本文關(guān)鍵詞： 凋亡 自噬 P62 1 10鄰二氮雜菲雙過(guò)氧釩酸鉀 半胱氨酸蛋白酶-1 脫乙�；�-6 微管 焦亡　出處：《安徽醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：腫瘤是威脅人類健康最嚴(yán)重的疾病之一,全世界每天約有2萬(wàn)人死于腫瘤。目前,腫瘤的發(fā)生機(jī)制尚不清楚,也沒(méi)有針對(duì)腫瘤的特效治療。腫瘤是多因素疾病,不僅與多種遺傳基因相關(guān),還與各種環(huán)境因素相關(guān)。Yusuf A Hannun于2016年在《nature》發(fā)表論文表明遺傳因素在腫瘤發(fā)生中只起到10-30%的作用,而環(huán)境因素對(duì)腫瘤的發(fā)生影響更大,環(huán)境因素通過(guò)影響細(xì)胞周期、調(diào)節(jié)細(xì)胞自噬、干擾正常細(xì)胞凋亡、抑制細(xì)胞免疫等因素影響腫瘤發(fā)生。自噬是真核生物特有的一種的生命現(xiàn)象,在維持細(xì)胞內(nèi)穩(wěn)態(tài),促進(jìn)細(xì)胞生存方面起重要作用,廣泛參與各種病理生理過(guò)程。近些年來(lái),自噬與腫瘤的關(guān)系受到廣泛關(guān)注,人們期待通過(guò)調(diào)控自噬干預(yù)腫瘤的發(fā)病進(jìn)程,甚至希望通過(guò)調(diào)控自噬來(lái)徹底治愈腫瘤。腫瘤是慢性的疾病過(guò)程,在腫瘤發(fā)生不同階段自噬可能起到不同甚至完全相反的作用。在腫瘤發(fā)生的起始階段,自噬通過(guò)改善細(xì)胞微環(huán)境抑制腫瘤發(fā)生;然而腫瘤進(jìn)展階段,自噬可能起到保護(hù)腫瘤細(xì)胞耐受代謝應(yīng)激,促進(jìn)了腫瘤發(fā)展、播散及轉(zhuǎn)移。但是,自噬對(duì)腫瘤的影響是直接作用還是間接作用,調(diào)控自噬能否改善腫瘤預(yù)后以及如何調(diào)控腫瘤自噬問(wèn)題亟待進(jìn)一步研究。釩是人體必需微量元素,具有多種生物學(xué)活性。在1987年Cantley發(fā)現(xiàn)釩酸根對(duì)ATP酶具有抑制作用,繼而科學(xué)家又發(fā)現(xiàn)釩酸鹽具有類胰島素樣作用,近年來(lái)又發(fā)現(xiàn)釩化合物的抗炎作用、殺精作用。1,10鄰二氮雜菲雙過(guò)氧釩酸鉀(BPV(phen))一種穩(wěn)定的過(guò)氧釩酸鹽,具有廣泛的生物學(xué)活性,Lada Rumora研究表明BPV(phen)能有誘導(dǎo)胰島細(xì)胞系RIN-m5F凋亡。Chandler L.Walker研究表明BPV(phen)可能通過(guò)抑制調(diào)節(jié)細(xì)胞自噬夠緩解頸髓損傷。但是BPV(phen)是否具有抗癌活性,是否調(diào)節(jié)腫瘤細(xì)胞自噬,以及如何調(diào)節(jié)細(xì)胞自噬機(jī)制十分不清。本研究擬探討B(tài)PV(phen)對(duì)細(xì)胞自噬影響機(jī)制,以期為釩化合物用于腫瘤治療提供理論基礎(chǔ)。全部研究?jī)?nèi)容分為以下四部分:1.BPV(phen)抑制細(xì)胞增殖、誘導(dǎo)細(xì)胞凋亡和細(xì)胞焦亡。探討B(tài)PV(phen)對(duì)Hep G2、He LA以及MEF細(xì)胞增殖和凋亡的影響。MTT試劑盒檢測(cè)BPV(phen)對(duì)細(xì)胞活力影響,觀察BPV(phen)對(duì)細(xì)胞形態(tài)學(xué)的影響,Western Blotting檢測(cè)細(xì)胞增殖和凋亡相關(guān)蛋白,流式細(xì)胞技術(shù)檢測(cè)細(xì)胞凋亡。MTT實(shí)驗(yàn)結(jié)果發(fā)現(xiàn)BPV(phen)抑制細(xì)胞增殖,LDH活性實(shí)驗(yàn)發(fā)現(xiàn)BPV(phen)誘導(dǎo)細(xì)胞釋放LDH,形態(tài)學(xué)發(fā)現(xiàn)BPV(phen)誘導(dǎo)細(xì)胞形態(tài)逐漸變圓,隨著劑量增大細(xì)胞數(shù)目減少、部分細(xì)胞形態(tài)改變;Western Blotting檢測(cè)結(jié)果發(fā)現(xiàn)PARP斷裂帶隨劑量依賴性增加,PCNA變化不明顯;Caspase1(對(duì)細(xì)胞焦亡的形成起決定作用,是細(xì)胞焦亡最重要的標(biāo)志蛋白)呈現(xiàn)劑量依賴性增加。流式細(xì)胞學(xué)凋亡檢測(cè)結(jié)果發(fā)現(xiàn)BPV(phen)10μM D2象限細(xì)胞明顯增加,凋亡明顯。以上實(shí)驗(yàn)結(jié)果提示BPV(phen)抑制細(xì)胞增殖,促進(jìn)細(xì)胞凋亡和細(xì)胞焦亡。2.BPV(phen)對(duì)細(xì)胞自噬的影響。鑒于細(xì)胞凋亡、細(xì)胞焦亡與細(xì)胞自噬的密切關(guān)系,本研究探討B(tài)PV(phen)對(duì)細(xì)胞自噬的影響。雌性C57BL/6小鼠適應(yīng)性飼養(yǎng)1周后,隨機(jī)分為兩組,實(shí)驗(yàn)組給予皮下注射BPV(phen)2.5μmol/30 g每天一次×14 d,對(duì)照組注射生理鹽水,第15天處死小鼠,取肝臟組織,Western Blotting檢測(cè)細(xì)胞自噬標(biāo)志性蛋白LC3。結(jié)果發(fā)現(xiàn)BPV(phen)腹腔注射小鼠肝臟組織LC3-Ⅱ表達(dá)水平明顯升高,提示自噬啟動(dòng)被激活或者自噬體降解受到抑制。進(jìn)一步通過(guò)引入自噬體降解抑制劑來(lái)闡明BPV(phen)是促進(jìn)自噬啟動(dòng)還是抑制自噬體降解。取6孔板培養(yǎng)He La細(xì)胞,分為CTRL和BAF組,每組設(shè)BPV0、BPV2.5、BPV5、BPV10、BPV20亞組,待細(xì)胞生長(zhǎng)狀態(tài)良好,各組分別加入BPV(phen)或DMSO至BPV(phen)藥物終濃度分別為0、2.5、5、10、20μM,繼續(xù)培養(yǎng)48 h,在終止細(xì)胞培養(yǎng)前12 h,CTRL和BAF組分別加入DMSO或者BAF2μl。收集細(xì)胞用Western Blotting實(shí)驗(yàn)檢測(cè)LC3蛋白。在Hep G2、MEF細(xì)胞重復(fù)以上實(shí)驗(yàn)。Western Blotting結(jié)果發(fā)現(xiàn)BPV(phen)劑量依賴性增加LC3-Ⅱ的表達(dá),在加入抑制劑后LC3-Ⅱ不隨BPV(phen)變化,在Hep G2、He LA以及MEF細(xì)胞系表現(xiàn)相同。在RFP-LC3細(xì)胞免疫熒光實(shí)驗(yàn),觀察10μM BPV(phen)在加入或不加入BAF兩種情況下對(duì)RFP-LC3表達(dá)的影響。通過(guò)共聚焦顯微鏡技術(shù)可以觀察到BPV(phen)10M明顯增加RFP-LC3紅色熒光顆粒數(shù)目,加入自噬體降解抑制劑BAF后,BPV(phen)組和CTRL組無(wú)明顯差別。以上實(shí)驗(yàn)提示,BPV(phen)不是促進(jìn)自噬的啟動(dòng)導(dǎo)致自噬體的增多,而是抑制了自噬體的降解而導(dǎo)致自噬體的增多。因此,本研究提示BPV(phen)抑制自噬體的降解。3.BPV(phen)降低P62蛋白水平及其機(jī)制。本研究在觀察BPV(phen)對(duì)細(xì)胞自噬影響時(shí),除了檢測(cè)細(xì)胞自噬最重要的標(biāo)志蛋白LC3之外,同時(shí)檢測(cè)了另一個(gè)重要的自噬相關(guān)蛋白P62,結(jié)果發(fā)現(xiàn)BPV(phen)劑量依賴性降低P62蛋白水平。通常情況下抑制自噬體的降解將會(huì)抑制蛋白質(zhì)通過(guò)自噬途徑的降解,表現(xiàn)為P62蛋白水平升高。而本研究發(fā)現(xiàn)BPV(phen)抑制自噬但是P62卻明顯降低,因此BPV(phen)可能是通過(guò)其他途徑影響P62蛋白水平。為闡明其機(jī)制,He LA細(xì)胞系加入蛋白生成抑制劑CHX后進(jìn)行細(xì)胞培養(yǎng),分為BPV(phen)組和CTRL組,觀察在抑制蛋白質(zhì)合成情況下BPV(phen)對(duì)P62水平的影響。結(jié)果發(fā)現(xiàn)在抑制蛋白質(zhì)生成的情況下BPV(phen)降低P62蛋白水平,提示BPV(phen)促進(jìn)P62的降解。為探明BPV(phen)對(duì)P62蛋白水平影響是通過(guò)自噬途徑還是蛋白酶體途徑,在He LA細(xì)胞系比較在加入自噬抑制劑BAF或和蛋白酶體降解抑制劑MG132情況下BPV(phen)對(duì)P62蛋白水平的影響,通過(guò)Western Blotting方法檢測(cè)P62蛋白水平。結(jié)果發(fā)現(xiàn)MG132幾乎逆轉(zhuǎn)BPV(phen)對(duì)P62的降低作用,而應(yīng)用BAF組僅部分逆轉(zhuǎn)BPV(phen)對(duì)P62的降低作用。此外,取穩(wěn)定表達(dá)RFP-LC3的He La細(xì)胞系分為三組,加入BPV(phen)培養(yǎng),實(shí)驗(yàn)第48小時(shí)收集載玻片對(duì)P62進(jìn)行免疫熒光染色,免疫熒光結(jié)果發(fā)現(xiàn)P62與RFP-LC3共定位在BAF應(yīng)用后出現(xiàn),而在MG132條件下P62和RFP-LC3沒(méi)有共定位。BPV(phen)可能干擾P62和RFP-LC3親和性。為檢測(cè)BPV(phen)對(duì)P62泛素化水平的影響,在293T細(xì)胞過(guò)表達(dá)P62和Poly-ubiquitin,用Western Blotting檢測(cè)分別在有和沒(méi)有MG132情況下觀察BPV(phen)對(duì)P62和泛素化蛋白的影響。在BPV(phen)作用下表現(xiàn)為非特異性Poly-ubiquitin水平升高。免疫共沉淀實(shí)驗(yàn)發(fā)現(xiàn),在BPV(phen)作用下泛素化的P62水平增加。本研究提示,BPV(phen)通過(guò)增加了P62泛素化水平,促進(jìn)其通過(guò)蛋白酶體途徑降解,從而降低P62蛋白水平。4.BPV(phen)抑制自噬分子機(jī)制。為闡明BPV(phen)抑制自噬體降解具體分子機(jī)制。通常情況下,自噬體形成后需要通過(guò)乙酰化的微管被運(yùn)送到溶酶體形成自噬溶酶體最終行使物質(zhì)降解功能,BPV(phen)影響P62穩(wěn)定性與抑制自噬體降解之間可能有某種聯(lián)系。在HeLA細(xì)胞系沉默P62基因表達(dá),檢測(cè)其對(duì)對(duì)自噬體降解的影響及微管蛋白α-Tubulin乙�；降挠绊憽estern Blotting和免疫熒光檢測(cè)結(jié)果發(fā)現(xiàn),P62沉默抑制自噬體的降解,同時(shí)α-Tubulin乙�；浇档�。而在He LA細(xì)胞系過(guò)表達(dá)P62基因,檢測(cè)自噬體降解以及α-Tubulin水平,結(jié)果與沉默實(shí)驗(yàn)相一致。在He LA細(xì)胞系,Western Blotting檢測(cè)BPV(phen)對(duì)微管蛋白α-Tubulin乙�；降淖兓约癏DAC6蛋白水平的變化。通過(guò)免疫共沉淀實(shí)驗(yàn),檢測(cè)P62蛋白水平降低對(duì)HDAC6蛋白水平的影響。沉默內(nèi)源性P62和過(guò)表達(dá)外源性P62,可以分別抑制和促進(jìn)自噬體降解。BPV(phen)導(dǎo)致HDAC6與P62相互作用減弱,釋放HDAC6。BPV(phen)通過(guò)P62-HDAC6通路抑制自噬體降解。綜上所述,本研究發(fā)現(xiàn)BPV(phen)抑制細(xì)胞增殖、促進(jìn)細(xì)胞凋亡和細(xì)胞焦亡,同時(shí)抑制自噬體降解。其影響自噬體降解的分子通路可能是,BPV(phen)促進(jìn)P62蛋白酶體降解,后者增強(qiáng)HDAC6活性,繼而HDAC6對(duì)乙酰化微管蛋白的去乙�；饔迷黾�,影響自噬體的轉(zhuǎn)運(yùn)。
[Abstract]:The tumor is one of the most serious threat to human health, there are about 20 thousand people died of cancer in the world every day. At present, the mechanism of tumorigenesis is not clear, no specific treatment for tumors. The tumor is a multi factor disease, not only related to multiple genes, but also with various ring related environmental factors A Hannun published a paper.Yusuf show that genetic factors in the occurrence of tumor only plays the role of 10-30% in in 2016, and the environmental factors and the occurrence of cancer is more influential environmental factors by influencing the cell cycle, regulation of autophagy, interfere with normal cell apoptosis, inhibition of cell immune factors in tumorigenesis. Autophagy is a unique phenomenon that real life in eukaryotes, cellular homeostasis, promotion plays an important role in cell survival, are involved in various pathophysiological processes. In recent years, the relationship between autophagy and tumor by wide Note, people look through the development process of regulation of autophagy interfere with tumor, even hope that through the regulation of autophagy to completely cure the tumor. The tumor is a chronic disease process in different stages of tumorigenesis, autophagy may play a different role and even completely opposite. In the initial stage of cancer, autophagy by improving cell microenvironment suppresses tumorigenesis; however tumor stage, autophagy may play a protective metabolic stress tolerance of tumor cells, promote tumor development, dissemination and metastasis. But the effect of autophagy on tumor is directly or indirectly, the regulation of autophagy can improve the prognosis of tumor and how to regulate tumor autophagy problems to be studied further. Vanadium is an essential trace element, has a variety of biological activity in 1987. Cantley found that vanadate has an inhibitory effect on ATP enzyme, then scientists found that vanadate with trypsin Insulin like effect, also found recently that the anti-inflammatory effects of vanadium compounds, spermicidal effect.1,10 two o phenanthroline diperoxovanadate acid potassium (BPV (phen)) a stable peroxy vanadate, has extensive biological activities, Lada Rumora study showed that the BPV (phen) can induce islet cell lines RIN-m5F.Chandler L.Walker apoptosis studies showed that BPV (phen) could inhibit the regulation of autophagy alleviated cervical cord injury. But BPV (phen) with anticancer activity, whether and how to regulate tumor cell autophagy, autophagy regulation mechanism is unclear. This study intends to explore the mechanism of BPV (phen) effect on autophagy, in order to to provide a theoretical basis for the treatment of tumors. For all vanadium compound research content is divided into the following four parts: 1.BPV (phen) inhibited cell proliferation, induced apoptosis and pyroptosis. To investigate the BPV (phen) of Hep G2, He LA and MEF cell proliferation and apoptosis .MTT kit to detect the effect of BPV death (phen) effects on cell viability, BPV (phen) to observe the effect on cell morphology, Western Blotting detection of cell proliferation and apoptosis related protein, flow cytometry to detect the apoptosis of.MTT BPV (phen) results showed that the inhibition of cell proliferation, LDH activity test showed that BPV (phen) induced cells to release LDH, BPV (phen) induced morphological cells gradually became round, with the dose increased the number of cells decreased, change cell morphology; Western Blotting showed that with a dose-dependent increase in PARP fault, PCNA did not change significantly; Caspase1 (on the formation of pyroptosis plays a decisive role, is the cell the most important sign of focal dead protein) in a dose-dependent manner. Flow cytometry apoptosis detection results showed that BPV (phen) M 10 quadrant D2 cells increased and apoptosis significantly. The above results suggest that BPV (pH EN) inhibited cell proliferation, promote cell apoptosis and pyroptosis.2.BPV (phen) effect on autophagy. Due to apoptosis, pyroptosis close relationship with autophagy, in this study, BPV (phen) effect on autophagy. Female C57BL/6 mice were fed for 1 weeks, were randomly divided into two groups, the experimental group received subcutaneous injection of BPV (phen) 2.5 mol/30 g * 14 d once a day, the control group were injected with saline for fifteenth days, the mice were killed, the liver tissue, Western Blotting detecting autophagy marker protein LC3. results showed that BPV (phen) expression in liver tissue of mice peritoneal injection of LC3- II level was significantly increased, suggesting that autophagy is activated or inhibited autophagy degradation. Further through the introduction of autophagy inhibitors to elucidate the degradation of BPV (phen) is to promote or inhibit autophagy autophagy degradation. 6 Kong Banpei had He La cells, divided into CTRL and BA F group, each group with BPV0, BPV2.5, BPV5, BPV10, BPV20 subgroups, the cells grew well and were joined BPV (phen or DMSO) to BPV (phen) concentration were 0,2.5,5,10,20 M, cultured for 48 h, at the end of cell culture before 12 h, CTRL and BAF components don't join DMSO or BAF2 L. cells were collected with LC3 Western protein was detected by Blotting experiment. In Hep G2 MEF cells, repeat the above experiment results showed that BPV.Western Blotting (phen) dose dependently increased the expression of LC3- II, before joining LC3- II with BPV inhibitor (phen) in Hep G2, He, and LA MEF cell lines showed the same. In RFP-LC3 immunofluorescence experiments, observation of 10 M BPV (phen) effect on the expression of RFP-LC3 in BAF is added or not under two conditions. By confocal microscopy can be observed in the BPV (phen) 10M significantly increased the number of RFP-LC3 red fluorescent particles, adding autophagy The biodegradation inhibitor BAF, BPV (phen) showed no significant difference between the group and CTRL group. The above experiments suggest that BPV (phen) is to promote autophagy start leads to increased autophagy, but inhibited the degradation of autophagy and leads to increased autophagy. Therefore, this study suggests that BPV (phen).3.BPV degradation and inhibition of autophagy the lower level of P62 protein (phen) and its mechanism. In this study, observation of BPV (phen) on autophagy effect, in addition to the most important detecting autophagy marker protein LC3, also detected another important autophagy related protein P62, the results showed that BPV (phen) dose dependently reduced P62 protein level the degradation will normally inhibit. Autophagy inhibition of protein degradation by autophagy pathway, increased P62 protein levels. The study found that BPV (phen) inhibition of autophagy but P62 was significantly reduced, so the BPV (phen) may be through the other Affect the protein level of P62. To elucidate the mechanism of He LA cell line into protein inhibitor CHX after cell culture, divided into BPV (phen) group and CTRL group were observed in the inhibition of protein synthesis by BPV (phen) effect on P62 level. The results found in the inhibition of protein generated by BPV (phen) P62 protein levels were reduced, suggesting that BPV (phen) to promote the degradation of P62. BPV (phen) to explore the influence on the level of P62 protein through the autophagy pathway or proteasome pathway, in He LA cell lines in autophagy inhibitor BAF or MG132 inhibitor and proteasome degradation under the condition of BPV (phen) effect on the protein level of P62, through the Western Blotting method to detect the protein level of P62. The results showed that MG132 BPV (phen) almost reversed the decrease in P62, and the application of group BAF was only partially reversed BPV (phen) of P62 decreased. In addition, the stable expression of RFP-LC3 The He La cell lines were divided into three groups, adding BPV (phen) training, forty-eighth hours to collect experimental slides for P62 immunofluorescence staining, immunofluorescence showed that P62 colocalized with RFP-LC3 in BAF application, and under the condition of MG132 P62 and RFP-LC3 have no co localization of.BPV (phen) and may interfere with P62 RFP-LC3 affinity. For the detection of BPV (phen) effect on P62 ubiquitination level, overexpression of P62 and Poly-ubiquitin in 293T cells by Western, Blotting and BPV were detected in the observation of no MG132 case (phen) effects on P62 and ubiquitin proteins. In BPV (phen) under the action of increased non the specific Poly-ubiquitin level. Co immunoprecipitation experiments revealed that in BPV (phen) P62 level of ubiquitination under the action of increasing. This study suggested that BPV (phen) by increasing P62 ubiquitination level, promote the degradation through the proteasome pathway, thereby reducing the level of P62 protein .4.BPV (phen) in order to elucidate the molecular mechanism of inhibition of autophagy. BPV (phen) inhibition of autophagy specific degradation mechanism. Under normal circumstances, after the formation of autophagosomes through acetylated microtubules are transported to lysosomes to form autolysosome final exercise material degradation function, BPV (phen) may have some relationship between the stability and the inhibition effect of P62 autophagic degradation. Expression of P62 gene silencing in HeLA cells, detect the effect on autophagy degradation and alpha tubulin acetylation level of -Tubulin the effect of.Western Blotting and immunofluorescence test results showed that the degradation of P62 silencing inhibited autophagy, while alpha acetylation level of -Tubulin decreased. Over expression of P62 gene in He LA cell line, detect autophagosome degradation and alpha -Tubulin level. The results are consistent with the experimental silence. In He LA cell line, Western Blotting BPV (phen) detection of micro tube protein alpha -Tubulin The change of histone acetylation and HDAC6 protein level changes. By CO immunoprecipitation assay to detect the protein level of P62, reduce the impact on the level of HDAC6 protein. The silencing of endogenous P62 and overexpression of exogenous P62, can inhibit and promote autophagic degradation of.BPV (phen) in HDAC6 and P62 interaction is weakened, the release of HDAC6.BPV (phen inhibition of autophagy by P62-HDAC6) degradation pathway. In summary, this study found that BPV (phen) inhibited cell proliferation, promote cell apoptosis and pyroptosis, while inhibiting autophagy degradation. The influence of molecular pathways of autophagy may be degradation, BPV (phen) P62 promote proteasome degradation, which enhance the activity of HDAC6, and HDAC6 the acetylated tubulin acetylation increased influence of autophagosome transport.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R96

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