本文選題：TCF21 + 抑癌基因��； 參考：《東南大學(xué)》2017年博士論文

【摘要】：第一部分TCF21基因在乳腺癌中的表達(dá)及其功能目的:檢測TCF21基因在人乳腺癌細(xì)胞和組織中的表達(dá),并分析其表達(dá)與乳腺癌臨床病理特征及預(yù)后的關(guān)系,同時觀察TCF21基因過表達(dá)對乳腺癌MDA-MB-231細(xì)胞生物學(xué)行為的影響。方法:(1)通過實時定量 PCR(real-time quantitative PCR,RT-qPCR)和蛋白免疫印跡(Westernblot)方法檢測TCF21基因在人乳腺癌細(xì)胞MDA-MB-231和MCF-7,人正常乳腺上皮細(xì)胞MCF-10A和39例術(shù)后乳腺癌組織及其癌旁正常組織中的表達(dá),并分析癌組織中TCF21 mRNA表達(dá)與臨床病理特征的關(guān)系。(2)利用生物信息軟件KM-plotter分析乳腺癌組織中TCF21 mRNA表達(dá)與預(yù)后的關(guān)系。(3)采用脂質(zhì)體介導(dǎo)法將重組質(zhì)粒pcDNA3.1-TCF21和空質(zhì)粒pcDNA3.1分別轉(zhuǎn)染至乳腺癌MDA-MB-231細(xì)胞,并運用RT-qPCR和Western blot方法檢測質(zhì)粒轉(zhuǎn)染后細(xì)胞中TCF21基因的表達(dá)情況。(4)CCK-8法和Annexin V-FITC/PI雙染色法分別被用于檢測TCF21基因過表達(dá)對乳腺癌MDA-MB-231細(xì)胞增殖和凋亡的影響。結(jié)果:(1)乳腺癌MDA-MB-231和MCF-7細(xì)胞中TCF21 mRNA和蛋白的表達(dá)水平均顯著低于正常乳腺上皮細(xì)胞MCF-10A。隨后采用同樣的方法檢測39例人乳腺癌組織及其癌旁正常組織中TCF21 mRNA的表達(dá),結(jié)果顯示TCF21 mRNA在36例乳腺癌組織中低表達(dá),在1例乳腺癌組織中表達(dá)無差異,在2例乳腺癌組織中高表達(dá)。對TCF21 mRNA低表達(dá)的乳腺癌組織進(jìn)行Western blot檢驗,發(fā)現(xiàn)TCF21蛋白在乳腺癌組織中的表達(dá)水平也顯著低于癌旁正常組織,與mRNA檢測結(jié)果一致。通過進(jìn)一步分析乳腺癌組織中TCF21 mRNA表達(dá)水平與臨床病理特征的關(guān)系,我們發(fā)現(xiàn)TCF21 mRNA表達(dá)水平與患者年齡、TNM分期、腫瘤分化程度、ER、PR及HER2的表達(dá)無關(guān),但與腫瘤大小、淋巴結(jié)轉(zhuǎn)移有關(guān)。TCF21 mRNA低表達(dá)更容易發(fā)生在大尺度腫瘤和淋巴結(jié)轉(zhuǎn)移陽性的腫瘤中。(2)KM-plotter分析結(jié)果顯示乳腺癌組織中TCF21 mRNA表達(dá)水平與患者總生存率無關(guān),但與患者無復(fù)發(fā)生存率有關(guān)。與TCF21 mRNA高表達(dá)患者相比,TCF21 mRNA低表達(dá)患者的無復(fù)發(fā)生存率顯著降低(P-=4.7e-07)。(3)重組質(zhì)粒轉(zhuǎn)染乳腺癌MDA-MB-231細(xì)胞后,細(xì)胞內(nèi)TCF21 mRNA和蛋白的表達(dá)量明顯增加。(4)與對照組相比,TCF21基因過表達(dá)不僅能抑制乳腺癌MDA-MB-231細(xì)胞的增殖,還能促進(jìn)細(xì)胞凋亡。結(jié)論:TCF21基因作為抑癌基因在人乳腺癌細(xì)胞及大多數(shù)乳腺癌組織中低表達(dá),并且TCF21基因低表達(dá)與乳腺癌淋巴結(jié)轉(zhuǎn)移、腫瘤體積增大及不良預(yù)后有關(guān)。進(jìn)一步體外實驗證實TCF21基因過表達(dá)能夠抑制乳腺癌MDA-MB-231細(xì)胞的增殖并促進(jìn)其凋亡。第二部分TCF21基因多態(tài)性與中國漢族女性乳腺癌發(fā)病風(fēng)險的關(guān)系及其機(jī)制目的:研究TCF21基因標(biāo)簽單核苷酸多態(tài)性(tag single nucleotide polymorphisms,tagSNPs)與中國漢族女性乳腺癌發(fā)病風(fēng)險的關(guān)系,并利用基因型-表型關(guān)聯(lián)分析及體外細(xì)胞實驗研究差異多態(tài)性位點參與乳腺癌發(fā)生的分子機(jī)制。方法:(1)利用Haploview 4.2軟件從HapMap數(shù)據(jù)庫中獲取中國漢族人群TCF21基因tagSNPs。(2)采用多重聚合酶鏈反應(yīng)-連接酶檢測反應(yīng)技術(shù)對901例乳腺癌患者(病例組)和1225例健康個體(對照組)TCF21基因tagSNPs進(jìn)行分型,并運用擬合優(yōu)度卡方檢驗分析對照組中各多態(tài)性位點基因型分布是否符合哈迪-溫伯格平衡(Hardy-Weinberg equilibrium,HWE)。(3)利用 logistic回歸模型分析TCF21基因tagSNPs與中國漢族女性乳腺癌發(fā)病風(fēng)險的關(guān)系。(4)通過RT-qPCR方法檢測乳腺癌組織和癌旁正常組織中TCF21 mRNA的表達(dá),并使用單因素方差分析檢測差異多態(tài)性位點(rsl2190287 CG)基因型與TCF21 mRNA表達(dá)量的關(guān)系。(5)鑒于rs12I90287位點位于TCF21基因3'非翻譯區(qū)(3'untranslated region,3'UTR),生物信息學(xué)軟件 TargetScan 和 miRanda 被用于預(yù)測與該多態(tài)性位點結(jié)合的特異miRNA。(6)采用RT-qPCR方法檢測乳腺癌細(xì)胞及組織中特異miRNA的表達(dá)。(7)通過直接測序法檢測乳腺癌MDA-MB-231細(xì)胞中rs12190287位點基因型。(8)使用miRecords軟件和TSGene數(shù)據(jù)庫獲取乳腺癌中特異miRNA的潛在靶基因。(9)化學(xué)合成特異miRNA mimic和inhibitor,并通過功能獲得性研究和功能缺失性研究分析乳腺癌MDA-MB-231細(xì)胞中特異miRNA對TCF21基因及其潛在靶基因(SMA4D4,PPP2R1B,GGNBP2,NUAK1)表達(dá)的影響。(10)采用DNA重組和定點突變技術(shù)構(gòu)建 pmirGLO-TCF21-3'UTR-C 和 pmirGLO-TCF21-3'UTR-G 雙熒光素酶報告基因載體,分析rs12190287位點不同等位基因?qū)μ禺恗iRNA發(fā)揮調(diào)控作用的影響。結(jié)果:(1)利用Haploview 4.2軟件和HapMap數(shù)據(jù)庫從TCF21基因中獲得 6 個 tagSNPs(rs2327429 TC,rs2327430 TC,rs2327433 AG,rs12190287 CG,rs7766238 GA,rs4896011 TA),其中 2 個 tagSNPs(rs2327429 TC,rs2327430TC)位于基因啟動子區(qū),1個tagSNP(rs2327433AG)位于基因內(nèi)含子區(qū),3 個 tagSNPs(rs12190287 CG,rs7766238 GA,rs4896011 TA)位于基因3'UTR。(2)基因分型結(jié)果表明,對照組中tagSNPs位點基因型頻率分布均符合HWE:rs2327429位點的PHWE值為0.61,rs2327430位點的PHWE值為0.79,rs2327433 位點的P PHWE值為 0.74,rs12190287 位點的 PHWE值為 0.94,rs7766238 位點的 PHWE值為 0.06,rs4896011 位點的P wE值為 0.08。(3)病例對照研究結(jié)果顯示,TCF21 rs12190287位點多態(tài)性與中國漢族女性乳腺癌發(fā)病風(fēng)險有關(guān)(G vs.C,OR=0.80,95%CI=0.71-0.91,P=0.001;GG vs.CC,OR=0.64,95%CI=0.49-0.84,P=0.001;CG vs.CC,OR=0.81,95%CI= 0.68-0.98,P=0.03;GG+ CG vs.CC,OR=0.77,95%CI=0.64-0.92,P=0.003;GG vs.CG + CC,OR=0.72,95%CI=0.56-0.92,P=0.007)。進(jìn)一步基于年齡的分層分析結(jié)果表明,rs12190287位點多態(tài)性不僅與50歲以下女性乳腺癌發(fā)病風(fēng)險有關(guān)(G vs.C,OR=0.85,95%CI=0.73-0.99,P=0.04;GG+CG vs.CC,OR=0.80,95%CI=0.64-0.99,P=0.04),還與50歲及以上女性乳腺癌發(fā)病風(fēng)險有關(guān)(G vs.C,OR=0.72,95%CI=0.58-0.89,P^0.002;GG vs.CC,OR=0.52,95%CI=0.34-0.80,P=0.003;GG+CG vs.CC,OR=0.72,95%CI=0.54-0.97,P^=0.03;GG vs.CG+CC,OR=0.58,95%CI=0.39-0.86,P=0.01)。基于病理類型的分層分析結(jié)果表明,TCF21rs12190287位點多態(tài)性只與乳腺浸潤性導(dǎo)管癌的發(fā)病風(fēng)險有關(guān)(G vs.C,OR=0.78,95%CI=0.68-0.89,P0.001;GG vs.CC,OR=0.59,95%CI= 0.45-0.79,P0.001;CG vs.CC,OR=0.82,95%CI=0.67-0.99,P=0.04;GG + CG vs.CC,OR=0.76,95%CI=0.83-0.91,P=0.003;GG vs.CG + CC,OR=0.67,95%CI= 0.51-0.86,P=0.002)。基于腫瘤期的分層分析結(jié)果表明,rs12190287位點多態(tài)性不僅與Ⅰ+Ⅱ期乳腺癌發(fā)病風(fēng)險有關(guān)(Gvs.C,OR=0.80,95%CI=0.70-0.92,P=0.002;GG vs.CC,OR=0.59,95%CI=0.44-0.80,P=0.001;GG+CG vs.CC,OR=0.79,95%CI=0.65-0.96,P=0.02;GG vs.CG+CC,OR=0.64,95%CI=0.49-0.85,P=0.002),還與 Ⅲ+Ⅳ 期乳腺癌發(fā)病風(fēng)險有關(guān)(G vs.C,OR=0.79,95%CI=0.65-0.97,P=0.03;GG vs.CC,OR=0.66,95%CI=0.44-0.99,P=0.05;CG vs.CC,OR=0.57,95%CI=0.41-0.79,P=0.001;GG+CG vs.CC,OR=0.60,95%CI=0.44-0.80,P=0.001)。(4)基因型-表型關(guān)聯(lián)分析顯示,癌旁正常組織中rs12190287位點基因型與TCF21 mRNA表達(dá)量相關(guān)。與rs12190287 CC基因型癌旁正常組織相比,GG基因型癌旁正常組織中TCF21 mRNA表達(dá)量顯著增加。(5)生物信息學(xué)分析結(jié)果表明,rs12190287位點位于hsa-miR-224與TCF21 mRNA 3'UTR結(jié)合的種子區(qū)域,其中rs12190287 C等位基因有助于hsa-miR-224對TCF21基因表達(dá)的調(diào)控。(6)RT-qPCR檢測結(jié)果表明hsa-miR-224在乳腺癌MDA-MB-231細(xì)胞中的表達(dá)水平顯著高于正常乳腺上皮細(xì)胞MCF-10A。通過檢測30例乳腺癌組織及其癌旁正常組織中hsa-miR-224的表達(dá),發(fā)現(xiàn)hsa-miR-224在14例乳腺癌組織中高表達(dá),在7例乳腺癌組織中表達(dá)無差異,在9例乳腺癌組織中低表達(dá)。(7)測序分型結(jié)果表明乳腺癌MDA-MB-231細(xì)胞中rs12190287位點基因型為CC純合子,提示hsa-miR-224可能參與調(diào)控乳腺癌MDA-MB-231細(xì)胞中TCT21基因的表達(dá)。(8)進(jìn)一步生物信息學(xué)分析結(jié)果表明,hsa-miR-224也可能參與調(diào)控乳腺癌MDA-MB-231細(xì)胞中SMAD4,PPP2R1 GGNBP2和NUAK1基因的表達(dá)。(9)功能獲得性研究結(jié)果表明,hsa-miR-224過表達(dá)能夠顯著抑制乳腺癌MDA-MB-231細(xì)胞中TCF21、PPP2R1B、GGNBP2和NUAK1基因mRNA的表達(dá)。功能缺失性研究結(jié)果表明,hsa-miR-224抑制能夠顯著上調(diào)乳腺癌MDA-MB-231細(xì)胞中TCF21和GGNBP2基因mRNA的表達(dá)。(10)雙熒光素酶活性分析結(jié)果表明,rs12190287 G等位基因能夠干擾hsa-miR-224與TCF21 mRNA 3'UTR的結(jié)合,從而增加TCF21基因的表達(dá)。結(jié)論:TCF21基因3'UTR中的rs12190287位點多態(tài)性與中國漢族女性乳腺癌發(fā)病風(fēng)險有關(guān)。與攜帶有rs12190287C等位基因的個體相比,攜帶有G等位基因的個體患乳腺癌的風(fēng)險顯著降低。進(jìn)一步功能研究表明,rs12190287 G等位基因能夠干擾hsa-miR-224對TCF21基因表達(dá)的調(diào)控。因此該多態(tài)性位點可能作為中國漢族女性乳腺癌發(fā)病風(fēng)險的生物標(biāo)記物,鑒定該多態(tài)性位點將有助于實施明確的個體化預(yù)防、干預(yù)及治療。
[Abstract]:Part 1: expression of TCF21 gene in breast cancer and its function objective: to detect the expression of TCF21 gene in human breast cancer cells and tissues, and to analyze the relationship between the expression and the clinicopathological features and prognosis of breast cancer, and to observe the effect of TCF21 gene overexpression on the biological behavior of breast cancer MDA-MB-231 cells. Methods: (1) through reality Quantitative PCR (real-time quantitative PCR, RT-qPCR) and protein immunoblotting (Westernblot) were used to detect the expression of TCF21 gene in human breast cancer cells MDA-MB-231 and MCF-7, normal mammary gland epithelial cells, MCF-10A and 39 cases of breast cancer tissues and the normal tissues adjacent to the cancer, and analyzed the TCF21 mRNA expression and Clinicopathology in the cancer tissues. (2) the relationship between the expression of TCF21 mRNA in breast cancer tissue and the relationship between the expression of mRNA and the prognosis. (3) transfection of recombinant plasmid pcDNA3.1-TCF21 and empty plasmid pcDNA3.1 to MDA-MB-231 cells of breast cancer by liposome mediated method, and RT-qPCR and Western blot method to detect TCF in the cells after transfection of the plasmid. The expression of 21 gene. (4) CCK-8 and Annexin V-FITC/PI double staining were used to detect the effect of TCF21 overexpression on the proliferation and apoptosis of MDA-MB-231 cells of breast cancer. Results: (1) the expression level of TCF21 mRNA and protein in MDA-MB-231 and MCF-7 cells of breast cancer were significantly lower than that of normal mammary epithelial cells after MCF-10A.. The same method was used to detect the expression of TCF21 mRNA in 39 cases of human breast cancer and normal tissues adjacent to cancer. The results showed that the expression of TCF21 mRNA was low in 36 cases of breast cancer tissue, and there was no difference in 1 breast cancer tissues, and high expression in 2 breast cancer tissues. The Western blot test of the breast cancer tissues with low TCF21 mRNA was detected by Western blot test and found to be found. The expression level of TCF21 protein in breast cancer tissues is also significantly lower than that of normal tissues adjacent to the carcinoma, which is consistent with the results of mRNA detection. By further analysis of the relationship between the expression level of TCF21 mRNA and the clinicopathological features in breast cancer tissue, we found that the expression level of TCF21 mRNA and the age of the patients, the TNM stage, the degree of tumor differentiation, the expression of ER, PR and HER2 The low expression of.TCF21 mRNA, related to tumor size, lymph node metastasis, was more likely to occur in large scale tumors and lymph node metastases. (2) KM-plotter analysis showed that the expression of TCF21 mRNA in breast cancer tissues was not related to the total survival rate of the patients, but was related to the non recurrent survival rate of the patients. The high expression of TCF21 mRNA was associated with the high expression of TCF21 mRNA. Compared with the low expression of TCF21 mRNA, the recurrence survival rate of the patients with low expression was significantly decreased (P-=4.7e-07). (3) the expression of TCF21 mRNA and protein in the cell transfected by recombinant plasmid was significantly increased. (4) compared with the control group, the overexpression of TCF21 gene could not only inhibit the proliferation of breast cancer MDA-MB-231 cells, but also promote cell withering. Conclusion: TCF21 gene is low expression in human breast cancer cells and most breast cancer tissues as tumor suppressor gene, and the low expression of TCF21 gene is associated with lymph node metastasis, tumor volume and bad prognosis. Further in vitro experiments have proved that TCF21 gene overexpression can inhibit the proliferation of MDA-MB-231 cells in breast cancer and promote the proliferation of breast cancer cells. The relationship between the second TCF21 gene polymorphism and the risk of breast cancer in Chinese Han women and its mechanism: the study of the relationship between the TCF21 gene label single nucleotide polymorphism (tag single nucleotide polymorphisms, tagSNPs) and the risk of breast cancer in Chinese Han women, and using genotype phenotypic correlation analysis and in vitro The molecular mechanism of polymorphic loci in the occurrence of breast cancer was investigated by cell experiments. Methods: (1) using Haploview 4.2 software to obtain TCF21 gene tagSNPs. (2) of Chinese Han population from HapMap database (2) using multiple polymerase chain reaction ligase detection reaction technology in 901 cases of breast cancer patients (case group) and 1225 healthy individuals. The TCF21 gene tagSNPs was typed and the genotype distribution of the polymorphic loci in the control group was analyzed by the TCF21 gene tagSNPs (Hardy-Weinberg equilibrium, HWE). (3) the relationship between the TCF21 gene tagSNPs and the risk of breast cancer in Chinese Han women was analyzed by logistic regression model (4). The expression of TCF21 mRNA in breast cancer tissues and adjacent normal tissues was detected by RT-qPCR method, and the relationship between the genotype of rsl2190287 CG and the expression of TCF21 mRNA was detected by single factor analysis of variance. (5) in view of the location of rs12I90287 loci in the non translation region of 3'of TCF21 gene (3'untranslated region,), bioinformatics Software TargetScan and miRanda were used to predict specific miRNA. (6) combining with the polymorphic loci (6) to detect the specific miRNA expression in breast cancer cells and tissues by RT-qPCR method. (7) the genotype of rs12190287 loci in breast cancer MDA-MB-231 cells was detected by direct sequencing. (8) use miRecords software and TSGene database to obtain milk. Potential target genes of specific miRNA in adenocarcinoma. (9) chemical synthesis of specific miRNA mimic and inhibitor, and the effects of specific miRNA on the expression of TCF21 gene and its potential target gene (SMA4D4, PPP2R1B, GGNBP2, NUAK1) in MDA-MB-231 cells of breast cancer by functional study and functional deletion. (10) DNA recombination and fixed-point mutation are used. The pmirGLO-TCF21-3'UTR-C and pmirGLO-TCF21-3'UTR-G double luciferase reporter gene vectors were constructed to analyze the effects of different alleles on the specific miRNA at the rs12190287 locus. Results: (1) 6 tagSNPs (rs2327429 TC, rs2327430 TC) were obtained from the TCF21 gene using the Haploview 4.2 software and the HapMap database. 7433 AG, rs12190287 CG, rs7766238 GA, rs4896011 TA), of which 2 tagSNPs (rs2327429 TC, rs2327430TC) are located in the gene promoter region, and 1 tagSNP are located in the intron of the gene, and the result of the gene typing (2) in the gene indicates that the locus gene is in the control group. The PHWE value of the type frequency distribution was 0.61, the PHWE value of the rs2327430 site was 0.79, the P PHWE value of the rs2327433 site was 0.74, the PHWE value of the rs12190287 site was 0.94, the PHWE value of the rs7766238 loci was 0.06. G vs.C, OR=0.80,95%CI=0.71-0.91, P=0.001; GG vs.CC, GG vs.CC, OR=0.64,95%CI=0.49-0.84, P=0.001; CG vs.CC, OR=0.81,95%CI= 0.68-0.98. The results showed that rs12190287 locus polymorphism was not only associated with the risk of breast cancer under 50 years of age (G vs.C, OR=0.85,95%CI=0.73-0.99, P=0.04, GG+CG vs.CC, OR=0.80,95%CI=0.64-0.99, P=0.04), but also associated with the risk of breast cancer at the age of 50 and above (G vs.C. 4-0.80, P=0.003; GG+CG vs.CC, OR=0.72,95%CI=0.54-0.97, P^=0.03; GG vs.CG+CC, OR=0.58,95%CI=0.39-0.86, P=0.01). The pathological type based stratified analysis shows that TCF21rs12190287 locus polymorphism is only related to the risk of invasive ductal carcinoma of the breast. .79, P0.001; CG vs.CC, OR=0.82,95%CI=0.67-0.99, P=0.04; GG + CG vs.CC, OR=0.76,95%CI=0.83-0.91, P=0.003; the stratified analysis based on the tumor stage shows that the polymorphism of the locus is not only associated with the risk of stage I and II stage of breast cancer. G vs.CC, OR=0.59,95%CI=0.44-0.80, P=0.001; GG+CG vs.CC, OR=0.79,95%CI=0.65-0.96, P=0.02; GG vs.CG+CC, OR=0.64,95%CI=0.49-0.85, P=0.002), but also related to the risk of breast cancer. Vs.CC, OR=0.60,95%CI=0.44-0.80, P=0.001). (4) genotype phenotype correlation analysis showed that the genotype of rs12190287 loci in the normal tissues adjacent to the cancer was associated with the TCF21 mRNA expression. The TCF21 mRNA expression in the normal tissues adjacent to the rs12190287 CC genotypes increased significantly. (5) the bioinformatics analysis result table The rs12190287 site is located in the seed region of the combination of hsa-miR-224 and TCF21 mRNA 3'UTR, in which rs12190287 C alleles contribute to the regulation of TCF21 gene expression. (6) RT-qPCR detection results show that hsa-miR-224 expression in breast cancer MDA-MB-231 cells is significantly higher than normal mammary epithelial cells. The expression of hsa-miR-224 in 30 cases of breast cancer tissue and its adjacent normal tissues showed that hsa-miR-224 was highly expressed in 14 breast cancer tissues. There was no difference in 7 breast cancer tissues and low expression in 9 breast cancer tissues. (7) sequencing results showed that the rs12190287 loci in MDA-MB-231 cells of breast cancer were CC homozygote, suggesting H Sa-miR-224 may participate in the regulation of the expression of TCT21 gene in breast cancer MDA-MB-231 cells. (8) further bioinformatics analysis shows that hsa-miR-224 may also be involved in the regulation of the expression of SMAD4, PPP2R1 GGNBP2 and NUAK1 in breast cancer MDA-MB-231 cells. (9) the results of functional acquisition showed that the overexpression of hsa-miR-224 could be significantly inhibited. The expression of TCF21, PPP2R1B, GGNBP2 and NUAK1 gene in breast cancer MDA-MB-231 cells. The results of functional deletion study showed that hsa-miR-224 inhibition could significantly increase the expression of TCF21 and GGNBP2 gene mRNA in breast cancer MDA-MB-231 cells. (10) the analysis of double luciferase activity indicates that the allele can interfere with the expression of the allele of the double luciferase activity. 24 combined with TCF21 mRNA 3'UTR to increase the expression of the TCF21 gene. Conclusion: the rs12190287 polymorphism in the TCF21 gene 3'UTR is associated with the risk of breast cancer in Chinese Han women. The risk of breast cancer carrying a G allele is significantly lower than that of individuals carrying rs12190287C alleles. The study shows that the rs12190287 G allele can interfere with the regulation of hsa-miR-224 on the expression of TCF21 gene. Therefore, the polymorphic loci may be used as a biomarker for the risk of breast cancer in Chinese women of Han nationality. Identification of the polymorphism site will be helpful for the implementation of specific individualized prevention, intervention and treatment.

【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R737.9

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