本文選題：肝細(xì)胞癌 + 乙型肝炎病毒�。� 參考：《中南大學(xué)》2013年博士論文

【摘要】：研究背景肝細(xì)胞癌(hepatocellular carcinoma, HCC)是世界范圍內(nèi)最常見的惡性腫瘤之一,大量流行病學(xué)調(diào)查表明,長(zhǎng)期慢性乙型肝炎病毒(hepatitis B virus, HBV)感染是導(dǎo)致HCC的主要病因。近年來(lái)研究發(fā)現(xiàn)乙型肝炎病毒X基因(hepatitis B virus X gene, HBx)在HBV相關(guān)HCC的發(fā)生發(fā)展中發(fā)揮重要的作用。HBx能通過(guò)多種方式影響肝細(xì)胞的凋亡,研究發(fā)現(xiàn)HBx對(duì)肝細(xì)胞凋亡的調(diào)節(jié)是HBV引起HCC的重要機(jī)制之一,然而HBx對(duì)肝細(xì)胞凋亡過(guò)程的調(diào)節(jié)作用仍存在爭(zhēng)議,其確切機(jī)制尚不清楚。有研究顯示HBx能促進(jìn)細(xì)胞凋亡,但是也有研究顯示HBx抑制細(xì)胞凋亡。有趣的是,一些研究發(fā)現(xiàn)在HBV相關(guān)的HCC組織中HBx基因常常發(fā)生缺失,尤其是羧基端的缺失。HBx羧基端的缺失可能改變了野生型HBx在控制細(xì)胞增殖、分化、凋亡方面的作用,從而在HBV相關(guān)HCC中發(fā)揮重要作用。我們前期的研究也顯示,與野生型HBx相比,缺失突變型HBx能明顯促進(jìn)肝細(xì)胞的惡性轉(zhuǎn)化,但其具體的分子機(jī)制尚有待闡明。 微小RNA(microRNA, miRNA)是一類在轉(zhuǎn)錄后水平調(diào)控基因表達(dá)的小分子RNA,參與發(fā)育、細(xì)胞增殖、分化、凋亡等多種生物學(xué)過(guò)程,在多種人類疾病包括腫瘤的發(fā)生中發(fā)揮著重要的作用。在腫瘤中miRNA表達(dá)的上調(diào)或下調(diào)可能起到癌基因或抑癌基因的作用。最近研究表明miRNA可能與HCC的發(fā)生與發(fā)展密切相關(guān),但是miRNA在HBV相關(guān)HCC中的作用機(jī)制尚不十分清楚。 研究目的通過(guò)對(duì)野生型HBx (HBx)和缺失突變型HBx (HBx-d382)真核表達(dá)載體轉(zhuǎn)染肝細(xì)胞的生物學(xué)行為、細(xì)胞凋亡和microRNA表達(dá)譜的研究,探討HBx與HBx-d382對(duì)肝細(xì)胞凋亡及microRNA表達(dá)的影響,以及這些變化在肝細(xì)胞惡性轉(zhuǎn)化中的作用。 研究方法(1)復(fù)蘇分別含pcDNA3.0、pcDNA3.0/HBx及pcDNA3.0/HBx-d382質(zhì)粒的重組細(xì)菌DH-5α,提取質(zhì)粒并用PCR、雙酶切法鑒定質(zhì)粒,對(duì)質(zhì)粒進(jìn)行DNA測(cè)序并應(yīng)用DNASIS MAX2.9、clusterW生物軟件進(jìn)行分析。(2)應(yīng)用脂質(zhì)體轉(zhuǎn)染的方法,將質(zhì)粒pcDNA3.0、pcDNA3.0/HBx和pcDNA3.0/HBx-d382轉(zhuǎn)染入L02肝細(xì)胞中,用G418篩選出穩(wěn)定表達(dá)HBx和HBx-d382蛋白的肝細(xì)胞株。(3)用放線菌素D (Actinomycin D, ActD)、腫瘤壞死因子a(tumor necrosis factor a, TNF-a)處理L02、L02/pcDNA3.0、 L02/HBx和L02/HBx-d382組肝細(xì)胞,誘導(dǎo)肝細(xì)胞凋亡。用膜聯(lián)蛋白V-異硫氰酸熒光素/碘化丙錠(Annexin V-fluorescein isothiocyanate/Propidium iodium, Annexin V-FITC/PI)雙染色流式細(xì)胞分析法檢測(cè)并比較ActD、TNF-a處理0小時(shí),12小時(shí),24小時(shí),48小時(shí)各組肝細(xì)胞凋亡情況；用終末脫氧核糖核苷酸轉(zhuǎn)移酶介導(dǎo)的原位缺口末端標(biāo)記(terminal deoxynucleotidy1transferase mediated dUTP nick end labelling, TUNEL)法檢測(cè)并比較ActD、TNF-a處理24小時(shí)各組肝細(xì)胞凋亡情況；用RT-PCR (reverse transcription polymerase chainreaction)和Western-blot檢測(cè)L02、L02/pcDNA3.0、L02/HBx和L02/HBx-d382組肝細(xì)胞中Survivin、PTEN (phosphatase and tensin homology deleted on chromosome Ten, PTEN) mRNA和蛋白的表達(dá)。(4)利用microRNA芯片,以L02/pcDNA3.0細(xì)胞為對(duì)照,研究分析HBx-d382和HBx轉(zhuǎn)染L02肝細(xì)胞后肝細(xì)胞內(nèi)miRNA表達(dá)譜的變化。 研究結(jié)果(1)證實(shí)了野生型HBx (HBx)和缺失突變型HBx (HBx-d382)真核表達(dá)載體構(gòu)建正確,并成功建立了穩(wěn)定表達(dá)HBx和HBx-d382蛋白的肝細(xì)胞株。(2) Annexin V-FITC/PI流式細(xì)胞分析顯示,ActD、TNF-a處理前,L02、L02/pcDNA3.0、L02/HBx-d382和L02/HBx組細(xì)胞早期凋亡率分別為(3.38±0.53)%、(3.95±0.29)%、(3.23±0.69)%、(10.34±0.74)%：ActD、TNF-a處理12小時(shí)時(shí)L02、L02/pcDNA3.0、L02/HBx-d382和L02/HBx組細(xì)胞早期凋亡率分別為(4.07±0.27)%、(4.69±1.04)%、(4.09±0.16)%、(9.83±1.02)%;ActD、TNF-a處理24小時(shí)時(shí)L02、L02/pcDNA3.0、L02/HBx-d382和L02/HBx組細(xì)胞早期凋亡率分別為(19.30±3.00)%、(20.82±2.43)%、(18.18±2.48)%、(28.37±3.50)%;ActD、TNF-a處理48小時(shí)時(shí)L02、L02/pcDNA3.0.L02/HBx-d382和L02/HBx組細(xì)胞早期凋亡率分別為(35.25±5.17)%、(35.73±4.21)%、(31.13±4.50)%、(45.65±3.37)%。ActD、TNF-a處理前及處理后,L02/HBx組細(xì)胞早期凋亡率均高于L02、L02/pcDNA3.0和L02/HBx-d382組(p0.05),而后3組細(xì)胞之間早期凋亡率差異無(wú)統(tǒng)計(jì)學(xué)意義(p0.05)；與ActD、TNF-a處理前相比,ActD、TNF-a處理12小時(shí)時(shí)L02、L02/pcDNA3.0、 L02/HBx-d382和L02/HBx組細(xì)胞早期凋亡率與處理前比較差異無(wú)統(tǒng)計(jì)學(xué)意義(p0.05); ActD、TNF-a處理24小時(shí)和48小時(shí)時(shí)L02、L02/pcDNA3.0、L02/HBx-d382和L02/HBx組細(xì)胞早期凋亡率均增加(p0.05),且處理48小時(shí)時(shí)各組肝細(xì)胞早期凋亡率均高于處理24小時(shí)時(shí)(p0.05)。TUNEL法檢測(cè)顯示ActD、TNF-a處理24小時(shí)時(shí)L02、L02/pcDNA3.0、L02/HBx-d382和L02/HBx組細(xì)胞凋亡指數(shù)分別為(21.97±4.91)%、(23.49±3.26)%、(22.55±4.86)%、(33.68±4.43)%。L02/HBx組細(xì)胞細(xì)胞凋亡指數(shù)高于L02、L02/pcDNA3.0和L02/HBx-d382組(p0.05),而后3組之間比較差異無(wú)統(tǒng)計(jì)學(xué)意義(p0.05)。Survivin mRNA和蛋白在L02、L02/pcDNA3.0、 L02/HBx-d382和L02/HBx細(xì)胞中的相對(duì)表達(dá)強(qiáng)度分別為0.66±0.09和0.69±0.12、0.66±0.07和0.76±0.09、0.63±0.13和0.77±0.14、0.26±0.09和0.13士0.12。PTEN mRNA和蛋白在L02、L02/pcDNA3.0、 L02/HBx-d382和L02/HBx細(xì)胞中的相對(duì)表達(dá)強(qiáng)度分別為0.21±0.09和0.19±0.13、0.24±0.12和0.21±0.07、0.22±0.11和0.23±0.06、0.52±0.09和0.71±0.04。與L02、L02/pcDNA3.0和L02/HBx-d382細(xì)胞相比,L02/HBx細(xì)胞中Survivin mRNA及蛋白表達(dá)下調(diào)(p0.01), PTEN mRNA及蛋白表達(dá)上調(diào)(p0.01); Survivin、PTEN mRNA和蛋白在L02、L02/pcDNA3.0細(xì)胞和L02/HBx-d382細(xì)胞中的表達(dá)差異無(wú)統(tǒng)計(jì)學(xué)意義(p0.05)。(3) microRNA芯片結(jié)果顯示,與L02/pcDNA3.0相比較,L02/HBx肝細(xì)胞內(nèi)hsa-miR-7、hsa-miR-1274a、hsa-miR-137、hsa-miR-6634種miRNA表達(dá)上調(diào),hsa-miR-338、 hsa-miR-24、hsa-miR-29、hsa-miR-744、hsa-miR-455、 hsa-miR-324、hsa-miR-551b、hsa-miR-340、hsa-miR-590hsa-miR-660、hsa-miR-11311種miRNA表達(dá)下調(diào)；而L02/HBx-d382肝細(xì)胞內(nèi)hsa-miR-501、hsa-miR-595、hsa-miR-1307、 hsa-miR-1180、hsa-miR-497、hsa-miR-1246、hsamiR-6237種miRNA表達(dá)上調(diào),hsa-miR-338、hsa-miR-551b、hsa-miR-1、hsa-miR-455、 hsa-miR-200c5種miRNA表達(dá)下調(diào)。除均能引起hsa-miR-338、 hsa-miR-455、hsa-miR-551b表達(dá)下調(diào)外,HBx與HBx-d382引起肝細(xì)胞內(nèi)表達(dá)上調(diào)或下調(diào)的miRNA的種類不同。 結(jié)論(1)證實(shí)了野生型HBx (HBx)和缺失突變型HBx (HBx-d382)真核表達(dá)載體構(gòu)建正確,并成功建立了穩(wěn)定表達(dá)HBx和HBx-d382蛋白的肝細(xì)胞模型,為深入研究HBx和HBx-d382基因及其蛋白在HBV相關(guān)HCC中的作用奠定了基礎(chǔ)。(2)野生型HBx(HBx)和缺失突變型HBx (HBx-d382)對(duì)肝細(xì)胞凋亡的影響是不同的。野生型HBx (HBx)可能通過(guò)下調(diào)Survivin表達(dá)并上調(diào)PTEN的表達(dá)發(fā)揮促細(xì)胞凋亡的作用,而缺失突變型HBx(HBx-d382)可能具有取消野生型HBx促細(xì)胞凋亡的能力。HBx基因可能通過(guò)缺失型突變修飾其生物學(xué)功能,在HCC發(fā)生中起著重要的作用。(3)HBx和HBx-d382基因轉(zhuǎn)染肝細(xì)胞后均能引起肝細(xì)胞內(nèi)miRNA表達(dá)譜發(fā)生變化,但兩者對(duì)肝細(xì)胞miRNA表達(dá)譜有不同的影響,HBx和HBx-d382可能通過(guò)影響不同miRNA的表達(dá)而影響肝細(xì)胞的凋亡。
[Abstract]:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. A large number of epidemiological investigations show that chronic hepatitis B virus (hepatitis B virus, HBV) infection is the main cause of HCC. In recent years, the X gene of hepatitis B virus (hepatitis B virus) has been found. ) it plays an important role in the development of HBV related HCC..HBx can affect the apoptosis of liver cells in a variety of ways. It is found that the regulation of HBx to hepatocyte apoptosis is one of the important mechanisms of HBV to cause HCC. However, the regulatory role of HBx on the process of hepatocyte apoptosis is still controversial, and its exact mechanism is not clear. Some studies show HBx energy Promoting apoptosis, but there are also studies showing that HBx inhibits apoptosis. Interestingly, some studies have found that the HBx gene is often missing in HBV related HCC tissues, especially the deletion of the carboxyl terminus of the carboxyl terminus may alter the role of wild type HBx in controlling cell proliferation, differentiation, and apoptosis, thus in HBV related HCC. Our previous study also showed that the missing mutant HBx could significantly promote the malignant transformation of hepatocytes compared with wild type HBx, but the specific molecular mechanisms still remain to be elucidated.
Small RNA (microRNA, miRNA) is a small molecule RNA that regulates gene expression at post transcriptional level. It participates in many biological processes, such as development, cell proliferation, differentiation, apoptosis and other biological processes. It plays an important role in the occurrence of a variety of human diseases including tumors. The up-regulation or down regulation of miRNA expression may be the oncogene or tumor suppressor gene in the tumor. Recent studies have shown that miRNA may be closely related to the occurrence and development of HCC, but the mechanism of miRNA in HBV related HCC is not yet clear.
Objective to investigate the effects of HBx and HBx-d382 on hepatocyte apoptosis and the expression of microRNA by transfection of wild type HBx (HBx) and deletion mutant HBx (HBx-d382) eukaryotic expression vector to hepatocytes, and to explore the effect of HBx and HBx-d382 on hepatocyte apoptosis and microRNA expression, and the role of these changes in the malignant transformation of liver cells.
Research methods (1) resuscitation of recombinant bacterial DH-5 alpha containing pcDNA3.0, pcDNA3.0/HBx and pcDNA3.0/HBx-d382 plasmids respectively, extract plasmids and identify plasmids with PCR, double enzyme digestion, DNA sequencing of the plasmid and analysis of DNASIS MAX2.9, clusterW biological software. (2) liposome transfection method, plasmid pcDNA3.0, pcDNA3.0/HBx and pcDNA3 .0/HBx-d382 transfected into L02 hepatocytes, using G418 to screen liver cell lines that stably express HBx and HBx-d382 protein. (3) use actinomycin D (Actinomycin D, ActD) and tumor necrosis factor A (tumor necrosis) to induce hepatocytes to induce apoptosis of liver cells. Fluorescein cyanate / Annexin V-fluorescein isothiocyanate/Propidium iodium (Annexin V-FITC/PI) double staining flow cytometry was used to detect and compare with ActD, TNF-a for 0 hours, 12 hours, 24 hours, 48 hours of hepatocyte apoptosis, and terminal deoxy nucleotidyl transferase mediated in situ nick end labeling. (terminal deoxynucleotidy1transferase mediated dUTP nick end labelling, TUNEL) method to detect and compare ActD, TNF-a treatment for 24 hours of liver cell apoptosis. The expression of hosphatase and tensin homology deleted on chromosome Ten, PTEN) mRNA and protein. (4) the changes in the expression profiles in hepatocytes after hepatocyte transfection were analyzed by microRNA chips.
The results (1) confirmed that the eukaryotic expression vector of wild type HBx (HBx) and deletion mutant HBx (HBx-d382) was constructed correctly, and the liver cell lines expressing HBx and HBx-d382 protein were successfully established. (2) Annexin V-FITC/PI flow cytometry showed that before ActD, TNF-a treatment, L02, L02/pcDNA3.0, and apoptotic cells were apoptotic. The rates of (3.38 + 0.53)%, (3.95 + 0.29)%, (3.23 + 0.69)%, (10.34 + 0.74)%:ActD, and TNF-a treatment for 12 hours at L02, L02/pcDNA3.0, L02/HBx-d382 and L02/HBx were respectively (4.07 + 0.27)%, (4.69 + 1.04)%, (4.69 + 3.23%)%, ActD, TNF-a processing L02, L02/pcDNA3.0, L02/HBx-d382, and L02/HBx groups. The early apoptosis rate was (19.30 + 3)%, (20.82 + 2.43)%, (18.18 + 2.48)%, (28.37 + 3.50)%, ActD, TNF-a treatment for 48 hours, L02, L02/pcDNA3.0.L02/HBx-d382 and L02/HBx group, respectively (35.25 + 5.17)%, (35.73 + 4.21)%, (35.73 + 18.18)%,%.ActD. Before and after TNF-a treatment, L02/HBx group cells were early The rate of apoptosis was higher than that of L02, L02/pcDNA3.0 and L02/HBx-d382 (P0.05), and there was no significant difference in the early apoptosis rate between the 3 groups (P0.05). Compared with ActD, TNF-a before TNF-a treatment, the apoptosis rates of L02, L02/pcDNA3.0, L02/HBx-d382, and before treatment were not statistically significant. .05); ActD, TNF-a treatment at 24 hours and 48 hours increased the apoptosis rate of cells in L02, L02/pcDNA3.0, L02/HBx-d382 and L02/HBx groups (P0.05), and the early apoptosis rate of the hepatocytes at 48 hours was higher than that of the treatment for 24 hours (P0.05).TUNEL assay display ActD, TNF-a treatment 24 hours. The apoptotic index was (21.97 + 4.91)%, (23.49 + 3.26)%, (22.55 + 4.86)% and (33.68 + 4.43)%.L02/HBx group cell apoptosis index higher than that of L02, L02/pcDNA3.0 and L02/HBx-d382 group (P0.05), and the difference between the 3 groups was not statistically significant (P0.05).Survivin mRNA and protein in L02, L02/pcDNA3.0, L02/HBx-d382 and L02/HBx cells. Relative expression intensity was 0.66 + 0.09 and 0.69 + 0.12,0.66 + 0.07 and 0.76 + 0.09,0.63 + 0.13 and 0.77 + 0.14,0.26 + 0.09 and 0.13 0.12.PTEN mRNA and protein in L02, L02/pcDNA3.0, L02/HBx-d382 and L02/HBx cells were 0.21 + 0.09 and 0.19 + 0.13,0.24 + 0.12 and 0.21 + 0.07,0.22 + 0.52 + 0.09 and 0.71 + 0.04. were compared with L02, L02/pcDNA3.0 and L02/HBx-d382 cells, Survivin mRNA and protein expression down regulated (P0.01), PTEN mRNA and protein expression up up (P0.01). Compared with L02/pcDNA3.0, the expression of hsa-miR-7, hsa-miR-1274a, hsa-miR-137 and hsa-miR-6634 in the liver cells of L02/HBx was up regulated, and hsa-miR-338, hsa-miR-24, hsa-miR-29, hsa-miR-744, hsa-miR-455. The expression of hsa-miR-501, hsa-miR-595, hsa-miR-1307, hsa-miR-1180, hsa-miR-497, hsa-miR-1246, hsamiR-6237 is up regulated in d382 liver cells, hsa-miR-338, hsa-miR-551b, hsa-miR-1, and down regulation. The expression of miRNA in cells was different.
Conclusion (1) the correctness of the eukaryotic expression vector of wild type HBx (HBx) and deletion mutant HBx (HBx-d382) was confirmed, and a hepatocyte model was successfully established for the stable expression of HBx and HBx-d382 protein, which laid the foundation for the in-depth study of HBx and HBx-d382 genes and their proteins in HBV related HCC. (2) wild type HBx (HBx) and deletion mutation types. The effect of (HBx-d382) on hepatocyte apoptosis is different. Wild type HBx (HBx) may play a role in promoting apoptosis by downregulating the expression of Survivin and up regulating the expression of PTEN, and the deletion mutant HBx (HBx-d382) may have the ability to cancel the apoptosis of the wild type HBx, and the.HBx gene may modify its biological work through the deletion mutation. Yes, it plays an important role in the occurrence of HCC. (3) the transfection of HBx and HBx-d382 genes to hepatocytes can cause changes in the miRNA expression profiles in hepatocytes, but both of them have different effects on the miRNA expression profiles of hepatocytes. HBx and HBx-d382 may affect the apoptosis of liver cells by affecting the expression of different miRNA.

【學(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R512.62;R735.7

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10 涂軼;梅金紅;;乳腺癌相關(guān)microRNA研究進(jìn)展[J];實(shí)用臨床醫(yī)學(xué);2010年11期

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6 孫佃臣;低磷脅迫響應(yīng)microRNA及靶基因的克隆和大豆遺傳轉(zhuǎn)化研究[D];中國(guó)農(nóng)業(yè)科學(xué)院;2011年

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10 孔飛飛;靶向YB-1基因的MicroRNA對(duì)乳腺癌MDA-MB-231細(xì)胞惡性生物學(xué)行為的影響[D];重慶醫(yī)科大學(xué);2011年

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