發(fā)布時間：2018-09-08 12:42

【摘要】：一、研究背景代謝改變是腫瘤的重要特征之一,其與腫瘤的發(fā)生發(fā)展密切相關(guān)。腫瘤細胞無論在有氧或無氧條件下,均需通過糖酵解(glycolysis)途徑吸收葡萄糖產(chǎn)生能量,滿足快速生長需求,腫瘤細胞的這一代謝特點是腫瘤細胞具有的普遍現(xiàn)象和規(guī)律,被稱為Warburg效應。Warburg效應不僅限于糖酵解和三羧酸循環(huán)的改變,脂肪酸、谷氨酰胺、絲氨酸、一碳單位等諸多代謝通路在腫瘤細胞均發(fā)生了代謝重編程(metabolic reprogramming),而且有關(guān)代謝性疾病(如肥胖、糖尿病等)的研究也顯示與腫瘤的發(fā)生發(fā)展密切相關(guān)。因此,更進一步研究Warburg效應的機制及其與腫瘤發(fā)生發(fā)展的關(guān)系,不僅有助于揭示腫瘤代謝改變與腫瘤進展的內(nèi)在關(guān)聯(lián),而且將為腫瘤的臨床診斷尋求高度特異性代謝標志物及以腫瘤代謝為靶向治療的新策略提供新的視野和契機。腫瘤細胞所表現(xiàn)出的有氧糖酵解(aerobic glycolysis),即Warburg效應使線粒體的氧化磷酸化(oxidative phosphorylation, OXPHOS)途徑減弱,而有氧糖酵解及磷酸戊糖(pentose phosphate pathway, PPP)形成核苷酸等代謝途徑增強。這種異常的糖代謝轉(zhuǎn)變促使腫瘤細胞具有選擇性生長優(yōu)勢,它不僅為快速增殖的腫瘤細胞提供能量(ATP)、生物大分子前體(氨基酸、核苷酸等)以及輔酶(Nicotinamide adenine dinucleotide phosphate NADPH),而且,腫瘤細胞通過Warburg效應形成的腫瘤酸化的微環(huán)境有利于腫瘤細胞的生長和浸潤轉(zhuǎn)移,此外,腫瘤細胞通過線粒體氧化磷酸化向糖酵解的代謝轉(zhuǎn)變,減少活性氧(reactive oxygen species,ROS)的產(chǎn)生,從而減輕ROS對腫瘤細胞的毒性。正因如此,近年來學者們把腫瘤代謝異常與腫瘤自我增殖能力、凋亡抵抗、無限的復制潛能、對抗生長信號的不敏感性、持續(xù)的血管生成能力、組織侵襲轉(zhuǎn)移能力和免疫監(jiān)控逃逸共同構(gòu)成了腫瘤新的八大特征性標志。多種因素導致腫瘤細胞Warburg效應的發(fā)生,主要有：腫瘤細胞中原癌基因的獲得性缺失或突變,抑癌基因的缺失等；腫瘤細胞中糖酵解通路中的關(guān)鍵酶的活性或表達發(fā)生改變；線粒體mtDNA突變引起呼吸鏈功能缺失或氧化磷酸化效率降低；適應低氧微環(huán)境,腫瘤細胞中低氧誘導因子高表達,激活下游多個腫瘤代謝尤其是糖酵解相關(guān)靶基因及乳酸分泌相關(guān)的轉(zhuǎn)運蛋白的表達。盡管Warburg效應是腫瘤最為重要的特征之一,但腫瘤細胞除了通過上述自身基因的突變及關(guān)鍵性的信號通路的激活以適應腫瘤缺氧微環(huán)境促進腫瘤的Warburg效應外,與腫瘤發(fā)生及進展密切相關(guān)的其他調(diào)控分子及關(guān)鍵信號通路在腫瘤Warburg效應調(diào)控中的作用仍不清楚。PKC屬于一類受酪氨酸激酶受體(Receptor Tyrosine kinase,RTK)和G-蛋白偶聯(lián)受體(G protein coupled receptor,GPCR)激活的絲氨酸／蘇氨酸家族的蛋白激酶,包括三個亞族,即Ca2+和DAG依賴的典型PKC(PKC-α,-β,-γ)；DAG-依賴而Ca2+非依賴的PKC(PKC-δ,-ε,-η,-θ)；DAG和Ca2+非依賴的不典型的PKC(PKC-ζ,-ι).PKC家族對細胞生長代謝、分裂增殖、細胞骨架蛋白的重塑等方面有重要作用。PKCζ是PKC家族的其中一個非典型亞型,在整合細胞外信號刺激,參與調(diào)控細胞生長、代謝、細胞極性等相關(guān)的關(guān)鍵信號傳導中起重要作用。有研究證明PKCζ可以促進腫瘤的增殖、侵襲和轉(zhuǎn)移,而且,在葡萄糖供應不足時,PKCζ基因缺失能促進腫瘤細胞代謝重編程。已有的研究表明,由組蛋白去乙�；�酶(HDACs)調(diào)控的表觀遺傳學改變在腫瘤的增殖、遷移、基因組的穩(wěn)定性、血管新生及腫瘤凋亡中扮演一個重要角色。它們主要由Class Ⅰ,ClassⅡ和ClassⅢ三型HDACs構(gòu)成。最近,有關(guān)HDACs在腫瘤代謝變化中的功能作用開始受到人們的關(guān)注,但與腫瘤增殖及進展密切相關(guān)的Class Ⅱ HDACs是否參與腫瘤代謝尤其是糖代謝的調(diào)控作用至今仍不清楚。二、研究目的本研究首次探討PKCζ和Ⅱa類HDACs在前列腺癌細胞糖酵解的功能作用及其相互作用對糖代謝和相關(guān)基因表達及細胞生長的影響,該研究不僅有助于深入了解PKCζ和Ⅱa類HDACs在前列腺癌癌的生長中的作用和分子機制,而且為進一步發(fā)現(xiàn)新的調(diào)控腫瘤代謝靶點奠定基礎。三、研究方法本研究主要通過過表達(質(zhì)粒)或干擾(si RNA)的策略探討PKCζ或Ⅱ aHDACs在前列腺癌細胞中對有氧糖酵解途徑中間產(chǎn)物及終產(chǎn)物的調(diào)節(jié)作用及其對相關(guān)蛋白的表達調(diào)節(jié)作用和分子機制；通過免疫熒光染色、免疫共沉淀等方法證實PKCζ與Ⅱa HDACs在核內(nèi)的共定位以及相互作用,調(diào)節(jié)前列腺癌細胞有氧糖酵解進而最終調(diào)節(jié)腫瘤細胞的生長。四、研究結(jié)果1. PKCζ促進前列腺癌細胞DU145的生長及Warburg效應的發(fā)生PKCζ的過表達促進前列腺癌DU145細胞的生長及葡萄糖的吸收和乳酸的分泌,相反,敲低前列腺癌細胞內(nèi)源性PKCζ的表達則明顯降低前列腺癌DU145細胞的生長及葡萄糖的吸收和乳酸的分泌。2. PKCζ促進前列腺癌細胞中Warburg效應相關(guān)蛋白的表達通過Real time quantitative RT-PCR和Western blot檢測顯示,PKCζ的過表達促進前列腺癌DU145細胞中糖酵解相關(guān)蛋白、葡萄糖及乳酸轉(zhuǎn)運蛋白(HKⅡ、PFKP、MCT4、CD 147)的表達,而敲低前列腺癌細胞內(nèi)源性PKCζ的表達則明顯降低前列腺癌DU145細胞中糖酵解相關(guān)蛋白、葡萄糖及乳酸轉(zhuǎn)運蛋白(HKⅡ、PFKP、MCT4、CD 147)的表達。上述結(jié)果提示PKCζ可能通過調(diào)節(jié)前列腺癌細胞中糖酵解相關(guān)蛋白的表達而促進Warburg效應的發(fā)生及腫瘤細胞生長。3.過表達Ⅱa型HDACs (HDAC4,5,7)降低前列腺癌DU145細胞的生長及葡萄糖吸收和乳酸的分泌有研究證明,HDACs與細胞代謝之間存在著一個反饋循環(huán)效應,為了探討Ⅱa型HDACs (HDAC4,5,7)對腫瘤細胞生長及糖酵解的影響,我們分別在前列腺癌DU145細胞中轉(zhuǎn)染HA-HDAC4,5,7,首先檢測其過表達對前列腺癌細胞生長的影響,結(jié)果表明,過表達HA-HDAC4,5,7均能明顯降低DU145細胞的生長及存活。而敲低內(nèi)源性HDAC7的表達則明顯促進DU145細胞的生長,其次,在敲低內(nèi)源性HDAC7表達的DU145細胞中添加乳酸轉(zhuǎn)運蛋白的抑制劑a-CHCA則拮抗內(nèi)源性HDAC7的敲低對細胞生長的促進作用。最后,我們進一步檢測Ⅱa型HDACs對葡萄糖的吸收和乳酸分泌的影響,結(jié)果表明,過表達HA-HDAC4,5,7能以時間依賴地降低前列腺癌細胞DU145和PC-3M中葡萄糖吸收和乳酸的分泌。提示Ⅱa型HDACs可能通過負性調(diào)節(jié)糖酵解的發(fā)生而抑制腫瘤細胞的生長。4.Ⅱa型HDACs的過表達降低前列腺癌DU145細胞中Warburg效應相關(guān)蛋白的表達Real time quantitative RT-PCR顯示,前列腺癌DU145細胞中HA-HDAC4,5,7的過表達明顯降低前列腺癌細胞中糖酵解相關(guān)蛋白、葡萄糖及乳酸轉(zhuǎn)運蛋白(HKⅡ、PFKP、MCT4、CD 147)的表達,而且Western blot更顯示HA-HDAC4,5,7的過表達除了明顯降低上述糖酵解相關(guān)蛋白的表達外,也明顯降低糖酵解關(guān)鍵酶(LDHA,PDH)和缺氧誘導因子(HIF-la)的表達。5.PKC⒔與II a HDACs在核內(nèi)共定位且二者相互作用,并且敲低PKCζ的表達能夠明顯降低HDAC出核關(guān)鍵性位點的磷酸化水平免疫熒光染色顯示內(nèi)源性PKCζ可與Ⅱa型HDACs的HDAC4,5,7在核內(nèi)共定位,免疫共沉淀進一步顯示HDAC4,5,7均能與PKCζ直接相互作用,此外,敲低PKCζ的表達能夠明顯降低HDAC出核關(guān)鍵性位點的磷酸化水平。提示PKCζ可能與HDAC4,5,7共同作用,通過調(diào)節(jié)Ⅱa HDACs的磷酸化出核,從而解除Ⅱa HDACs對糖酵解相關(guān)基因表達的抑制作用。6. HDAC7可拮抗PKCζ對DU145細胞生長的促進作用細胞生長檢測表明,敲低內(nèi)源性PKCζ的表達能明顯抑制DU145細胞的生長,而敲低HDAC7的表達則明顯促進DU145細胞的生長,si-HDAC7和si-PKCζ的共轉(zhuǎn)染進一步顯示,敲低內(nèi)源性HDAC7的表達則可拮抗內(nèi)源性PKCζ的敲低對DU145細胞生長的抑制作用。五、結(jié)論本研究結(jié)果表明PKCζ通過與Ⅱ a型HDACs相互作用,調(diào)節(jié)前列腺癌細胞Warburg效應相關(guān)基因的表達及乳酸的分泌,從而促進腫瘤細胞的生長,這一研究將為進一步探討前列腺癌糖代謝改變與腫瘤生長及進展的內(nèi)在關(guān)聯(lián)奠定基礎,并為前列腺癌的診斷和治療提供新的潛在靶點。
[Abstract]:1. Background Metabolism is one of the most important characteristics of cancer, which is closely related to the occurrence and development of tumor. Tumor cells absorb glucose to produce energy through glycolysis pathway in both aerobic and anaerobic conditions to meet the needs of rapid growth. The Warburg effect is not only limited to changes in glycolysis and tricarboxylic acid cycles, but also to metabolic reprogramming of fatty acids, glutamine, serine, and mono-carboxylic units in tumor cells. Therefore, further study on the mechanism of Warburg effect and its relationship with tumor development will not only help to reveal the intrinsic relationship between tumor metabolic changes and tumor progression, but also seek highly specific metabolic markers for clinical diagnosis and targeted treatment of tumor metabolism. New therapeutic strategies offer new insights and opportunities. The aerobic glycolysis (Warburg effect) shown by tumor cells weakens the oxidative phosphorylation (OXPHOS) pathway in mitochondria, while the metabolic pathways such as aerobic glycolysis and pentose phosphate pathway (PPP) to form nucleotides increase. Strong. This abnormal glycometabolic transformation promotes the selective growth of tumor cells. It not only provides energy (ATP), biological macromolecular precursors (amino acids, nucleotides, etc.) and coenzymes (Nicotinamide adenine dinucleotide phosphate NADPH) for rapidly proliferating tumor cells, but also forms tumor cells through Warburg effect. Acidified microenvironment is conducive to the growth, invasion and metastasis of tumor cells. In addition, the metabolic transformation of tumor cells from mitochondrial oxidative phosphorylation to glycolysis reduces the production of reactive oxygen species (ROS) and thus reduces the toxicity of ROS to tumor cells. Proliferation, apoptosis resistance, unlimited replication potential, insensitivity to growth signals, persistent angiogenesis, tissue invasion and metastasis, and immune surveillance and escape constitute the eight new characteristic markers of tumor. Acquired deletion or mutation, loss of tumor suppressor genes, changes in the activity or expression of key enzymes in the glycolysis pathway in tumor cells, loss of respiratory chain function or decreased oxidative phosphorylation due to mitochondrial mtDNA mutation, high expression of hypoxia-inducible factors in tumor cells, activation of downstream multiple tumors, and adaptation to hypoxia microenvironment Although Warburg effect is one of the most important characteristics of tumors, tumor cells adapt to the Warburg effect of hypoxic microenvironment by mutation of these genes and activation of key signaling pathways. The role of other regulatory molecules and key signaling pathways closely related to tumorigenesis and progression in the regulation of the Warburg effect is still unclear. PKC belongs to a family of serine/threonine proteins activated by Receptor Tyrosine kinase (RTK) and G-protein coupled receptor (GPCR). Kinases, including three subgroups, namely Ca2+ and DAG-dependent typical PKC (PKC-a, -beta, -gamma); DAG-dependent but Ca2+ independent PKC (PKC-delta, -e, -_, -theta); DAG and Ca2+ independent atypical PKC (PKC-_, -_). PKC family plays an important role in cell growth and metabolism, mitosis and proliferation, cytoskeleton protein remodeling. One of the atypical subtypes plays an important role in integrating extracellular signal stimuli and regulating key signaling pathways related to cell growth, metabolism and cell polarity. Programming. Previous studies have shown that epigenetic changes regulated by histone deacetylases (HDACs) play an important role in tumor proliferation, migration, genome stability, angiogenesis and tumor apoptosis. They are mainly composed of Class I, Class II and Class III HDACs. Recently, HDACs have been involved in tumor metabolism. However, it is still unclear whether Class II HDACs, which are closely related to tumor proliferation and progression, are involved in the regulation of tumor metabolism, especially glucose metabolism. This study not only helps to understand the role and molecular mechanism of PKC_and Class II a HDACs in the growth of prostate cancer, but also lays a foundation for further discovery of new targets for regulating tumor metabolism. 3. Research methods This study mainly through overexpression (plasmid) or interference. (si RNA) strategy to investigate the role of PKC_or II a HDACs in regulating the expression of intermediate and end products of aerobic glycolysis pathway and their molecular mechanisms in prostate cancer cells; the co-location and interaction of PKC_and II a HDACs in the nucleus were confirmed by immunofluorescence staining and immunoprecipitation PKC promotes the growth of prostate cancer cell DU145 and Warburg effect. Overexpression of PKC promotes the growth of prostate cancer cell DU145 and glucose uptake and lactic acid secretion. On the contrary, it knocks down prostate cancer cells. The expression of PKC_significantly decreased the growth, glucose uptake and lactic acid secretion of prostate cancer DU145 cells. 2. PKC_promoted the expression of Warburg effect-related proteins in prostate cancer cells. Real-time quantitative RT-PCR and Western blot analysis showed that the over-expression of PKC_promoted the glycolysis of prostate cancer DU145 cells. The expression of related proteins, glucose and lactate transporters (HK II, PFKP, MCT4, CD 147) was significantly decreased by knocking down the expression of endogenous PKC_in prostate cancer DU145 cells, while the expression of glucose and lactate transporters (HK II, PFKP, MCT4, CD 147) was significantly decreased by knocking down the expression of endogenous PKC_. Overexpression of type II a HDACs (HDAC4,5,7) reduces the growth, glucose uptake and lactic acid secretion of prostate cancer DU145 cells. Studies have shown that there is a feedback loop between HDACs and cell metabolism. The effects of type II a HDACs (HDAC4,5,7) on the growth and glycolysis of tumor cells were studied. HA-HDAC4,5,7 was transfected into prostate cancer DU145 cells. The results showed that overexpression of HA-HDAC4,5,7 significantly decreased the growth and survival of DU145 cells. In addition, lactate transporter inhibitor a-CHCA was added to knock down endogenous HDAC7 expression DU145 cells to antagonize the growth-promoting effect of endogenous HDAC7 knockdown. Finally, we further examined the effects of type II a HDACs on glucose uptake and lactate secretion. Expression of HA-HDAC4,5,7 in prostate cancer cells DU145 and PC-3M decreased glucose uptake and lactic acid secretion in a time-dependent manner, suggesting that type II a HDACs may inhibit tumor cell growth by negatively regulating glycolysis. 4. Overexpression of type II a HDACs decreased the expression of Warburg effect-related proteins in prostate cancer DU145 cells. L-time quantitative RT-PCR showed that the overexpression of HA-HDAC4,5,7 in prostate cancer DU145 cells significantly decreased the expression of glycolysis-related proteins, glucose and lactate transporters (HKII, PFKP, MCT4, CD 147) in prostate cancer DU145 cells, and Western blot showed that the overexpression of HA-HDAC4,5,7 in addition to significantly reducing the above-mentioned glycolysis-related proteins. PKC_and II a HDACs were co-localized in the nucleus and interacted with each other, and knocking down the expression of PKC_could significantly reduce the phosphorylation level of the nucleus key sites of HDAC. Immunofluorescence staining showed that endogenous PKC_could be associated with type II a HDACs. HDAC4,5,7 were co-localized in the nucleus. Immunocoprecipitation further showed that HDAC4,5,7 could interact directly with PKC. In addition, knocking down the expression of PKC could significantly reduce the phosphorylation level of the key sites of HDAC exocytosis. Inhibitory effect of HDAC7 on the expression of glycolysis-related genes.6.HDAC7 could antagonize the growth-promoting effect of PKC_on DU145 cells.The results showed that knocking down the expression of endogenous PKC_significantly inhibited the growth of DU145 cells, while knocking down the expression of HDAC7 significantly promoted the growth of DU145 cells. Tapping down the expression of endogenous HDAC7 may antagonize the inhibition of endogenous PKC_on the growth of DU145 cells. 5. Conclusion PKC_can regulate the expression of Warburg-related genes and the secretion of lactic acid in prostate cancer cells by interacting with type II a HDACs. This study will promote the growth of tumor cells. It lays a foundation for further study of the relationship between the changes of glucose metabolism and the growth and progression of prostate cancer, and provides a new potential target for the diagnosis and treatment of prostate cancer.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R737.25

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