【摘要】：ALEX/ARMCX(Arm proteins lost in epithelial cancers on chromosome X)蛋白是Arm蛋白家族的成員之一,因只具有一或二個(gè)Arm repeat結(jié)構(gòu),不同于經(jīng)典Arm蛋白具有的6-13個(gè)Arm repeat結(jié)構(gòu),而被單獨(dú)列為ALEX蛋白家族。其家族成員包括ALEX1、ALEX2和ALEX3�；虮磉_(dá)分析顯示ALEX1 mRNA在人類多種正常組織中高表達(dá)而在上皮組織來(lái)源的癌組織低表達(dá)或不表達(dá)。ALEX1基因受CREB和Wnt/p-catenin通路調(diào)節(jié)并能夠抑制人直腸癌細(xì)胞的克隆形成。這些研究表明ALEX1很可能在上皮來(lái)源的腫瘤中發(fā)揮抑癌作用。目前,ALEX1在乳腺癌中的表達(dá)及其作用和機(jī)制仍不清楚,故本論文主要研究ALEX1在乳腺癌組織標(biāo)本中的表達(dá)水平及對(duì)乳腺癌細(xì)胞增殖、細(xì)胞周期、細(xì)胞凋亡和侵襲轉(zhuǎn)移等方面的影響及其分子機(jī)制。第一部分：ALEX1在乳腺標(biāo)本中的表達(dá)分析目的：檢測(cè)乳腺癌組織及對(duì)應(yīng)癌旁組織中的ALEX1表達(dá)水平,比較兩者之間的表達(dá)是否存在差異,明確ALEX1與臨床病理特征是否具有相關(guān)性。方法：應(yīng)用real-time PCR、免疫組化及western blot方法檢測(cè)乳腺癌組織及其對(duì)應(yīng)的癌旁組織中ALEX1 mRNA和蛋白表達(dá)水平,統(tǒng)計(jì)分析免疫組化檢測(cè)的ALEX1的表達(dá)量與病人年齡、腫瘤大小、腫瘤病理分級(jí)、臨床分期、淋巴結(jié)轉(zhuǎn)移和分子分型之間的關(guān)系。結(jié)果：對(duì)62對(duì)乳腺癌及對(duì)應(yīng)癌旁臨床組織標(biāo)本進(jìn)行免疫組化染色,結(jié)果顯示：ALEX1表達(dá)主要定位于胞漿。統(tǒng)計(jì)分析表明：乳腺癌組織ALEX1蛋白的表達(dá)水平低于乳腺癌旁組織中的表達(dá)(p0.01)；進(jìn)一步對(duì)ALEX1的染色評(píng)分與乳腺癌患者臨床病理特征之間的關(guān)系進(jìn)行分析,發(fā)現(xiàn)乳腺癌中ALEX1的表達(dá)與病理分級(jí)(1 vs.3,p=0.026; 2 vs.3,p=0.045),臨床分期(I vs.Ⅲ,p=0.008;Ⅱ vs.Ⅲ, p=0.011),淋巴結(jié)轉(zhuǎn)移(p=0.03)和分子分型(Luminal A型vs. HER-2過(guò)表達(dá)型,p=0.02)有關(guān),而與病人年齡、腫瘤大小和腫瘤類型無(wú)關(guān)(p0.05)。此外,隨機(jī)抽取30對(duì)乳腺癌與癌旁組織利用real-time PCR進(jìn)行檢測(cè),發(fā)現(xiàn)20例乳腺癌組織中ALEX1 mRNA的表達(dá)明顯低于對(duì)應(yīng)的癌旁組織中的表達(dá)(p0.01)；隨機(jī)抽取6對(duì)乳腺癌與癌旁組織采用western blot對(duì)ALEX1蛋白進(jìn)行檢測(cè),結(jié)果顯示：乳腺癌組織ALEX1蛋白表達(dá)水平均低于對(duì)應(yīng)的癌旁組織中的蛋白表達(dá)。結(jié)論：本研究發(fā)現(xiàn)ALEX1在乳腺癌組織中的表達(dá)明顯低于相應(yīng)的癌旁組織,乳腺癌的病理分級(jí)、臨床分期越高,ALEX1的表達(dá)水平越低；在有淋巴結(jié)轉(zhuǎn)移的乳腺癌組織中ALEX1表達(dá)水平明顯低于無(wú)淋巴結(jié)轉(zhuǎn)移的乳腺癌組織,而且在乳腺癌的分子分型中乳腺癌HER-2過(guò)表達(dá)型組織中ALEX1的表達(dá)水平低于Luminal A型。第二部分：ALEXl對(duì)乳腺癌細(xì)胞增殖、細(xì)胞周期及凋亡的影響目的：研究過(guò)表達(dá)／沉默ALEX1對(duì)乳腺癌細(xì)胞SK-BR3/MCF-7增殖、周期和凋亡的影響。方法：Real-time PCR和western blot方法檢測(cè)ALEX1在正常乳腺細(xì)胞MCF-10A和乳腺癌細(xì)胞MCF-7、T47D、SK-BR3、MDA-MB-231中表達(dá)情況,免疫熒光細(xì)胞化學(xué)技術(shù)檢測(cè)ALEX1亞細(xì)胞定位。過(guò)表達(dá)ALEX1慢病毒感染乳腺癌細(xì)胞SK-BR3后,熒光顯微鏡觀察重組慢病毒　LV5-ALEX1的感染效率,real-time PCR和western blot方法檢測(cè)ALEX1 mRNA和蛋白表達(dá)水平。利用合成的三條RNAi序列瞬時(shí)轉(zhuǎn)染MCF-7后,用real-time PCR和western blot方法檢測(cè)ALEX1 mRNA和蛋白表達(dá)情況。過(guò)表達(dá)／沉默ALEX1后CCK8(Cell Counting Kit)檢測(cè)細(xì)胞增殖能力,流式細(xì)胞術(shù)檢測(cè)細(xì)胞周期和凋亡情況。結(jié)果：Real-time PCR和western blot結(jié)果顯示：在乳腺癌各細(xì)胞株中ALEX1的表達(dá)水平均低于正常乳腺細(xì)胞MCF-10A,但ALEX1在MCF-7細(xì)胞株中表達(dá)水平高于其他乳腺癌細(xì)胞株,在SK-BR3中表達(dá)水平最低且ALEX1蛋白定位于胞漿中。過(guò)表達(dá)ALEX1慢病毒感染乳腺癌細(xì)胞SK-BR3 72h后,熒光顯微鏡觀察感染效率達(dá)90%以上；與對(duì)照組LV5-NC (LV5-Negative Control)相比,實(shí)驗(yàn)組LV5-ALEX1中ALEX1 mRNA和蛋白的表達(dá)明顯增高。CCK8結(jié)果顯示：LV5-ALEX1組感染LV5-ALEX1慢病毒48 h到96 h SK-BR3細(xì)胞生長(zhǎng)明顯受到抑制(p0.05)。Hoechst染色和流式細(xì)胞術(shù)結(jié)果顯示LV5-ALEX1組凋亡細(xì)胞數(shù)量多于LV5-NC (p0.05)。利用小RNA干擾技術(shù)瞬時(shí)轉(zhuǎn)染MCF-7細(xì)胞48 h后,real-time PCR和western blot結(jié)果顯示三條RNAi序列中其中RNAi-2序列沉默ALEX1效果明顯,選擇作為后續(xù)實(shí)驗(yàn)。實(shí)驗(yàn)分兩組：實(shí)驗(yàn)組SiALEX1和陰性對(duì)照組SiCon。CCK8結(jié)果顯示：轉(zhuǎn)染SiALEX148 h到96 h,MCF-7細(xì)胞生長(zhǎng)強(qiáng)于陰性對(duì)照組SiCon(p0.05)。Hoechst染色和流式細(xì)胞術(shù)結(jié)果顯示：MCF-7細(xì)胞中SiALEX1組的凋亡細(xì)胞數(shù)量少于SiCon組(p0.05)。流式細(xì)胞儀檢測(cè)細(xì)胞周期分布結(jié)果顯示：過(guò)表達(dá)／沉默ALEX1對(duì)乳腺癌細(xì)胞周期變化均沒有影響。結(jié)論：過(guò)表達(dá)ALEX1抑制乳腺癌SK-BR3細(xì)胞的增殖,誘導(dǎo)細(xì)胞凋亡；沉默ALEX1促進(jìn)乳腺癌MCF-7細(xì)胞的增殖,抑制細(xì)胞凋亡。第三部分：ALEX1誘導(dǎo)乳腺癌細(xì)胞凋亡的機(jī)制目的：深入研究ALEX1誘導(dǎo)乳腺癌細(xì)胞凋亡的分子機(jī)制。方法：Western blot方法檢測(cè)過(guò)表達(dá)／沉默ALEX1乳腺癌細(xì)胞中凋亡相關(guān)蛋白的表達(dá)情況。利用生物信息學(xué)方法預(yù)測(cè)調(diào)控ALEX1的miRNAs。Western blot方法和雙熒光素酶報(bào)告實(shí)驗(yàn)驗(yàn)證miR-590-5p調(diào)控ALEX1。然后分別以MCF-7和SK-BR3乳腺癌細(xì)胞為實(shí)驗(yàn)?zāi)Ｐ?在MCF-7細(xì)胞中將實(shí)驗(yàn)分為NC mimics組和miR-590-5P mimics組;SK-BR3細(xì)胞中分為NC inhibitor組和miR-590-5P inhibitor組,利用western blot方法檢測(cè)ALEX1及凋亡相關(guān)蛋白表達(dá)情況。接下來(lái),我們利用“功能回復(fù)實(shí)驗(yàn)”在MCF-7細(xì)胞中將實(shí)驗(yàn)分為NCmimics+GV230-NC組、GV230-NC+miR-590-5P mimics組、NC mimics+GV230-ALEX1和miR-590-5P mimics+GV230-ALEX1組；在SK-BR3細(xì)胞中分為NC inhibitor+SiCon組、SiCon+miR-590-5P inhibitor組、NC inhibitor+SiALEX1和miR-590-5P inhibitor+SiALEX1組,進(jìn)一步明確ALEX1受miR-590-5P調(diào)控誘導(dǎo)乳腺癌細(xì)胞凋亡。結(jié)果：Western blot結(jié)果顯示：SK-BR3細(xì)胞中過(guò)表達(dá)ALEX1后,上調(diào)Bax、active caspase 9和active caspase 3蛋白表達(dá),下調(diào)Bcl-2蛋白表達(dá)。MCF-7細(xì)胞中沉默ALEX1后,下調(diào)Bax、active caspase 9和active caspase 3蛋白表達(dá),上調(diào)Bcl-2蛋白表達(dá)。Western blot方法和雙熒光素酶報(bào)告實(shí)驗(yàn)驗(yàn)證結(jié)果顯示：miR-590-5p與ALEX1 3'-UTR結(jié)合調(diào)控ALEX1mRNA和蛋白水平的表達(dá)。在MCF-7細(xì)胞中與NC mimics組相比,miR-590-5p mimics組中,ALEX1、Bax、active caspase 9和active caspase 3蛋白表達(dá)下調(diào),Bcl-2蛋白表達(dá)上調(diào)。SK-BR3細(xì)胞中miR-590-5P inhibitor組與NC inhibitor對(duì)照組相比,ALEX1、Bax. active caspase 9和active caspase 3蛋白表達(dá)上調(diào),Bcl-2蛋白表達(dá)下調(diào)。功能回復(fù)實(shí)驗(yàn)中顯示外源性補(bǔ)充／沉默ALEX1能夠逆轉(zhuǎn)上述各凋亡蛋白的表達(dá)水平。結(jié)論：過(guò)表達(dá)ALEX1通過(guò)內(nèi)源性凋亡通路誘導(dǎo)SK-BR3細(xì)胞凋亡;沉默ALEX1通過(guò)內(nèi)源性凋亡通路抑制MCF-7細(xì)胞凋亡。ALEX1是miR-590-5P新的靶基因。ALEX1受miR-590-5P調(diào)控通過(guò)內(nèi)源性凋亡通路誘導(dǎo)乳腺癌細(xì)胞發(fā)生凋亡。第四部分：ALEX1在乳腺癌細(xì)胞上皮間質(zhì)轉(zhuǎn)化中作用機(jī)制的初探目的：初步探明ALEX1在乳腺癌細(xì)胞上皮間質(zhì)轉(zhuǎn)化過(guò)程中的作用機(jī)制。方法：在乳腺癌細(xì)胞MDA-MB-231/MCF-7中過(guò)表達(dá)／沉默ALEX1后,顯微鏡觀察細(xì)胞形態(tài)變化；細(xì)胞劃痕愈合和Transwell實(shí)驗(yàn)檢測(cè)乳腺癌細(xì)胞遷移侵襲能力；western blot檢測(cè)上皮間質(zhì)標(biāo)志物的表達(dá)情況。結(jié)果：乳腺癌MDA-MB-231細(xì)胞中過(guò)表達(dá)ALEX1后,細(xì)胞形態(tài)由長(zhǎng)梭形變?yōu)槎噙呅�；�?xì)胞劃痕實(shí)驗(yàn)結(jié)果顯示：實(shí)驗(yàn)組遷移距離明顯小于LV5-NC對(duì)照組；Transwell結(jié)果顯示：細(xì)胞穿膜數(shù)量明顯少于對(duì)照組；western blot結(jié)果顯示：實(shí)驗(yàn)組中間質(zhì)類型標(biāo)志物N-cadherin和Vimentin的表達(dá)消失,Snail-1、Slug未見明顯變化,Twist表達(dá)水平降低；上皮類型標(biāo)志物E-cadherin的表達(dá)水平升高。乳腺癌MCF-7細(xì)胞中沉默ALEX1后,細(xì)胞形態(tài)由扁圓形變?yōu)樯斐鰝巫愕亩噙呅�；�?xì)胞劃痕愈合實(shí)驗(yàn)結(jié)果顯示：實(shí)驗(yàn)組遷移距離明顯大于SiCon對(duì)照組；Transwell結(jié)果顯示：細(xì)胞穿膜數(shù)量明顯多于對(duì)照組,western blot結(jié)果顯示：實(shí)驗(yàn)組中上皮類型標(biāo)志物E-cadherin的表達(dá)消失,間質(zhì)類型標(biāo)志物N-cadherin、Vimentin和Twist表達(dá)水平升高,Snail-1和Slug表達(dá)未見明顯變化。結(jié)論：過(guò)表達(dá)ALEX1能夠減弱MDA-MB-231侵襲遷移能力,誘導(dǎo)MDA-MB-231由間質(zhì)細(xì)胞向上皮細(xì)胞轉(zhuǎn)化；沉默ALEX1能夠增強(qiáng)MCF-7侵襲遷移能力,誘導(dǎo)MCF-7由上皮細(xì)胞向間質(zhì)細(xì)胞轉(zhuǎn)化。我們推測(cè)ALEX1的低表達(dá)或缺失很可能引起Twist轉(zhuǎn)錄因子的表達(dá)上調(diào),進(jìn)而引起E-cad等上皮標(biāo)志物的表達(dá)的下調(diào)和間質(zhì)類型標(biāo)志物N-cad和Vimentin的表達(dá)的上調(diào),導(dǎo)致細(xì)胞發(fā)生EMT。
[Abstract]:ALEX/ARMCX (Arm proteins lost in epithelial cancers on chromosome X) is one of the members of the Arm protein family. It has only one or two Arm repeat structures, which is different from the 6-13 Arm repeat structures of classical Arm proteins. Its family members include ALEX1, ALEX2 and ALEX3. Gene expression analysis ALEX1 gene is regulated by CREB and Wnt/p-catenin pathway and can inhibit the cloning of human rectal cancer cells. These studies suggest that ALEX1 may play an inhibitory role in epithelial tumors. The expression and mechanism of ALEX1 in breast cancer are still unclear, so this paper mainly studies the expression level of ALEX1 in breast cancer tissue specimens and its effects on proliferation, cell cycle, apoptosis, invasion and metastasis of breast cancer cells and its molecular mechanism. The expression level of ALEX1 in breast cancer tissues and adjacent tissues was measured, and the expression difference between the two tissues was compared to determine the correlation between ALEX1 and clinicopathological features.Methods: The expression of ALEX1 mRNA and protein in breast cancer tissues and adjacent tissues were detected by real-time PCR, immunohistochemistry and Western blot. Results: Immunohistochemical staining of 62 pairs of breast cancer and adjacent clinical tissues showed that the expression of ALEX1 was mainly localized in cytoplasm. Statistical analysis showed that the expression level of ALEX1 protein in breast cancer tissue was lower than that in adjacent tissues (p0.01); furthermore, the relationship between the staining score of ALEX1 and the clinicopathological characteristics of breast cancer patients was analyzed. It was found that the expression of ALEX1 in breast cancer was related to the pathological grade (1 vs. 3, P = 0.026; 2 vs. 3, P = 0.045), clinical stage (I). Vs. III, P = 0.008; II vs. III, P = 0.011; lymph node metastasis (p = 0.03) and molecular typing (Luminal A vs. HER-2 overexpression, P = 0.02), but not related to patient's age, tumor size and tumor type (p0.05). In addition, 30 randomly selected breast cancer and adjacent tissues were detected by real-time PCR. ALEX 1m was found in 20 breast cancer tissues. The expression of ALEX1 protein in breast cancer and adjacent tissues was significantly lower than that in corresponding adjacent tissues (p0.01). Six pairs of breast cancer and adjacent tissues were randomly selected and detected by Western blot. The results showed that the expression of ALEX1 protein in breast cancer tissues was lower than that in corresponding adjacent tissues. The expression of ALEX1 in breast cancer tissues with lymph node metastasis was significantly lower than that in breast cancer tissues without lymph node metastasis. The expression of ALEX1 in breast cancer tissues with lymph node metastasis was significantly lower than that in breast cancer tissues without lymph node metastasis. The expression of ALEX1 in breast cancer cells was lower than that in Luminal A. Part II: Effects of ALEXl on proliferation, cell cycle and apoptosis of breast cancer cells Objective: To investigate the effects of overexpression/silencing of ALEX1 on proliferation, cycle and apoptosis of breast cancer cells SK-BR3/MCF-7. Methods: Real-time PCR and Western blot were used to detect the expression of ALEX1 in normal breast cells MCF-10A. The expression of MCF-7, T47D, SK-BR3, MDA-MB-231 in breast cancer cells and the subcellular localization of ALEX1 were detected by immunofluorescence cytochemistry. The expression of ALEX1 mRNA and protein was detected by real-time PCR and Western blot after transfection of MCF-7 with three synthetic RNAi sequences. Cell Counting Kit (CCK8) was detected after overexpression/silencing of ALEX1. Cell cycle and apoptosis were detected by flow cytometry. The results showed that the expression level of ALEX1 in breast cancer cell lines was lower than that in normal breast cell line MCF-10A, but the expression level of ALEX1 in MCF-7 cell line was higher than that in other breast cancer cell lines. The expression level of ALEX1 in SK-BR3 was the lowest and ALEX1 protein was localized in the cytoplasm. Compared with LV5-Negative Control, the expression of ALEX1 mRNA and protein in LV5-ALEX1 increased significantly. CCK8 results showed that the growth of SK-BR3 cells infected with LV5-ALEX1 lentivirus from 48 h to 96 h was inhibited significantly in LV5-ALEX1 group (p0.05). Hoechst staining and flow cytometry results The number of apoptotic cells in LV5-ALEX1 group was more than that in LV5-NC group (p0.05). After 48 hours of transient transfection of MCF-7 cells with small RNA interference, real-time PCR and Western blot results showed that the silencing effect of ALEX1 in three RNAi sequences was obvious. The experiment was divided into two groups: experimental group SiALEX1 and negative control group SiCon.CCK. The results of Hoechst staining and flow cytometry showed that the number of apoptotic cells in the SiALEX1 group was less than that in the SiCon group (p0.05). The results of flow cytometry showed that the cell cycle distribution in the over-expression/silencing ALEX1 group was fine for breast cancer. Conclusion: Overexpression of ALEX1 inhibits proliferation and induces apoptosis of breast cancer SK-BR3 cells; silencing of ALEX1 promotes proliferation and inhibits apoptosis of breast cancer MCF-7 cells. Part III: Mechanism of ALEX1-induced apoptosis of breast cancer cells Objective: To investigate the molecular mechanism of ALEX1-induced apoptosis of breast cancer cells. Methods: Western blot was used to detect the expression of apoptosis-related proteins in over-expressed/silenced ALEX1 breast cancer cells. Bioinformatics methods were used to predict the regulation of ALEX1 by microRNAs. Western blot and double luciferase reporter assays were used to verify the regulation of ALEX1 by microRNAs-590-5p. Then MCF-7 and SK-BR3 breast cancer cells were used as experimental models respectively. SK-BR3 cells were divided into NC inhibitor group and MIC-590-5P inhibitor group, and ALEX1 and apoptosis-related proteins were detected by Western blot. Next, we divided the experiment into NC MICs + GV230-NC by functional recovery test in MCF-7 cells. Groups GV230-NC+Mi-590-5P mics, NC mimics+GV230-ALEX1 and Mi-590-5P mics+GV230-ALEX1 were divided into NC inhibitor+SiCon group, SiCon+Mi-590-5P inhibitor group, NC inhibitor+SiALEX1 and Mi-590-5P inhibitor+SiALEX1 groups. Western blot analysis showed that after overexpression of ALEX1 in SK-BR3 cells, the expression of Bax, active caspase 9 and active caspase 3 was up-regulated, and the expression of Bcl-2 protein was down-regulated. After silencing ALEX1 in MCF-7 cells, the expression of Bax, active caspase 9 and active caspase 3 was down-regulated, and the expression of Bcl-2 protein was up-regulated. Compared with NC mimics, the expression of ALEX1, Bax, active caspase 9, and active caspase 3 proteins were down-regulated and the expression of Bcl-2 protein was up-regulated in MFC-7 cells and NC inhibiibited cells. Compared with tor control group, the expression of ALEX1, Bax. active caspase 9 and active caspase 3 protein was up-regulated, while the expression of Bcl-2 protein was down-regulated. Inhibiting apoptosis of MCF-7 cells via endogenous apoptosis pathway. ALEX1 is a novel target gene for microarray-590-5P. ALEX1 is regulated by microarray-590-5P and induces apoptosis of breast cancer cells through endogenous apoptosis pathway. Part IV: The role of ALEX1 in epithelial-mesenchymal transformation of breast cancer cells: Preliminary exploration of the mechanism of ALEX1 in breast cancer cells Methods: After overexpression or silencing of ALEX1 in breast cancer cells MDA-MB-231/MCF-7, the morphological changes of cells were observed under microscope; the ability of breast cancer cells to migrate and invade was detected by scratch healing and Transwell assay; and the expression of epithelial-mesenchymal markers was detected by Western blot. After overexpression of ALEX1 in MDA-MB-231 cells, the morphology of cells changed from long shuttle to polygon; the results of cell scratch test showed that the migration distance of experimental group was significantly smaller than that of LV5-NC control group; Transwell results showed that the number of cell membrane penetration was significantly less than that of control group; Western blot results showed that the type of intermediate marker N-cadhe in experimental group. The expression of RIN and Vimentin disappeared, the expression of Snail-1 and Slug did not change significantly, but the expression of Twist decreased. The expression of E-cadherin, a marker of epithelial type, increased. Transwell results showed that the number of cell membrane penetration was significantly higher than that of the control group. Western blot results showed that the expression of E-cadherin, N-cadherin, Vimentin and Twist, the expression of Snail-1 and Slug, the epithelial markers, disappeared, and the expression of N-cadherin, Vimentin and Twist, increased in the experimental group. ALEX1 can attenuate the invasion and migration of MDA-MB-231, induce MDA-MB-231 to transform from mesenchymal cells to epithelial cells; silencing ALEX1 can enhance the invasion and migration of MCF-7, and induce MCF-7 to transform from epithelial cells to mesenchymal cells. We speculate that the low expression or deletion of ALEX1 may induce the up-regulation of Twist transcription factor, and then lead to E-MB-231 transformation from mesenchymal cells. The down-regulation of epithelial markers such as CAD and the up-regulation of interstitial markers N-cad and Vimentin lead to EMT.
【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R737.9

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