,從而促進(jìn)了癌基因的表達(dá)。ERK1/2信號(hào)通路與惡性腫瘤的發(fā)生和發(fā)展存在顯著相關(guān)性。目的本研究通過(guò)檢測(cè)ACY-1在結(jié)直腸癌組織中的表達(dá),明確其臨床意義,同時(shí)對(duì)其在結(jié)直腸癌細(xì)胞增殖、凋亡、侵襲以及轉(zhuǎn)移過(guò)程中的相關(guān)作用機(jī)制進(jìn)行研究,旨在探討ACY-1與結(jié)直腸癌發(fā)生和發(fā)展的相關(guān)性,從而為尋找新的腫瘤分子標(biāo)志物以及藥物作用靶點(diǎn)奠定基礎(chǔ)。方法(1)采集132例結(jié)直腸組織樣本均來(lái)自于山東大學(xué)附屬省立醫(yī)院胃腸外科2015年6月～2016年6月結(jié)直腸癌手術(shù)切除組織樣本,按照性別進(jìn)行劃分,其中男性為70例,女性為62例;按照年齡進(jìn)行劃分,其中≤50歲為57例,50歲為75例;按照是否淋巴結(jié)轉(zhuǎn)移進(jìn)行劃分,其中發(fā)生轉(zhuǎn)移的為52例,未發(fā)生轉(zhuǎn)移的為80例;TNM分期進(jìn)行劃分,其中Ⅰ期為44例、Ⅱ期為62例、Ⅲ期+Ⅳ為26例。另外選取120例健康志愿者血清作為對(duì)照組。采集上述入選者的癌組織、相應(yīng)癌旁正常組織或血清,分別運(yùn)用熒光定量PCR、western blot法以及ELISA法檢測(cè)ACY-1 mRNA及其蛋白的表達(dá),并分析其與患者性別、年齡、TNM分期和淋巴結(jié)轉(zhuǎn)移的相關(guān)性。(2)將攜帶有siRNA-ACY-1基因的慢病毒載體GV218-EGFP-ACY-1轉(zhuǎn)染人293T細(xì)胞,待包裝出病毒之后將之感染人結(jié)腸癌HT29細(xì)胞,以此構(gòu)建ACY-1過(guò)抑制表達(dá)HT29細(xì)胞系。用倒置熒光顯微鏡對(duì)人293T細(xì)胞的轉(zhuǎn)染效率進(jìn)行觀察。熒光定量PCR檢測(cè)ACY-1表達(dá)抑制的HT29細(xì)胞中ACY-1 mRNA的表達(dá);運(yùn)用Transwell小室法檢測(cè)該細(xì)胞系的侵襲能力;流式細(xì)胞術(shù)測(cè)定細(xì)胞的凋亡情況,CCK-8法檢測(cè)細(xì)胞的增殖活性。(3)分別將 siRNA-NC 和 siRNA-ACY-1 轉(zhuǎn)染 HT-29 細(xì)胞,運(yùn)用 western blot法分別檢測(cè)ACY-1抑制表達(dá)的人結(jié)腸癌細(xì)胞HT29細(xì)胞中p-ERK1/2和TGF-β1蛋白的表達(dá)。結(jié)果(1)熒光定量PCR檢測(cè)表明,ACY-1 mRNA在癌旁相應(yīng)正常組織(對(duì)照組)中的表達(dá)量為0.324±0.012,在結(jié)直腸癌組織中的表達(dá)量為0.614±0.051,顯著高于對(duì)照組(P0.05)。western blot檢測(cè)結(jié)果表明,ACY-1蛋白在癌旁相應(yīng)正常組織中的表達(dá)量為0.231±0.065,在結(jié)直腸癌組織中的表達(dá)量為0.646±0.038,顯著高于對(duì)照組(P0.05)。ELISA檢測(cè)結(jié)果表明,癌旁正常組織中ACY-1的含量為36.88±5.65 pg/mL,結(jié)直腸癌患者血清中的含量為57.11±6.32pg/mL,明顯高于健康志愿者(P0.05)。對(duì)ACY-1的表達(dá)與結(jié)直腸癌患者臨床病例參數(shù)的相關(guān)性進(jìn)行分析,結(jié)果表明ACY-1的表達(dá)與結(jié)直腸癌患者的性別和年齡之間無(wú)顯著相關(guān)性(P0.05),而與TNM分期和是否發(fā)生淋巴結(jié)轉(zhuǎn)移有關(guān)(P0.05)。(2)熒光定量PCR檢測(cè)結(jié)果表明,構(gòu)建的ACY-1抑制表達(dá)HT29細(xì)胞中的ACY-1 mRNA的表達(dá)量明顯低于對(duì)照組,表明成功構(gòu)建ACY-1抑制表達(dá)HT29細(xì)胞系。CCK-8檢測(cè)結(jié)果表明,轉(zhuǎn)染siRNA-ACY-1后細(xì)胞的增殖活性明顯低于對(duì)照組(P0.01)。流式細(xì)胞術(shù)檢測(cè)結(jié)果表明,ACY-1抑制表達(dá)的HT29細(xì)胞的凋亡細(xì)胞數(shù)量顯著高于對(duì)照組(P0.01)。Transwell檢測(cè)結(jié)果表明,感染siRNA-ACY-1后HT29細(xì)胞的侵襲能力顯著低于對(duì)照組(P0.05)。(3)western blot法檢測(cè)結(jié)果表明,對(duì)照組ACY-1蛋白的相對(duì)表達(dá)量為0.78±0.11,siRNA-ACY-1 組為 0.16±0.04。與對(duì)照組相比,siRNA-ACY-1組ACY-1蛋白的表達(dá)量明顯低于對(duì)照組(P0.01)。對(duì)照組p-ERK1/2蛋白的相對(duì)表達(dá)量為 0.89±0.13,TGF-β1 蛋白為 0.78±0.14;siRNA-ACY-1組p-ERK1/2蛋白的相對(duì)表達(dá)量為0.33±0.09,TGF-β1蛋白為0.21±0.06。與對(duì)照組相比,p-ERK1/2、TGF-β1蛋白的表達(dá)量均顯著降低,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。結(jié)論ACY-1在結(jié)直腸癌組織中呈高表達(dá),且其表達(dá)量與結(jié)直腸癌患者的TNM分期以及淋巴結(jié)轉(zhuǎn)移密切相關(guān)。ACY-1能夠通過(guò)直接調(diào)控TGF-β-ERK1/2信號(hào)通路來(lái)實(shí)現(xiàn)對(duì)結(jié)直腸癌細(xì)胞增殖、侵襲以及凋亡的調(diào)控。
[Abstract]:Background colorectal cancer is one of the most common malignant tumors in the world. It is second only to gastric cancer and esophagus cancer in the incidence of digestive tract malignancies. In China, the incidence of colorectal cancer has been increasing in the past twenty years, and the age of the population is gradually becoming younger. The incidence of colorectal cancer is particularly evident in urban residents. Colorectal cancer has a high incidence, high mortality, and high metastasis rate, which poses a great threat to human life and health. Although with the continuous development and improvement of modern medical technology, the treatment of colorectal cancer has been done. The survival rate of colorectal cancer patients remained unchanged. There was a correlation between the survival rate of colorectal cancer patients and the degree of malignancy at the time of diagnosis, that is, the five year survival rate of patients with stage I colorectal cancer was up to 93%, while the 5 year survival rate of patients with stage III colorectal cancer was only 8%.. Most of the causes of death in patients with colorectal cancer are due to tumor recurrence. Currently, a comprehensive treatment based on surgery can only make about 50% of the patients with colorectal cancer without progress within three years after the operation, but more than 40% of the colorectal cancer patients have recurrence and metastasis after operation, and the recurrence of colorectal cancer is at the peak period. It is often concentrated at about 2 years after the operation. Therefore, it is the key and hot topic in the medical field to find the molecular markers related to the process of colorectal cancer and the process of malignancy, and to explore the related functions and mechanisms of action. It is ten for the early detection, treatment and prognosis of colorectal cancer patients. It is of great significance. The malignant process of colorectal cancer is usually a multistep and complex process involved in a variety of factors in the body and the body. It affects the biological behavior of colorectal cancer through network regulation. With the continuous exploration of the molecular biology of the tumor, more and more genes have been proved to be involved in the process of the occurrence and development of rectal cancer. Aminoacylase 1 (aminoacylase-1, ACY-1) is a cytoplasmic enzyme that can make acetylation of alpha acylated amino acids on the N terminal peptide chain of the intracellular protein. After this process, the stability of the protein can be enhanced. When the oncogene is activated in the body or when Yi Aiji is inactivated, the cell growth and differentiation process will occur. The study of ACY-1 is mostly focused on the activity of its acylated amino acid hydrolase. The serum ACY-1 is usually used as a prognostic indicator of renal transplantation, but it still lacks the study of its role in the development and development of malignant tumors. Currently, research has shown that A The expression of CY-1 in a variety of solid malignant tumor tissues is down, suggesting that ACY-1 may be involved in the occurrence and development of the tumor. It is also reported that the low expression of ACY-1 in the serum of the patients with neuroblastoma often indicates that the prognosis of the patients is poor, but there is no table for ACY-1 in colorectal cancer. Transforming growth factor beta (TGF- beta) is a growth factor superfamily with biological functions in various physiological and pathological processes in human body. The main function is to regulate cell proliferation and differentiation, and also plays an important role in the process of embryonic development. In addition, TGF- beta also promotes the extracellular matrix. 6 isomers (TGF- beta 1~6) are included in the formation of the substance and the regulation of the body's immune response, including 6 isomers (TGF- beta 1~6). The TGF- beta 1 is the most common, almost involved in all the pathological and physiological processes in the biological machine. It is closely related to the occurrence and development of various clinical diseases. The study found that TGF- beta is in the occurrence and development of malignant tumors and embryos. Development, the formation of extracellular matrix and immunomodulation play a very important role in the process of immunoregulation. TGF- beta 1 has been proved to be highly expressed in malignant tumor tissues such as breast cancer, gastric cancer, colon cancer, prostate cancer, cervical cancer and bladder cancer, and its expression level is associated with the progression and metastasis of the above tumor. Extracellular regulated kinase (ERK), one of the important members of the mitogen activated protein kinase (MAPK) family, is one of the important members of the mitogen-activatedprotein kinase (MAPK) family. The.MAPK pathway can be activated by a variety of factors, including cytokines, neurotransmitters, growth factors, hormones, cell stress, and cell adhesion. The downstream target genes include a variety of protein kinases, phospholipases and transcription factors. When these downstream target genes are activated, they can directly phosphorylate the nuclear transcription factors and other protein kinase and other substrates, thereby regulating the transcriptional processes of the related genes, which ultimately affect the growth, development and division of the body cells. The integrity of.ERK1 and ERK2, with its normal physiological function, is the two important member of the MAPK/ERK signal transduction pathway, which regulates the physiological processes, such as cell growth, development, differentiation and apoptosis, and plays an important role in the process of cell malignant transformation. The signal transduction pathway mediated by ERK is derived from and from the cell. The stimulation and stress of a variety of mitogens make the substrates of ERK activate, ultimately regulate cell cycle and inhibit cell apoptosis, and can also promote cell proliferation, migration and invasion and other physiological and pathological processes, which tend to indicate the function of the MAPK signal transduction pathway of.ERK1/2. The study showed that the majority of ERK1/2 existed in the cytoplasm in the cells that were not stimulated, and when the cells were stimulated, some of the ERK1/2 gathered in the nucleus, thus forming p-ERK1/2.p-ERK1/2 that could interact with a variety of transcription factors in the nucleus, thereby promoting the expression of the oncogene expression of.ERK1/2. There is a significant correlation between the occurrence and development of malignant tumors. Objective to investigate the clinical significance of the expression of ACY-1 in colorectal cancer tissue, and to study the mechanism of its role in the proliferation, apoptosis, invasion and metastasis of colorectal cancer cells, and to explore the occurrence and development of ACY-1 and colorectal cancer. The correlation of the exhibition lay the foundation for finding new biomarkers and drug targets. Methods (1) the samples of 132 colorectal tissues were collected from the gastrointestinal surgery of the Provincial Hospital Affiliated to Shandong University from June 2015 to June 2016, and were divided by sex. Among them, 70 cases were male. Women were 62 cases; in accordance with age, 57 cases were 50 years old and 75 cases were 50 years old. According to whether lymph node metastasis was divided, 52 cases were metastasize and 80 cases were not metastasize; TNM stage was divided into 44 cases, 62 cases in stage II, and 26 cases of stage III + IV, and another 120 healthy volunteers serum as the same. The expression of ACY-1 mRNA and its protein were detected by fluorescence quantitative PCR, Western blot and ELISA, and the correlation with sex, age, TNM stage and lymph node metastasis of the patients was analyzed by fluorescence quantitative PCR, Western and ELISA. (2) the lentivirus carrier with siRNA-ACY-1 gene was carried. 8-EGFP-ACY-1 transfected to human 293T cells and infected human colon cancer HT29 cells after the virus was packaged. In order to construct a ACY-1 overexpressed HT29 cell line, the transfection efficiency of human 293T cells was observed by inverted fluorescence microscopy. The expression of ACY-1 mRNA in the HT29 cells inhibited by ACY-1 expression was detected by fluorescence quantitative PCR. The cell method was used to detect the invasion ability of the cell line. Flow cytometry was used to determine the cell apoptosis and CCK-8 assay was used to detect the cell proliferation activity. (3) HT-29 cells were transfected by siRNA-NC and siRNA-ACY-1, and the expression of p-ERK1/2 and TGF- beta 1 protein in human colon cancer cell HT29 cells expressed by ACY-1 was detected by Western blot respectively. Fruit (1) fluorescence quantitative PCR detection showed that the expression of ACY-1 mRNA in the corresponding normal tissue (control group) was 0.324 + 0.012, and the expression in colorectal cancer tissues was 0.614 + 0.051, which was significantly higher than that of the control group (P0.05).Western blot detection results showed that the expression of ACY-1 egg white in the normal tissues adjacent to the cancer was 0.231 + 0.065. The expression in colorectal cancer tissue was 0.646 + 0.038, which was significantly higher than that of the control group (P0.05).ELISA detection results showed that the content of ACY-1 in the normal tissues adjacent to the cancer was 36.88 + 5.65 pg/mL, the content of the serum in the patients with colorectal cancer was 57.11 + 6.32pg/mL, obviously higher than that of the healthy volunteers (P0.05). The expression of ACY-1 and the clinical cases of colorectal cancer patients The correlation of the parameters was analyzed. The results showed that there was no significant correlation between the expression of ACY-1 and the sex and age of colorectal cancer patients (P0.05), but it was related to TNM staging and lymph node metastasis (P0.05). (2) the results of fluorescence quantitative PCR showed that the expression of ACY-1 mRNA in the constructed ACY-1 inhibited expression of HT29 cells was significantly lower. In the control group, the results of the successful construction of the ACY-1 inhibition expression HT29 cell line.CCK-8 showed that the proliferation activity of the cells after siRNA-ACY-1 transfection was significantly lower than that of the control group (P0.01). The results of flow cytometry showed that the number of apoptotic cells of the HT29 cells expressed by ACY-1 was significantly higher than that of the control group (P0.01).Transwell detection results. The invasion ability of HT29 cells after siRNA-ACY-1 infection was significantly lower than that of the control group (P0.05). (3) the results of Western blot assay showed that the relative expression of ACY-1 protein in the control group was 0.78 + 0.11, and the siRNA-ACY-1 group was 0.16 + 0.04. compared with the control group, the amount of the ACY-1 protein in the siRNA-ACY-1 group was significantly lower than that of the control group (P0.01). The control group p-ERK1/2 eggs The relative expression of white was 0.89 + 0.13, TGF- beta 1 protein was 0.78 + 0.14, the relative expression of p-ERK1/2 protein in siRNA-ACY-1 group was 0.33 + 0.09, TGF- beta 1 protein was 0.21 + 0.06. compared with the control group, and the expression of TGF- beta 1 protein was significantly decreased, and the difference was statistically significant (P0.05). Conclusion ACY-1 is high in colorectal cancer tissue. Expression, and its expression is closely related to TNM staging and lymph node metastasis in colorectal cancer patients,.ACY-1 can regulate the proliferation, invasion and apoptosis of colorectal cancer cells by direct regulation of TGF- beta -ERK1/2 signaling pathway.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R735.34

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