本文選題：非小細(xì)胞肺癌 + 黃芪甲甙��； 參考：《成都中醫(yī)藥大學(xué)》2016年博士論文

【摘要】：研究背景與目的：肺癌(Lung cancer)是我國最常見的惡性腫瘤,2015年國家癌癥中心發(fā)布的數(shù)據(jù)顯示,肺癌是發(fā)病率最高的腫瘤,也是癌癥死因之首。其中以非小細(xì)胞肺癌(non-small cell lung cancer. NSCLC)最為多見,約占肺癌總數(shù)的80%-87%。隨著對NSCLC研究的深入,表皮生長因子(Epidermal Growth Factor Receptor. EGFR,又稱ErbB1或HER1)在NSCLC的發(fā)病機制、啟動基因、腫瘤細(xì)胞生長、細(xì)胞異質(zhì)性和侵襲力增加過程中的作用被逐漸闡明,使EGFR成為靶向治療的重要靶點之一。盡管靶向藥物能夠使腫瘤緩解率增加、無癥狀生存期延長,但隨著TKIS使用時間的延長,不可避免的出現(xiàn)耐藥。因此,研發(fā)延緩或者逆轉(zhuǎn)靶向治療耐藥的方法是靶向治療的熱門領(lǐng)域。黃芪是常用的中藥材,含有許多化學(xué)成分,大量基礎(chǔ)及臨床研究報道,黃芪在體內(nèi)和體外均有抗腫瘤作用,黃芪甲甙(Astragaloside Ⅳ,AS-Ⅳ)是黃芪的主要成分之一,研究表明,AS-IV可以通過調(diào)節(jié)性T細(xì)胞和細(xì)胞毒性T淋巴細(xì)胞以及通過相關(guān)的信號傳導(dǎo)途徑抑制肺癌細(xì)胞的增殖、遷移和侵襲。SIRT6是NAD+依賴性第Ⅲ類組蛋白去乙酞化酶家族(Sirtuin家族)中重要的一份子。表觀遺傳調(diào)控是目前腫瘤研究的熱點,通過DNA、組蛋白等甲基化、乙酞化、磷酸化以及染色體重塑等一系列生物過程來調(diào)節(jié)基因表達(dá)�，F(xiàn)在研究發(fā)現(xiàn),SIRT6在腫瘤組織中的表達(dá)情況與腫瘤發(fā)生、腫瘤轉(zhuǎn)移、術(shù)后生存率、術(shù)后復(fù)發(fā)率以及化療敏感性密切相關(guān),目前認(rèn)為SIRT6是一個新的腫瘤相關(guān)基因、減輕或者抑制,甚至逆轉(zhuǎn)化療耐藥的新靶點。研究目的是(1)探究SIRT6在NSCLC組織中的表達(dá)豐度及表達(dá)定位,以及SIRT6在人肺癌NCI-H1299、PC9/GR、A549細(xì)胞中的表達(dá)；(2)不同濃度黃芪甲甙作用于人肺癌NCI-H1299、PC9/GR、A549細(xì)胞,觀察其對不同突變狀態(tài)的肺癌細(xì)胞增殖抑制作用；(3)不同濃度黃芪甲甙聯(lián)合吉非替尼作用于人肺癌NCI-H1299、PC9/GR、A549細(xì)胞,觀察其對不同突變狀態(tài)的肺癌細(xì)胞增殖抑制作用；(4)AS-Ⅳ單獨干預(yù)細(xì)胞以及AS-Ⅳ聯(lián)合吉非替尼聯(lián)合干預(yù)的細(xì)胞后SIRT6的表達(dá)水平變化;(5)慢病毒轉(zhuǎn)染PC9/GR細(xì)胞,檢測AS-Ⅳ聯(lián)合吉非替尼對轉(zhuǎn)染后PC9/GR細(xì)胞增殖水平的影響；(6)探討在耐藥的肺癌細(xì)胞中SIRT6和NF-κB信號通路之間相互作用。研究方法：1、利用免疫組化法檢測NSCLC腫瘤組織、癌旁組織及良性病變組織中SIRT6的表達(dá)量,并收集患者臨床資料,分析SIRT6與臨床參數(shù)的關(guān)系；2、 采用qRT-PCR和Western blot實驗方法檢測人正常肺組織腺上皮細(xì)胞BEAS-2B、NCI-H1299、PC9/GR、A549細(xì)胞中SIRT6的表達(dá)；3、 不同濃度吉非替尼作用于人肺癌NCI-H1299、PC9/GR、A549細(xì)胞,以CCK-8法檢測細(xì)胞增殖抑制率,使用酶標(biāo)儀讀取OD值,按公式計算細(xì)胞生長抑制率,描繪細(xì)胞生長曲線；4、 不同濃度AS-Ⅳ作用于人肺癌NCI-H1299、PC9/GR、A549細(xì)胞,以CCK-8法檢測細(xì)胞增殖抑制率,使用酶標(biāo)儀讀取OD值,按公式計算細(xì)胞生長抑制率,描繪細(xì)胞生長曲線；5、 不同濃度AS-Ⅳ聯(lián)合吉非替尼作用于人肺癌NCI-H1299、PC9/GR、A549細(xì)胞,以CCK-8法檢測細(xì)胞增殖抑制率,計算細(xì)胞生長抑制率,描繪細(xì)胞生長曲線；6、 不同濃度AS-Ⅳ聯(lián)合吉非替尼,吉非替尼不同濃度單獨作用于人肺癌PC9/GR細(xì)胞,使用qRT-PCR檢測SERT6 mRNA表達(dá)變化；使用Western-blot技術(shù)檢測SIRT6的蛋白表達(dá)變化；7、選擇慢病毒進(jìn)行介導(dǎo)轉(zhuǎn)染,使SIRT6基因真核表達(dá)載體轉(zhuǎn)染PC9/GR細(xì)胞,倒置熒光顯微鏡觀察熒光表達(dá),測定病毒滴度。Western Blot檢測,SIRT6蛋白的表達(dá)。檢測AS-Ⅳ聯(lián)合吉非替尼對轉(zhuǎn)染后PC9/GR細(xì)胞增殖水平的影響；8、Western-blot檢測IκB及NF-κBp65,探討在耐藥的肺癌細(xì)胞中SIRT6和NF-κB信號通路之間相互作用。結(jié)果：1、結(jié)果SIRT6在NSCLC組織中低于癌旁組織及良性病變組織；分化程度高者平均IOD高于分化程度中、低的患者。發(fā)生淋巴結(jié)轉(zhuǎn)移和未發(fā)生淋巴結(jié)轉(zhuǎn)移的患者SIRT6的平均IOD之間存在顯著性差異；2、通過CCK-8實驗,A549、PC9/GR和H1299經(jīng)不同濃度吉非替尼干預(yù)48h后,細(xì)胞增殖抑制率,隨著濃度的增高,體現(xiàn)劑量依賴性抑制作用。與對照相比,吉非替尼的細(xì)胞抑制作用顯著差異。吉非替尼半抑制濃度分別為21.29μM、 45.98±1.62μM、26.29±2.25μM;3、采用CCK-8法,選取不同濃度的AS-Ⅳ作用于A549和PC9/GR細(xì)胞株,研究發(fā)現(xiàn),當(dāng)干預(yù)時間為48h時,3ng/ml和6ng/ml濃度的AS-Ⅳ對A549和PC9/GR細(xì)胞均不能產(chǎn)生明顯的抑制作用,而大于12ng/ml的AS-Ⅳ可明顯抑制細(xì)胞是的生長。選取不同濃度的AS-Ⅳ作用于H1299細(xì)胞株,當(dāng)干預(yù)時間為48h時,大于6ng/ml的AS-Ⅳ可明顯抑制細(xì)胞是的生長；4、用含4個濃度(3ng/ml、6ng/ml、12ng/ml、24ng/ml)的AS-Ⅳ和10μM的吉非替尼培養(yǎng)液聯(lián)合作用于A549、H11299、PC9/GR細(xì)胞,48小時后使用CCK-8試劑酶標(biāo)儀檢測,同一grfitinib濃度,不同濃度的AS-Ⅳ作用于同一細(xì)胞株,細(xì)胞增殖抑制率顯著不同,細(xì)胞增殖抑制率隨AS-Ⅳ濃度增加而增加。3種細(xì)胞均可見gefitinib聯(lián)合AS-Ⅳ濃度為24ng/ml時細(xì)胞增值抑制率最高,但同一grfitinib濃度下,隨藥物濃度增加,不同細(xì)胞的增殖能力不同,PC9/GR細(xì)胞增殖能力最差。在12ng/ml的AS-Ⅳ聯(lián)合10 μ M的吉非替尼作用下Q值最大；5、通過qRT-PCR和Western blotting技術(shù),肺癌PC9/GR、A549、H1299細(xì)胞與正常肺組織腺上皮BEAS-2B細(xì)胞相比,SIRT6 mRNA和蛋白的表達(dá)水平顯著下降；6. qRT-PCR分析結(jié)果顯示,與對照組相比,AS-Ⅳ 12ng/ml聯(lián)合吉非替尼10μM干預(yù)PC9/GR, SITR6mRNA的表達(dá)增加,P0.01。單獨AS-Ⅳ 12ng/ml單獨干預(yù)PC9/GR,與對照組比較,而吉非替尼單獨干預(yù)PC9/GR,與對照組比較,無統(tǒng)計學(xué)意義；Western blotting檢測結(jié)果,與對照組相比,AS-Ⅳ 12ng/ml聯(lián)合吉非替尼10μ M干預(yù)PC9/GR, SITR6蛋白的表達(dá)增加。單獨AS-IV 12ng/ml單獨干預(yù)PC9/GR,與對照組比較；7、吉非替尼濃度梯度0、5、10、20、40μM單獨干預(yù)PC9/GR,與對照組比較,細(xì)胞的SIRT6mRNA及蛋白水平均有所提高,但沒有明顯統(tǒng)計意義；8、構(gòu)建了穩(wěn)定轉(zhuǎn)染SIRT6過表達(dá)載體的PC/GR,倒置熒光顯微鏡下觀察,細(xì)胞轉(zhuǎn)染效率估計大約在80%-85%,通過Western Blot檢測,與對照比較,SIRT6蛋白的表達(dá)量有大幅度的提高；9、予以10rtM的吉非替尼和濃度梯度的AS-IV干預(yù)pLVTHM-SIRT6和pLVTHM-scramble細(xì)胞,SIRT6、吉非替尼和AS-IV聯(lián)合作用時細(xì)胞的生長抑制現(xiàn)象,與其他三組比較明顯增強；pLVTHM-SIRT6組與pLVTHM-scramble+吉非替尼組比較無明顯統(tǒng)計意義,但與pLVTHM-scramble組比較有統(tǒng)計意義；予以12ng/ml的AS-IV和濃度梯度吉非替尼干預(yù)pLVTHM-SIRT6和pLVTHM-scramble細(xì)胞,SIRT6、AS-IV和吉非替尼聯(lián)合作用時細(xì)胞的生長抑制現(xiàn)象明顯,pLVTHM-SIRT6組與pLVTHM-scramble+AS-Ⅳ比較無明顯統(tǒng)計意義,但與pLVTHM-scramble組比較有差異；10、Western blot檢測pLVTHM-scramble細(xì)胞和Plvthm-SIRT6細(xì)胞,IκB在pLVTHM-scramble細(xì)胞中的表達(dá)水平低于Plvthm-SIRT6細(xì)胞,予以AS-IV24ng/ml干預(yù)pLVTHM-scramble細(xì)胞和Plvthm-SIRT6細(xì)胞,IκB在pLVTHM-scramble細(xì)胞表達(dá)水平低于Plvthm-SIRT6細(xì)胞,但與未干預(yù)細(xì)胞相比,兩種細(xì)胞IκB水平均有上調(diào)：予以AS-IV24ng/m干預(yù)pLVTHM-scramble細(xì)胞和Plvthm-SIRT6細(xì)胞48h后,提取各組細(xì)胞核蛋白,Western blot檢測NF-κBP65亞單位的表達(dá),NF-κBp65亞單位在Plvthm-SIRT6+AS-IV干預(yù)細(xì)胞中表達(dá)最低,與pLVTHM-scramble細(xì)胞相比,SIRT6過表達(dá)降低了NF-κBp65亞單位在Plvthm-SIRT6細(xì)胞核中的積累。結(jié)論：研究表明,1、SIRT6在NSCLC組織及肺癌細(xì)胞中的表達(dá)下降；2、AS-IV對肺癌細(xì)胞有抑制作用,呈現(xiàn)濃度趨勢；3、AS-IV聯(lián)合吉非替尼可增加腫瘤細(xì)胞抑制率；4、過表達(dá)SIRT6可以抑制NF-κB的活化；5、AS-IV可通過上調(diào)SITR6,抑制NF-κB活化,促進(jìn)了吉非替尼的敏感性。
[Abstract]:Background and objective: lung cancer (Lung cancer) is the most common malignant tumor in China. The data released by the National Cancer Center in 2015 showed that lung cancer is the highest incidence of cancer and the leading cause of cancer death. Non small cell lung cancer (non-small cell lung cancer. NSCLC) is the most common, and the 80%-87%. of the total number of lung cancer is associated with NSC In LC research, the role of epidermal growth factor (Epidermal Growth Factor Receptor. EGFR, also known as ErbB1 or HER1) is gradually clarified in the pathogenesis of NSCLC, the promoter gene, tumor cell growth, cell heterogeneity and increase of invasiveness, which makes EGFR become one of the important targets in target therapy. Although targeted drugs can make tumors The remission rate increases and the asymptomatic life prolongs, but with the prolonged use of TKIS, drug resistance inevitably occurs. Therefore, developing a method to postpone or reverse the drug resistance is a hot field in target therapy. Astragalus is a common medicinal herb with many chemical components, a large number of basic and clinical research reports, Astragalus membranaceus in the body and in the body. There are anti-tumor effects in vitro. Astragalin (Astragaloside IV, AS- IV) is one of the main components of Astragalus membranaceus. The study shows that AS-IV can inhibit the proliferation of lung cancer cells through regulatory T cells and cytotoxic T lymphocytes and the related signal transduction pathway. Migration and invasion of.SIRT6 are NAD+ dependent group III histone group B An important part of the phthalidase family (Sirtuin family). Epigenetic regulation is a hot spot in cancer research. Through a series of biological processes such as DNA, histone methylation, phthalide, phosphorylation and chromosome remodeling, the expression of SIRT6 in tumor tissue and tumor, tumor, tumor, and tumor are found. Metastasis, postoperative survival rate, postoperative recurrence rate and chemosensitivity are closely related. At present, SIRT6 is considered as a new tumor related gene, alleviating or inhibiting, and even reversing the new target of chemotherapeutic resistance. The purpose of this study is (1) to explore the expression and expression of SIRT6 in NSCLC tissues, and SIRT6 in human lung cancer NCI-H1299, PC9/GR, A54 The expression of 9 cells; (2) different concentrations of astragalin acted on human lung cancer NCI-H1299, PC9/GR, A549 cells, and observed its inhibitory effect on the proliferation of lung cancer cells with different mutant states. (3) different concentrations of astragalin combined with gefitinib on human lung cancer NCI-H1299, PC9/ GR, A549 cells, and observed their different mutant states of lung cancer cells. Proliferation inhibition; (4) AS- IV alone intervention cells and AS- IV combined with gefitinib combined with the intervention of the expression level of SIRT6; (5) lentivirus transfected PC9/GR cells, AS- IV combined with gefitinib on the proliferation of PC9/GR cells after transfection; (6) to explore the resistance of lung cancer cells in the SIRT6 and NF- kappa B signal Interaction between roads. 1. 1, using immunohistochemical method to detect the expression of SIRT6 in NSCLC tumor tissue, paracancerous tissue and benign pathological tissue, and collect the clinical data of patients, analyze the relationship between SIRT6 and clinical parameters. 2, using qRT-PCR and Western blot test method to detect human normal lung gland epithelial cells BEAS-2B, NCI-H 1299, PC9/GR, A549 cells in the expression of SIRT6; 3, different concentrations of gefitinib in human lung cancer NCI-H1299, PC9/GR, A549 cells, CCK-8 method to detect cell proliferation inhibition rate, use an enzyme labeled instrument to read the OD value, calculate cell growth inhibition rate and describe cell growth curve according to formula; 4, different concentration AS- IV action on human lung cancer NCI-H1299, PC9/G R, A549 cells, the cell proliferation inhibition rate was detected by CCK-8 method, the OD values were read by the enzyme labeling instrument, the cell growth inhibition rate and the cell growth curve were calculated according to the formula. 5, different concentrations AS- IV combined with gefitinib to the human lung cancer NCI-H1299, PC9/GR, A549 cells, and the cell proliferation inhibition rate was detected by CCK-8 method and the cell growth inhibition rate was calculated. Draw the cell growth curve; 6, different concentrations AS- IV combined gefitinib, gefitinib acts on human lung cancer PC9/GR cells separately, using qRT-PCR to detect the expression of SERT6 mRNA, and Western-blot technique to detect the protein expression changes of SIRT6; 7, select the lentivirus to mediate transfection and make the SIRT6 gene eukaryotic expression vector. PC9/GR cells were stained, fluorescence microscopy was inverted to observe fluorescence expression,.Western Blot detection of virus titer and expression of SIRT6 protein. The effect of AS- IV combined with gefitinib on the proliferation of PC9/GR cells after transfection was detected. 8, Western-blot was used to detect I kappa B and NF- kappa Bp65, and to explore the phase between SIRT6 and nuclear kappa signaling pathway in drug-resistant lung cancer cells. Results: results: results: 1, SIRT6 was lower in NSCLC tissues than para cancerous tissue and benign lesion tissue; the average IOD of high differentiated patients was higher than that of differentiation. The average IOD of SIRT6 in patients with lymph node metastasis and non lymph node metastasis was significantly different; 2, A549, PC9/GR, and H1299 via CCK-8 experiment. After different concentrations of gefitinib intervened for 48h, the inhibitory rate of cell proliferation was dose-dependent. Compared with the control, the inhibitory effects of gefitinib were significantly different. The hemi inhibitory concentration of gefitinib was 21.29 mu M, 45.98 + 1.62 micron M, 26.29 + 2.25 micron M; 3, the CCK-8 method was used to select AS- IV of different concentrations. As the A549 and PC9/GR cell lines, it was found that when the intervention time was 48h, the AS- IV concentration of 3ng/ml and 6ng/ml had no obvious inhibitory effect on A549 and PC9/GR cells, while AS- IV greater than 12ng/ml could inhibit the growth of the cells. AS- IV in 6ng/ml could obviously inhibit the growth of cells; 4, a gefitinib culture containing 4 concentrations (3ng/ml, 6ng/ml, 12ng/ml, 24ng/ml) combined with a gefitinib culture of 10 mu M to act on A549, H11299, PC9/GR cells. 48 hours later, a CCK-8 reagent enzyme scale was used to detect the same concentration, and the same cell strain was acted on the same cell strain. The inhibitory rate of cell proliferation was significantly different, the proliferation inhibition rate of cell proliferation was increased with the concentration of AS- IV, and the proliferation inhibition rate of.3 cells was the highest when the concentration of gefitinib combined with AS- IV was 24ng/ml, but with the same grfitinib concentration, the proliferation ability of different cells was different and the proliferation ability of PC9/GR cells was the worst with the same grfitinib concentration. A in 12ng/ml was in A. The Q value of S- IV combined with gefitinib was the largest. 5, the expression level of SIRT6 mRNA and protein decreased significantly compared with BEAS-2B cells of normal lung tissue by qRT-PCR and Western Blotting Technology. The results showed that compared with the control group, the expression of Q, PC9/GR, A549, H1299 cells and BEAS-2B cells in normal lung tissue showed a significant decrease. The expression of PC9/GR, SITR6mRNA increased and P0.01. alone AS- IV 12ng/ml intervened PC9/GR alone, compared with the control group, while gefitinib intervened PC9/GR alone, and there was no significant difference between the control group and the control group. The Western blotting test results showed that AS- IV 12ng/ml combined with gefitinib interfered with the control group as compared with the control group. AS-IV 12ng/ml alone intervention PC9/GR, compared with the control group; 7, gefitinib concentration gradient 0,5,10,20,40 M alone intervention PC9/GR, compared with the control group, the level of SIRT6mRNA and protein increased, but no significant statistical significance; 8, the construction of the stable transfection of SIRT6 overexpressed carrier PC/GR, inverted fluorescence display Microscopically, the cell transfection efficiency was estimated at about 80%-85% and detected by Western Blot. Compared with the control, the expression of SIRT6 protein was greatly improved; 9, 10rtM's gefitinib and concentration gradient AS-IV intervention pLVTHM-SIRT6 and pLVTHM-scramble cells, SIRT6, gefitinib and AS-IV were combined to inhibit the growth of cells. The system was significantly enhanced with the other three groups; the pLVTHM-SIRT6 group had no statistical significance compared with the pLVTHM-scramble+ gefitinib group, but had a statistical significance compared with the pLVTHM-scramble group; the AS-IV and concentration gradient gefitinib of 12ng/ml were used to interfere with pLVTHM-SIRT6 and pLVTHM-scramble cells, SIRT6, AS-IV and gefitinib cooperation. The growth inhibition of cell growth was obvious. The pLVTHM-SIRT6 group had no significant statistical significance compared with pLVTHM-scramble+AS- IV, but compared with the pLVTHM-scramble group, 10, Western blot detected pLVTHM-scramble and Plvthm-SIRT6 cells. The expression level of I kappa B in pLVTHM-scramble cells was lower than that of Plvthm-SIRT6 cells. G/ml interfered with pLVTHM-scramble and Plvthm-SIRT6 cells, and the expression level of I kappa B in pLVTHM-scramble cells was lower than that of Plvthm-SIRT6 cells, but the level of I kappa B was up to up in the two cells compared with that of the untreated cells. The expression of NF- kappa BP65 subunit was measured, NF- kappa Bp65 subunit was expressed the lowest in Plvthm-SIRT6+AS-IV intervention cells. Compared with pLVTHM-scramble cells, SIRT6 overexpression reduced the accumulation of NF- kappa Bp65 subunits in Plvthm-SIRT6 nuclei. Conclusion: the study showed that the expression of 1, SIRT6 in NSCLC tissues and lung cancer cells decreased; 2. Cancer cells have inhibitory effect, showing a concentration trend; 3, AS-IV combined with gefitinib can increase tumor cell inhibition rate; 4, overexpression of SIRT6 can inhibit the activation of NF- kappa B; 5, AS-IV can inhibit the activation of NF- kappa B by up regulation of SITR6, and promotes the sensitivity of gefitinib.
【學(xué)位授予單位】：成都中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R734.2

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