本文選題：腺樣囊性癌 + 組蛋白H3賴氨酸9三甲基化�。� 參考：《上海交通大學(xué)》2014年博士論文

【摘要】：目的:分析組蛋白H3賴氨酸9三甲基化(H3 lysine 9 trimethylation,H3K9me3)與唾液腺腺樣囊性癌(adenoid cystic carcinoma,ACC)患者臨床病理特征和預(yù)后的關(guān)系,并探討H3K9me3對(duì)ACC中相關(guān)基因的調(diào)控作用及其對(duì)ACC生物學(xué)行為的影響。方法:免疫組織化學(xué)分析66例ACC樣本中H3K9me3、EDNRB和CHL1蛋白表達(dá)及與臨床病理特征、預(yù)后的關(guān)系。染色質(zhì)免疫共沉淀結(jié)合啟動(dòng)子芯片技術(shù)(Ch IP on chip)檢測(cè)ACC細(xì)胞中可能與H3K9me3結(jié)合的基因,通過(guò)在線工具分析結(jié)果。Western Blot方法檢測(cè)28對(duì)腫瘤和瘤旁組織中EDNRB和CHL1蛋白表達(dá),Ch IP-PCR檢測(cè)ACC組織中H3K9me3與EDNRB和CHL1基因啟動(dòng)子區(qū)結(jié)合情況。Chaetocin處理細(xì)胞后檢測(cè)EDNRB和CHL1 m RNA表達(dá)水平改變。統(tǒng)計(jì)分析采用SPSS軟件分析。結(jié)果:1.H3K9me3表達(dá)在ACC中明顯高于瘤旁腺體(P0.001),在實(shí)體型中明顯高于篩狀管狀型(P=0.002),在發(fā)生遠(yuǎn)處轉(zhuǎn)移者明顯高于未發(fā)生遠(yuǎn)處轉(zhuǎn)移者(P=0.001)。H3K9me3高表達(dá)的患者總體生存率、無(wú)病生存率都比H3K9me3低表達(dá)組低。H3K9me3高表達(dá)可以作為獨(dú)立預(yù)測(cè)ACC總生存率和無(wú)病生存率的預(yù)測(cè)因子。2.SACC-83、SACC-LM中基因啟動(dòng)子區(qū)與H3K9me3結(jié)合的基因分別為877、1191個(gè),其中兩個(gè)細(xì)胞系均有的基因有551個(gè),這些基因主要參與了嗅覺(jué)傳導(dǎo)和神經(jīng)活性配體受體相互作用信號(hào)通路以及與G蛋白偶聯(lián)受體和細(xì)胞粘附等。最終篩選出ACC中與H3K9me3關(guān)系較為密切的兩個(gè)基因,分別為EDNRB和CHL1。3.EDNRB和CHL1蛋白在ACC組織中表達(dá)低于瘤旁腺體組織。H3K9me3與EDNRB和CHL1啟動(dòng)子區(qū)結(jié)合有區(qū)域特異性。H3K9me3主要結(jié)合于EDNRB基因轉(zhuǎn)錄起始位點(diǎn)上游-1069~-877bp、-1332~-1111bp和-373~-176bp區(qū)域。H3K9me3主要結(jié)合于CHL1基因轉(zhuǎn)錄起始位點(diǎn)上游-1997~-1803bp和-239~-70bp區(qū)域。這種結(jié)合可能是這些蛋白表達(dá)降低的機(jī)制之一,Chaetocin處理SACC-83和SACC-LM可使EDNRB和CHL1 m RNA水平升高。4.T晚期ACC患者EDNRB表達(dá)低于T早期患者(P=0.039),CHL1低表達(dá)的患者呈現(xiàn)出腫瘤易發(fā)生淋巴結(jié)轉(zhuǎn)移的趨勢(shì)(P=0.062)。結(jié)論:ACC中H3K9me3的表達(dá)明顯高于瘤旁腺體中的表達(dá),H3K9me3表達(dá)可以作為獨(dú)立預(yù)測(cè)ACC總生存率和無(wú)病生存率的預(yù)測(cè)因子。H3K9me3主要結(jié)合于EDNRB基因轉(zhuǎn)錄起始位點(diǎn)上游-1069~-877bp、-1332~-1111bp和-373~-176bp區(qū)域,而在CHL1中主要結(jié)合于基因轉(zhuǎn)錄起始位點(diǎn)上游-1997~-1803bp和-239~-70bp區(qū)域。H3K9me3可能通過(guò)調(diào)控EDNRB、CHL1的表達(dá)在部分腫瘤中促進(jìn)腫瘤的生長(zhǎng)、淋巴結(jié)轉(zhuǎn)移。H3K9me3對(duì)ACC的組織學(xué)亞型、遠(yuǎn)處轉(zhuǎn)移、預(yù)后的影響是通過(guò)調(diào)節(jié)其它基因的功能實(shí)現(xiàn)的。
[Abstract]:Objective: to analyze the relationship between histone H3 lysine 9 trimethylation H3 lysine 9 trimethylation (H3K9me3) and the clinicopathological characteristics and prognosis of salivary adenoid cystic carcinoma (ACCs), and to investigate the regulatory role of H3K9me3 in ACC and its effect on the biological behavior of ACC. Methods: the expression of H3K9ME3EDNRB and CHL1 protein and its relationship with clinicopathological features and prognosis in 66 cases of ACC were analyzed by immunohistochemistry. Chromatin immunoprecipitation combined with promoter chip technique was used to detect H3K9me3 binding genes in ACC cells. The expression of EDNRB and CHL1 protein in 28 pairs of tumor tissues and adjacent tissues was detected by online tool analysis. Western Blot method was used to detect the binding of H3K9me3 to EDNRB and CHL1 promoter region in ACC tissue. The expression of EDNRB and CHL1 m RNA were detected after treated with H3K9me3. The statistical analysis was carried out by SPSS software. Results 1. The expression of H3K9me3 in ACC was significantly higher than that in the adjacent gland (P0.001), and in the solid type was significantly higher than that in the sieve tubular type (P0. 002). The overall survival rate of the patients with distant metastasis was significantly higher than that of the patients with high expression of P0. 001. H3K9me3 in patients without distant metastasis. The disease-free survival rate was lower than that in the low expression group of H3K9me3. H3K9me3 expression could be used as an independent predictor of the overall and disease-free survival rates of ACC. 2. The number of genes binding to H3K9me3 in SACC-83nSACC-LM was 877or 1191, respectively. There are 551 genes in both cell lines, which are involved in olfactory conduction, neuroactive ligand receptor interaction signaling pathway, G-protein coupled receptor and cell adhesion. Finally, two genes in ACC which are closely related to H3K9me3 were screened out. The expression of EDNRB, CHL1.3.EDNRB and CHL1 protein in ACC tissue is lower than that in adjacent gland tissue. H3K9me3 binds to EDNRB and CHL1 promoter region. H3K9me3 mainly binds to EDNRB gene transcriptional initiation site upstream -1069n -877bpfU -1332ng-1111bp and -373-176bp region. H3K9me3 mainly binds to EDNRB gene transcription initiation site upstream. H3K9me3 mainly binds to H3K9me3. The region of-1997-1803 BP and-239-70 BP were upstream of CHL1 gene transcription initiation site. This binding may be one of the mechanisms of decreasing the expression of these proteins. Chaetocin treatment with SACC-83 and SACC-LM can increase the level of EDNRB and CHL1 m RNA. 4. The EDNRB expression in late ACC patients is lower than that in early T patients. Conclusion the expression of H3K9me3 in EDNRB is significantly higher than that in adjacent glands. The expression of H3K9me3 can be used as an independent predictor of overall and disease-free survival of ACC. H3K9me3 mainly binds to the upstream region of EDNRB gene transcriptional initiation locus -1069 ~ (-877) BP ~ (-1) 32 ~ (32) ~ (-1111) BP and ~ -3733 ~ (-176) BP. In CHL1, the binding to the upstream of gene transcription initiation locus -1997 ~ 1803bp and -239A ~ 70bp region. H3K9me3 may promote the growth of some tumors by regulating the expression of EDNRBN CHL1. Lymph node metastasis. H3K9me3 has histological subtype and distant metastasis of ACC. The effect of prognosis is achieved by regulating the function of other genes.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R739.8

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