本文選題：高遷移率族蛋白 + 非小細(xì)胞肺癌　； 參考：《山東大學(xué)》2012年博士論文

【摘要】：肺癌的發(fā)病率和死亡率都持續(xù)增高,探討肺癌的相關(guān)細(xì)胞因子及發(fā)病機(jī)制,對(duì)減少肺癌發(fā)病率有非常重要的作用。研究表明,HMGB1與非小細(xì)胞肺癌的發(fā)生、發(fā)展、轉(zhuǎn)移有非常密切的關(guān)系。 高遷移率族蛋白B1(high-mobility group box-B1, HMGB1)廣泛存在于真核生物細(xì)胞內(nèi),在許多生物學(xué)過(guò)程中,HMGB1都有非常重要的作用。HMGB1的表達(dá)水平增高可以導(dǎo)致細(xì)胞分化、細(xì)胞遷移并促進(jìn)細(xì)胞增殖。HMGB1可以促進(jìn)細(xì)胞生長(zhǎng)和基因轉(zhuǎn)錄,高遷移率族蛋白與腫瘤的許多生物學(xué)特性也有非常密切的關(guān)系,如腫瘤的發(fā)生、浸潤(rùn)、轉(zhuǎn)移等。 高遷移率族蛋白的各種生物學(xué)活性都是與其相應(yīng)受體的結(jié)合而實(shí)現(xiàn)的,晚期糖基化終末產(chǎn)物(RAGE)受體是HMGB1的最主要受體。當(dāng)HMGB1與RAGE結(jié)合時(shí),有兩條主要的下游信號(hào)轉(zhuǎn)導(dǎo)通路被激活：第一條通路是鳥(niǎo)苷三磷酸酶(Rac)和CDC42途徑被激活,產(chǎn)生相應(yīng)的生物學(xué)效應(yīng),包括細(xì)胞骨架的重塑、細(xì)胞運(yùn)動(dòng)、細(xì)胞遷移和腫瘤的生長(zhǎng)、遷移及增殖；第二條通路是絲裂原活化蛋白激酶途徑被激活,在這個(gè)過(guò)程中核因子-κB (NF κB)被活化,產(chǎn)生了大量的細(xì)胞因子和趨化因子,促使免疫細(xì)胞的成熟,在免疫受體的表達(dá)也有非常重要的作用；可能還可以激活另外一條信號(hào)轉(zhuǎn)導(dǎo)通路即MAPK, P38, JNK及P42/P44等信號(hào)通路,這條通路可以激活MMP—2和—9,二者是系統(tǒng)纖維蛋白溶酶激活級(jí)聯(lián)的下游目標(biāo),通過(guò)系統(tǒng)纖維蛋白溶酶降解細(xì)胞外基質(zhì),使腫瘤進(jìn)一步浸潤(rùn)和轉(zhuǎn)移。 目的 本研究的目的是通過(guò)檢測(cè)非小細(xì)胞肺癌的HMGB1表達(dá)水平的變化,HMGB1與腫瘤臨床生物學(xué)特性的關(guān)系,進(jìn)一步探討和研究HMGB1在非小細(xì)胞肺癌中的作用及發(fā)病機(jī)制。 方法 應(yīng)用逆轉(zhuǎn)錄聚合酶鏈反應(yīng)(RT-PCR)方法檢測(cè)HMGB1在非小細(xì)胞肺癌中的mRNA的表達(dá)；應(yīng)用蛋白印跡法檢測(cè)非小細(xì)胞肺癌HMGB1蛋白水平的表達(dá)；比較肺癌不同分期、不同大小、手術(shù)前后HMGB1蛋白水平的變化。 結(jié)果 1RT-PCR檢測(cè)人肺癌A549細(xì)胞系、支氣管上皮細(xì)胞系HBE中HMGB1mRNA的表達(dá)結(jié)果 支氣管上皮細(xì)胞系HBE為對(duì)照細(xì)胞,根據(jù)公式2-average△△CT×100%計(jì)算目的基因相對(duì)表達(dá)量。結(jié)果顯示肺腺癌A549細(xì)胞系HMGB1表達(dá)量明顯高于支氣管上皮細(xì)胞系HBE,為其11.450倍。 2人肺癌A549細(xì)胞系、支氣管上皮細(xì)胞系HBE HMGB1蛋白的表達(dá) 人肺腺癌細(xì)胞株A549、支氣管上皮細(xì)胞系HBE蛋白相對(duì)表達(dá)量分別為80.44±3.51、6.83±0.75、肺癌細(xì)胞株A549HMGB1蛋白表達(dá)水平明顯高于支氣管上皮細(xì)胞系HBE,并存在統(tǒng)計(jì)學(xué)差異(P0.001)。圖2顯示兩株細(xì)胞HMGB1蛋白表達(dá)的差異。 3肺癌患者與肺良性病患者血清HMGB1蛋白的表達(dá) 145例肺癌患者血清HMGB1平均水平為76.1±37.0ng/ml,肺良性病組HMGB1平均水平為39.8±10.8ng/ml),健康志愿者HMGN1平均水平為7.7±6.1ng/ml,肺癌HMGB1表達(dá)水平明顯高于良性病患者及健康對(duì)照組,并且有統(tǒng)計(jì)學(xué)差異(p0.001)。 4肺癌不同分期血清HMGB1蛋白的表達(dá) 肺癌Ⅰ,Ⅱ,Ⅲ及Ⅳ期患者血清HMGBl水平分別為30.2±5.9ng/ml,60.9±22.5ng/ml,99.0±23.1ng/ml及133.4±18.9ng/ml。四組間有顯著的統(tǒng)計(jì)學(xué)差異(p0.0001),并且每?jī)山M間也有顯著的統(tǒng)計(jì)學(xué)差異。進(jìn)一步的研究發(fā)現(xiàn),有遠(yuǎn)處轉(zhuǎn)移的肺癌患者其HMGB1水平為(133.4±18.9ng/ml)明顯高于無(wú)遠(yuǎn)處轉(zhuǎn)移的肺癌患者(68.46±31.9ng/ml,p
[Abstract]:The incidence and mortality of lung cancer continue to increase. To explore the cytokine and pathogenesis of lung cancer has a very important role in reducing the incidence of lung cancer. The study shows that HMGB1 is closely related to the occurrence, development and metastasis of non-small cell lung cancer.
High mobility group protein B1 (high-mobility group box-B1, HMGB1) is widely found in eukaryotic cells. In many biological processes, HMGB1 has a very important role in the expression level of.HMGB1, which can lead to cell differentiation. Cell migration and proliferation of cell proliferation and proliferation of.HMGB1 can promote cell growth and gene transcription and high mobility. The family proteins are also closely related to many biological characteristics of tumors, such as tumours, infiltration and metastasis.
All kinds of biological activities of high mobility group proteins are combined with their corresponding receptors, and late glycosylated terminal product (RAGE) receptor is the most important receptor of HMGB1. When HMGB1 and RAGE are combined with RAGE, two major downstream signal transduction pathways are activated: the first pathway is the excitation of guanosine three phosphatase (Rac) and CDC42 pathway Biological effects, including the remodeling of cytoskeleton, cell movement, cell migration and tumor growth, migration and proliferation; the second pathway is activated by mitogen activated protein kinase pathway, in which the nuclear factor kappa B (NF kappa B) is activated, producing a large number of cytokines and chemokines to induce immunization. The maturation of the cell is also very important in the expression of the immune receptor; it may also activate another signal transduction pathway, such as MAPK, P38, JNK and P42/P44, which can activate MMP - 2 and - 9. The two is the downstream target of the system of system fibrinolytic enzyme activation cascade, and is degraded through systematic fibrinolytic enzyme degradation. The extracellular matrix makes the tumor infiltrate and metastases further.
objective
The purpose of this study is to further explore and study the role and pathogenesis of HMGB1 in non-small cell lung cancer by detecting the changes in the expression level of HMGB1 in non-small cell lung cancer, the relationship between HMGB1 and the clinical biological characteristics of the tumor.
Method
The expression of mRNA in non-small cell lung cancer was detected by reverse transcription polymerase chain reaction (RT-PCR), and the expression of HMGB1 protein in non small cell lung cancer was detected by Western blot, and the changes of the level of HMGB1 protein in different stages and sizes of lung cancer before and after operation were compared.
Result
The expression of HMGB1mRNA in human lung cancer A549 cell line and bronchial epithelial cell line HBE was detected by 1RT-PCR.
The bronchial epithelial cell line HBE was a control cell, and the relative expression of the target gene was calculated according to the formula 2-average Delta CT x 100%. The results showed that the expression of HMGB1 in the A549 cell line of lung adenocarcinoma was significantly higher than that of the bronchial epithelial cell line HBE, which was 11.450 times that of the cell line.
Expression of HBE HMGB1 protein in 2 human lung cancer cell line A549 and bronchial epithelial cell line
The relative expression of HBE protein in the human lung adenocarcinoma cell line A549 and the bronchial epithelial cell line was 80.44 + 3.51,6.83 + 0.75 respectively. The expression level of A549HMGB1 protein in lung cancer cell lines was significantly higher than that of the bronchial epithelial cell line HBE, and there were statistical differences (P0.001). Figure 2 showed the difference in the expression of HMGB1 protein in the two cell lines.
Expression of serum HMGB1 protein in 3 patients with lung cancer and pulmonary benign diseases
The average serum HMGB1 level of 145 cases of lung cancer was 76.1 + 37.0ng/ml, the average level of HMGB1 in the lung benign disease group was 39.8 + 10.8ng/ml, the average level of HMGN1 in healthy volunteers was 7.7 + 6.1ng/ml, and the expression level of HMGB1 in lung cancer was significantly higher than that of the benign and healthy controls, and there were statistical differences (p0.001).
Expression of serum HMGB1 protein in 4 different stages of lung cancer
The levels of serum HMGBl in patients with stage I, II, III and IV were 30.2 + 5.9ng/ml, 60.9 + 22.5ng/ml, 99 + 23.1ng/ml and 133.4 + 18.9ng/ml., respectively, and there were significant statistical differences (P0.0001), and there were significant differences between the two groups. Further study showed that the level of HMGB1 in patients with distant metastasis was (133.4 +). 18.9ng/ml) was significantly higher in lung cancer patients without distant metastasis (68.46 + 31.9ng/ml, P)
【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】：2012
【分類號(hào)】：R734.2;R563.8

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