【摘要】：研究背景內(nèi)質(zhì)網(wǎng)是細(xì)胞重要的細(xì)胞器,在蛋白質(zhì)的折疊、質(zhì)量控制、維持鈣穩(wěn)態(tài)等方面都極其重要,直接參與并影響細(xì)胞的各種生命活動。內(nèi)質(zhì)網(wǎng)的各種定位蛋白,如分子伴侶、酶等通過對新合成的蛋白肽鏈進(jìn)行加工、折疊修飾,幫助蛋白質(zhì)形成特定的空間構(gòu)象并定向轉(zhuǎn)運。Ca2+結(jié)合蛋白、二硫鍵異構(gòu)酶等內(nèi)質(zhì)網(wǎng)定位蛋白不僅可以發(fā)揮分子伴侶作用,還可定位于細(xì)胞胞液、細(xì)胞外,參與細(xì)胞的增殖、遷移及惡性疾病如腫瘤的發(fā)生發(fā)展。Reticulocalbin 1(RCN1)具有鈣離子結(jié)合蛋白的特點,是CREC家族成員之一。人源RCN1蛋白由位于染色體11p13的RCN1基因編碼,全長331個氨基酸殘基,其結(jié)構(gòu)特點是:N端是一段信號肽,由29個氨基酸殘基組成;中間區(qū)域包含6個EF-hand結(jié)構(gòu)域;在羧基末端是一段內(nèi)質(zhì)網(wǎng)駐留信號HDEL。RCN1的定位與分布:RCN1是內(nèi)質(zhì)網(wǎng)定位蛋白,但也發(fā)現(xiàn)RCN1可定位干骨內(nèi)皮細(xì)胞、前列腺癌細(xì)胞的表面,但機(jī)制不詳;而且RCN1的C端的HDEL與典型的內(nèi)質(zhì)網(wǎng)定位信號KDEL有別,因此,RCN1也可分泌至胞外。RCN1主要分布于·分泌器官,不同器官的組成細(xì)胞中RCN1的表達(dá)高低不同。RCN1的功能:RCN1功能研究不多。研究顯示,鼠源RCN1基因的純合缺失可導(dǎo)致胚胎致死;另外,分泌的RCN1可作為配體,介導(dǎo)凋亡的神經(jīng)細(xì)胞被吞噬。RCN1的表達(dá)異常與疾病、特別是腫瘤的關(guān)系引起關(guān)注,RCN1在高侵襲性的乳腺癌細(xì)胞、結(jié)直腸癌細(xì)胞、胃癌細(xì)胞、肝癌細(xì)胞中均呈高表達(dá)。而在前列腺癌中,RCN1在侵襲力較高的細(xì)胞中呈低表達(dá)�；赗CN1功能不詳,相關(guān)研究初露端倪,尚需詳盡探討。本論文首先從臨床樣本、數(shù)據(jù)庫對其表達(dá)進(jìn)行分析,并通過細(xì)胞和動物實驗初步探討了 RCN1在前列腺癌中的作用。研究結(jié)果第一部分RCN1在前列腺癌組織中高表達(dá)1.RCN1在前列腺癌組織中高表達(dá)根據(jù)腫瘤基因數(shù)據(jù)庫TCGA,oncomine已有的數(shù)據(jù)分析前列腺癌中RCN1的mRNA水平高,但是生存分析卻顯示高水平的mRNA與病人的生存率無顯著相關(guān)性。本論文分別收集了前列腺癌組織樣本11例,良性前列腺增生組織樣本15例,利用免疫組化檢測RCN1在癌組織和增生組織中的蛋白表達(dá)水平。結(jié)果發(fā)現(xiàn)前列腺癌組織中RCN1顯著高表達(dá)。為了確定RCN1是否與前列腺癌的發(fā)生有關(guān),利用免疫組化檢測周期蛋白CyclinD1,臨床樣本檢測結(jié)果顯示,CyclinD1不僅在前列腺癌組織中低表達(dá),在良性增生組織中也呈現(xiàn)低表達(dá),且與RCN1的表達(dá)無相關(guān)性。2.RCN1表達(dá)與細(xì)胞增殖無相關(guān)性細(xì)胞水平的檢測結(jié)果顯示,RCN1的表達(dá)水平在激素非依賴、侵襲性較強(qiáng)的PC3細(xì)胞中RCN1的表達(dá)最低,低于RWPE1,即前列腺正常上皮細(xì)胞。前列腺癌LNCaP細(xì)胞中RCN1表達(dá)最高,DU145細(xì)胞中RCN1表達(dá)介于PC3和LNCaP細(xì)胞之間。因此,選用RCN1低表達(dá)的PC3過表達(dá)RCN1,細(xì)胞增殖結(jié)果卻顯示過表達(dá)RCN1對細(xì)胞增殖無顯著影響。因此,RCN1可能與細(xì)胞增殖無關(guān)。第二部分下調(diào)RCN1的表達(dá)可促進(jìn)不同前列腺癌細(xì)胞凋亡或壞死性凋亡DU145和LNCaP細(xì)胞RCN1表達(dá)高,我們利用流式細(xì)胞術(shù)分析降低RCN1表達(dá)對細(xì)胞周期、細(xì)胞存活的影響。1.下調(diào)RCN1阻滯DU145細(xì)胞于S期下調(diào)RCN1可影響細(xì)胞周期。下調(diào)DU145細(xì)胞中的RCN1,發(fā)現(xiàn)細(xì)胞周期阻滯于S期。下調(diào)LNCaP細(xì)胞中的RCN1可使周期阻滯在G2/M期。檢測S期和G2/M期關(guān)鍵調(diào)控蛋白Cyclin B在前列腺癌組織和良性增生組織的表達(dá),結(jié)果顯示,前列腺癌組織中CyclinB顯著高表達(dá),且與RCN1具有一定正相關(guān)性。2.下調(diào)RCN1誘導(dǎo)DU145細(xì)胞凋亡DU145細(xì)胞中下調(diào)RCN1可以抑制細(xì)胞活力,引起細(xì)胞死亡。下調(diào)RCN1后DU145細(xì)胞凋亡現(xiàn)象明顯,Caspase-3酶活性升高,WB結(jié)果顯示PARP剪切帶明顯。Z-VAD-FMK是Caspase抑制劑,在下調(diào)RCN1后加入,可以逆轉(zhuǎn)細(xì)胞凋亡。為了進(jìn)一步驗證,將DU145細(xì)胞注入裸鼠皮下成瘤,瘤內(nèi)注射siRCN1。結(jié)果顯示,瘤內(nèi)注射siRCN1后腫瘤重量和體積顯著低于NC組。結(jié)果證明,瘤內(nèi)注射siRCN1可以下調(diào)瘤內(nèi)細(xì)胞RCN1的表達(dá),促進(jìn)腫瘤細(xì)胞凋亡。所以,下調(diào)RCN1使DU145發(fā)生細(xì)胞凋亡。3.下調(diào)RCN1促進(jìn)LNCaP細(xì)胞發(fā)生壞死性凋亡下調(diào)RCN1可引起LNCaP細(xì)胞死亡。下調(diào)RCN1后,LNCaP細(xì)胞壞死明顯。但是,Caspase-3無明顯變化,同時其底物PARP剪切無差異,Z-VAD-FMK不能逆轉(zhuǎn)下調(diào)RCN1造成的LNCaP死亡。然而,Necrostatin-1,壞死性凋亡抑制劑,可以部分逆轉(zhuǎn)LNCaP死亡。這說明下調(diào)RCN1能引起LNCaP細(xì)胞壞死性凋亡。第三部分下調(diào)RCN1引起DU145和LNCaP凋亡和壞死性凋亡的機(jī)制研究1.RCN1 下調(diào)引起內(nèi)質(zhì)網(wǎng)應(yīng)激參與細(xì)胞凋亡和壞死性凋亡(1)下調(diào)RCN1誘導(dǎo)內(nèi)質(zhì)網(wǎng)應(yīng)激下調(diào)RCN1可增強(qiáng)分子伴侶GRP78活性,同時PERK活性增強(qiáng),eIF2α活性降低,表明內(nèi)質(zhì)網(wǎng)應(yīng)激產(chǎn)生。下調(diào)RCN1可使DU145細(xì)胞CHOP被激活,誘導(dǎo)凋亡產(chǎn)生。另外,內(nèi)質(zhì)網(wǎng)應(yīng)激抑制劑4-PBA 可逆轉(zhuǎn)下調(diào)RCN1造成的DU145和LNCaP細(xì)胞死亡,說明內(nèi)質(zhì)網(wǎng)應(yīng)激參與了 RCN1下調(diào)引起的DU145細(xì)胞凋亡和LNCaP細(xì)胞的壞死性凋亡。(2)Ca2+釋放誘導(dǎo)細(xì)胞凋亡和壞死性凋亡下調(diào)RCN1后,CaMKⅡ被激活,說明胞液中的Ca2+增加。加入內(nèi)質(zhì)網(wǎng)鈣庫釋放通道受體蛋白IP3R的抑制劑XestosponginC,可以部分逆轉(zhuǎn)細(xì)胞死亡。而蘭尼堿受體RyR抑制劑Ryanodine對下調(diào)RCN1造成的細(xì)胞死亡卻無明顯逆轉(zhuǎn)作用。說明下調(diào)RCN1導(dǎo)致內(nèi)質(zhì)網(wǎng)內(nèi)Ca2+通過IP3R通道釋放到胞液中,Ca2+信號通路被激活,導(dǎo)致細(xì)胞凋亡和壞死性凋亡發(fā)生。2.PTEN參與下調(diào)RCN1誘導(dǎo)的細(xì)胞凋亡(1)PTEN參與下調(diào)RCN1誘導(dǎo)的DU145細(xì)胞凋亡通過前期實驗數(shù)據(jù)初步推測,RCN1可能更多的參與維持細(xì)胞存活,而不是促進(jìn)細(xì)胞增殖。結(jié)果證實,下調(diào)DU145細(xì)胞中的RCN1可降低AKT活性,LNCaP細(xì)胞無變化。這說明AKT通路參與了 RCN1下調(diào)誘導(dǎo)的DU145細(xì)胞的凋亡。通過遺傳學(xué)背景分析,DU145是PTEN野生型前列腺癌細(xì)胞,在DU145細(xì)胞中,下調(diào)RCN1可使PTEN活性升高,AKT活性降低。而同時下調(diào)RCN1和PTEN,DU145細(xì)胞凋亡緩解,AKT活性水平升高,說明下調(diào)RCN1影響細(xì)胞的存活是通過PTEN/AKT通路。(2)AR和TP53可能參與下調(diào)RCN1誘導(dǎo)的LNCaP細(xì)胞壞死性凋亡雄激素依賴的LNCaP癌細(xì)胞,其增殖很大程度上依賴于雄激素/雄激素受體(AR),但實驗結(jié)果證明,下調(diào)AR,RCN1略有變化,說明其可能參與介導(dǎo)RCN1下調(diào)引起的LNCaP死亡。LNCaP中TP53可以發(fā)揮正常功能,下調(diào)RCN1,TP53表達(dá)略有降低,說明AR和TP53可能參與了下調(diào)RCN1誘導(dǎo)的LNCaP細(xì)胞壞死性凋亡過程。結(jié)論:1.前列腺癌組織中RCN1顯著高表達(dá),但與病人生存率無相關(guān)性。周期蛋白Cyclin D1表達(dá)水平較低,與RCN1無顯著相關(guān)性。過表達(dá)RCN1對細(xì)胞增殖無顯著影響。2.下調(diào)RCN1后,DU145阻滯于S期,誘導(dǎo)DU145細(xì)胞凋亡。DU145裸鼠實驗同樣表明,在體內(nèi)干擾RCN1也可以促進(jìn)細(xì)胞凋亡。3.下調(diào)RCN1可引起前列腺癌LNCaP細(xì)胞發(fā)生細(xì)胞壞死性凋亡。4.下調(diào)RCN1引起的細(xì)胞凋亡和壞死性凋亡均依賴于內(nèi)質(zhì)網(wǎng)應(yīng)激以及Ca2+釋放。但不同的是,下調(diào)RCN1激活了 DU145細(xì)胞內(nèi)的PTEN,抑制AKT活性,細(xì)胞凋亡產(chǎn)生。而AR和TP53可能參與了下調(diào)RCN1引起的LNCaP細(xì)胞的壞死性凋亡。創(chuàng)新點與不足之處1.創(chuàng)新點(1)首次報道內(nèi)質(zhì)網(wǎng)蛋白Reticulocalbin-1(RCN1)在前列腺癌組織中高表達(dá),并通過腫瘤基因數(shù)據(jù)庫分析RCN1表達(dá)水平與病人生存率無顯著相關(guān)性。(2)首次報道RCN1可能參與調(diào)控細(xì)胞周期,但對TP53野生的LNCaP細(xì)胞作用并不顯著;且與促進(jìn)細(xì)胞增殖相比,RCN1可能更多的參與維持細(xì)胞存活。(3)首次報道RCN1下調(diào)可通過內(nèi)質(zhì)網(wǎng)應(yīng)激、CaMKⅡ的活化、PTEN活化、抑制AKT活性參與DU145細(xì)胞凋亡。對TP53野生的LNCaP細(xì)胞,下調(diào)RCN1可通過內(nèi)質(zhì)網(wǎng)應(yīng)激、CaMKⅡ的活化調(diào)控誘導(dǎo)LNCaP細(xì)胞壞死性凋亡。2.不足(1)文獻(xiàn)報道,CaMKⅡ活化可介導(dǎo)壞死性凋亡,因此本論文中對于LNCaP的壞死性凋亡并未做過多研究。(2)本論文只探討了與細(xì)胞增殖、存活相關(guān)的AKT信號通路,而與細(xì)胞增殖相關(guān)的ERK通路是否也參與了 RCN1的作用需要進(jìn)一步探討和討論。
[Abstract]:Background endoplasmic reticulum (endoplasmic reticulum) is an important cell organelle, which is extremely important in protein folding, quality control, and calcium homeostasis. It directly participates in and affects the various life activities of the cells. The various localization proteins of the endoplasmic reticulum, such as molecular chaperones, enzymes, etc., are processed, folded, and helped to help the protein peptide chain. The formation of specific space conformation and directional transport of.Ca2+ binding proteins, two sulfur bond isomerase and other endoplasmic reticulum localizing proteins can not only play the role of molecular chaperone, but also be located in cell fluid, extracellular, cell proliferation, migration and malignant diseases such as the occurrence of tumor development.Reticulocalbin 1 (RCN1) with calcium binding protein It is one of the members of the CREC family. The human RCN1 protein is encoded by the RCN1 gene located on the chromosome 11p13 and has a full length of 331 amino acid residues. The structure of the protein is that the N end is a signal peptide and consists of 29 amino acid residues; the middle region contains 6 EF-hand domains; the end of the carboxyl group is the localization of a segment of the endoplasmic reticulum signal HDEL.RCN1. And distribution: RCN1 is a endoplasmic reticulum localizing protein, but it is also found that RCN1 can locate the stem bone endothelial cells, the surface of the prostate cancer cells, but the mechanism of the HDEL at the C end of RCN1 is different from the typical endoplasmic reticulum location signal KDEL, so RCN1 can also be secreted to the extracellular.RCN1, mainly distributed in the secretory organs, and RCN1 in the constituent cells of different organs. The function of high and low.RCN1 is expressed as the function of the RCN1 function. The study shows that the homozygous deletion of the mouse RCN1 gene can lead to the death of the embryo; in addition, the secreted RCN1 can be used as a ligand to mediate the abnormal expression of the apoptotic neurons by phagocytic.RCN1 and the relationship between the disease, especially the tumor, and RCN1 in highly invasive breast cancer cells, Colorectal cancer cells, gastric cancer cells and hepatoma cells are highly expressed. In the prostate cancer, RCN1 is low in the aggressive cells. Based on the unknown RCN1 function, the related research has been revealed. This paper first analyzed the expression from the clinical samples, and through the initial cell and animal experiments. The role of RCN1 in prostate cancer is discussed. Part 1, the high expression of RCN1 in prostate cancer tissue is high in prostate cancer tissue based on the tumor gene database TCGA, and oncomine has been used to analyze the high mRNA level of RCN1 in prostate cancer, but the survival analysis shows the high level of mRNA and the patients in the prostate cancer. There was no significant correlation between survival rate and survival rate. 11 samples of prostate cancer tissue and 15 samples of benign prostatic hyperplasia were collected in this paper. The protein expression levels of RCN1 in cancer tissues and proliferative tissues were detected by immunohistochemistry. The results showed that RCN1 was significantly high in prostate cancer tissue. To determine whether RCN1 was associated with prostate cancer. The results of detection of cyclin CyclinD1 by immunohistochemistry showed that CyclinD1 not only expressed low expression in the prostate cancer tissue, but also showed low expression in benign hyperplasia tissue, and there was no correlation between the expression of.2.RCN1 expression and cell proliferation without correlation with RCN1 expression, and the expression of RCN1 expressed water. The expression of RCN1 is the lowest in PC3 cells with strong invasiveness, which is lower than RWPE1, that is, normal prostate epithelial cells. The expression of RCN1 in prostate cancer LNCaP cells is the highest, and the expression of RCN1 in DU145 cells is between PC3 and LNCaP cells. Therefore, PC3 overexpression RCN1 is used for RCN1 low expression, but the cell proliferation results show excessive expression. There is no significant effect on cell proliferation. Therefore, RCN1 may not be related to cell proliferation. Second down regulation of RCN1 expression can promote the apoptosis of different prostate cancer cells or necrotic apoptosis of DU145 and LNCaP cells, RCN1 expression is high. We use flow cytometry to reduce RCN1 expression to cell cycle, cell survival effect.1. down RCN1 block DU1 The down-regulation of RCN1 in the S phase of 45 cells could affect the cell cycle. Down regulation of RCN1 in DU145 cells, the cell cycle was blocked at S stage. The RCN1 in the down-regulation of LNCaP cells could block the cycle at G2/M stage. The expression of Cyclin B in the prostate cancer tissue and benign hyperplasia tissues was detected in S and G2/M phase. The results showed that the prostate cancer tissues were expressed. The expression of inB was significantly higher, and it had a positive correlation with RCN1..2. down regulated the apoptosis of DU145 cells induced by RCN1. The downregulation of RCN1 could inhibit cell viability and cause cell death. The apoptotic phenomenon of DU145 cells was obvious, the Caspase-3 enzyme activity increased after the downregulation of RCN1. WB results showed that the PARP shear zone was obviously a inhibitor. The addition of N1 could reverse the apoptosis of cells. In order to further verify, the DU145 cells were injected into the nude mice subcutaneously into a tumor. The results of intratumoral injection of siRCN1. showed that the weight and volume of the tumor were significantly lower than that of the NC group. The results showed that the intra tumor injection of siRCN1 could downregulate the expression of RCN1 in the tumor cells and promote the apoptosis of the tumor cells. So, down regulation of RC. N1 makes DU145 apoptosis.3. down-regulation and RCN1 promotes necrotizing apoptosis of LNCaP cells and leads to LNCaP cell death. The LNCaP cell necrosis is obvious after RCN1 down regulation. However, Caspase-3 does not change obviously, and its substrate PARP shear no difference, Z-VAD-FMK can not reverse the death caused by the downward adjustment. The inhibitor of death apoptosis can partly reverse LNCaP death. This indicates that down regulation of RCN1 can cause necrotic apoptosis of LNCaP cells. Third the mechanism of down regulation of RCN1 induced apoptosis and necrotic apoptosis of DU145 and LNCaP, 1.RCN1 downregulation causes endoplasmic reticulum stress to participate in cell apoptosis and necrotic death (1) down regulation of RCN1 induced endoplasmic reticulum stress down regulation N1 enhanced the activity of molecular chaperone GRP78, while PERK activity increased and eIF2 alpha activity decreased, indicating that endoplasmic reticulum stress was produced. Down regulation of RCN1 could activate CHOP in DU145 cells and induce apoptosis. In addition, endoplasmic reticulum stress inhibitor 4-PBA can reverse DU145 and LNCaP cell death caused by RCN1, indicating that endoplasmic reticulum stress is involved in RCN1 down. Induced apoptosis of DU145 cells and necrotic apoptosis of LNCaP cells. (2) after Ca2+ release induced apoptosis and necrotic apoptosis, CaMK II was activated to indicate an increase in Ca2+ in the cytoplasm. XestosponginC, a inhibitor of the receptor protein IP3R added to the endoplasmic reticulum calcium pool, could partly reverse the cell death. The preparation of Ryanodine has no obvious reversal effect on the cell death caused by the downregulation of RCN1. It is suggested that the down-regulation of RCN1 leads to the release of Ca2+ in the endoplasmic reticulum through the IP3R channel to the cytoplasm, and the Ca2+ signaling pathway is activated, leading to the apoptosis and necrotic apoptosis of the.2.PTEN involved in the down-regulation of RCN1 induced apoptosis (1) PTEN involved in DU145 fine RCN1 induced RCN1 Apoptosis was preliminarily hypothesized that RCN1 might be more involved in maintaining cell survival, rather than promoting cell proliferation. The results showed that the downregulation of RCN1 in DU145 cells could reduce AKT activity and LNCaP cells were not changed. This indicates that the AKT pathway participates in the apoptosis of DU145 cells induced by RCN1 downregulation. By genetic background analysis, DU145 It is a PTEN wild type prostate cancer cell. In DU145 cells, the downregulation of RCN1 can increase the activity of PTEN and decrease the activity of AKT. While down regulation of RCN1 and PTEN, the apoptosis of DU145 cells is relieved and the level of AKT activity increases. It shows that the down regulation of RCN1 affects the survival of cells through PTEN/AKT pathway. (2) AR and may participate in the necrosis induced cell necrosis induced by down regulation. The proliferation of androgen dependent LNCaP cells depends largely on androgen / androgen receptor (AR), but the experimental results show that the downregulation of AR and RCN1 changes slightly, indicating that it may participate in the LNCaP death induced by RCN1 down.LNCaP and TP53 can play normal work energy, down RCN1, TP53 expression a slight decrease, indicating AR and TP53. Can participate in the necrosis of apoptosis induced by RCN1 induced LNCaP cells. Conclusion: 1. the expression of RCN1 in the prostate cancer tissues is highly expressed, but there is no correlation with the survival rate of the patients. The expression level of cyclin Cyclin D1 is low, and there is no significant correlation with RCN1. The overexpression of RCN1 has no significant effect on the proliferation of.2. in.2., and DU145 is blocked in S stage. The apoptosis of DU145 cells in nude mice also showed that the interference of RCN1 in vivo could also promote apoptosis and.3. down regulation of RCN1, which could induce apoptosis and apoptosis of LNCaP cells in prostate cancer cells,.4. down regulation and necrotizing apoptosis were dependent on endoplasmic reticulum stress and Ca2+ release. However, down regulated RCN1 activates D. PTEN in U145 cells inhibit AKT activity and apoptosis, and AR and TP53 may be involved in necrotizing apoptosis of LNCaP cells induced by RCN1. Innovation and deficiency 1. innovation point (1) first reported the high expression of endoplasmic reticulum Reticulocalbin-1 (RCN1) in prostate cancer tissue, and the expression of RCN1 expression through a tumor gene database There was no significant correlation between the level and the survival rate of patients. (2) it was reported that RCN1 might participate in the regulation of cell cycle for the first time, but it did not play a significant role in the TP53 wild LNCaP cells; and RCN1 may be more involved in maintaining cell survival compared with the promotion of cell proliferation. (3) it is the first time to report that RCN1 can be regulated by endoplasmic reticulum stress, activation of CaMK II, activation of PTEN, and inhibition. AKT activity is involved in DU145 cell apoptosis. Down regulation of RCN1 in TP53 wild LNCaP cells can be regulated by endoplasmic reticulum stress, and CaMK II activation induces necrotizing apoptosis of LNCaP cells (1), and CaMK II activation can mediate necrotic apoptosis. Therefore, the necrotic apoptosis of LNCaP has not been much studied in this paper. (2) this paper The AKT signaling pathway related to cell proliferation and survival is discussed only, and whether the ERK pathway associated with cell proliferation is also involved in the role of RCN1 needs further discussion and discussion.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.25

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