化疗药物诱导胃癌SGC7901细胞向肿瘤干细胞转化的EMT机制研究
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摘要
【背景】
胃癌是世界上第四高发的肿瘤,在每年因癌症死亡的100万人口中,胃癌致死率位列第二。近年来的研究阐明了肿瘤干细胞(cancer stem cell,CSC)的存在，CSC具有再生肿瘤及自我更新和分化的特殊能力，与组织干细胞具有很多相似的特性，其与肿瘤发生、复发和转移有着重要关系。近些年的研究发现在胃癌细胞中存在有胃癌干细胞。但是由于缺乏特异性标志，不了解调节胃干细胞增殖分化的分子通路，目前还没有理想的分离纯化出人类胃干细胞的技术及其具体作用机制目前尚不完全明确。
上皮间质转化（epithelial-mesenchymal transition，EMT）赋予上皮细胞间质特征，与肿瘤细胞获取侵犯特征密切相关，是上皮细胞来源肿瘤局部浸润和远处转移的一个重要途径。EMT发生及调控机制对于寻找恶性肿瘤浸润转移的靶点，进行临床干预有重要意义。这种转分化现象同时会伴有干细胞样特性，这说明有一部分不具有分化能力的肿瘤细胞可以通过EMT逆分化为肿瘤干细胞。然而在胃癌中，胃癌干细胞是否能通过EMT对胃癌发生、转移及多药耐药性起关键作用，其中的具体机制尚不清楚，这些问题的研究对我们揭示胃癌干细胞的来源，明确胃癌发生、转移、多药耐药的机制以及胃癌的潜在治疗靶点有着重要意义。
【目的】
1．通过化疗药物诱导再经无血清培养法分离鉴定胃癌干样细胞。
2．研究EMT在胃癌细胞向胃癌干样细胞转化过程中的作用及其分子机制。
【方法】
1．胃癌干样细胞的培养及鉴定
长春新碱体外诱导胃癌SGC7901细胞72小时后无血清培养法分离胃癌干样细胞。对成功分离出的胃癌干样细胞的干细胞特性进行鉴定，包括干细胞表面标记物SOX2、OCT4a、OCT4b，BMI-1检测，通过Matrigel细胞群落外观区分实验及透射电镜观察胃癌干样细胞的分化能力，通过PKH-26标记细胞，观察其增殖、分化情况。通过药物敏感试验和体外成瘤实验验证肿瘤干样细胞耐药性及成瘤能力。
2．EMT在胃癌细胞向胃癌干样细胞转化过程中的作用研究
通过实时定量PCR技术分别在蛋白水平和mRNA水平检测胃癌干样细胞中间质标志物Snail、Twist、Vimentin和上皮细胞标志物E-cadherin表达改变。构建Twist重组质粒，转染SGC7901细胞，筛选获得稳定转染株，Western-Blot证实载体的有效性。通过诱导稳定高表答Twist的SGC7901细胞获得新的高表达Twist的肿瘤干样细胞，比较其与化疗药物诱导而来的胃癌干样细胞的干细胞标志物的表达、克隆形成能力、EMT表型、耐药性是否一致。
3．用ITRAQ技术高通量筛选参与胃癌细胞向胃癌干样细胞转化过程的分子靶点。
【结果】
1．成功培养并鉴定胃癌干样细胞
长春新碱体外诱导胃癌SGC7901细胞并通过无血清培养法成功分离胃癌干样细胞。Western Blot实验显示肿瘤干样细胞较亲本细胞SGC7901其干细胞表面标记物SOX2、OCT4a、OCT4b、BMI-1表达明显升高。用matrigel细胞群落外观区分实验观察到肿瘤干样细胞可以形成二维的管样结构及三维的管腔样结构，其与胃隐窝的分化形式十分相似，通过透射电镜也可观察到的胃癌干样细胞出现干细胞特征。使用PKH-26标记细胞，可以观察到肿瘤干样细胞具有明显的不对称分裂能力。平板克隆实验证明胃癌干样细胞较其亲本细胞有更强的克隆形成能力。药物敏感性实验和异种移植实验证明这种细胞具有多药耐药性和显著地体内致瘤性。.
2．EMT参与胃癌细胞向胃癌干样细胞的转化
实时定量PCR实验显示肿瘤干样细胞与亲本细胞SGC7901相比，其间质标志物Snail、Twist、Vimentin表达增强，上皮细胞标志物E-cadherin表达降低。成功构建Twist重组质粒，并通过质粒转染技术获得稳定的Twist高表达的胃癌干样细胞系CSLCsTwist+，实时定量PCR显示CSLCsTwist+较亲本细胞SGC7901高表达间质标志物Snail、Twist、Vimentin，而上皮细胞标志物E-cadherin表达降低，其耐药性，克隆形成能力及干细胞标志物SOX2、OCT4、BMI-1表达均明显增强，结果与化疗药物诱导而来的胃癌干样细胞特征一致。
3．用iTRAQ高通量技术筛选出了一批胃癌细胞向胃癌干样细胞转化过程中的差异蛋白
【结论】
在胃癌SGC7901细胞系中成功用化疗药物诱导获得胃癌干样细胞，此肿瘤干细胞具有明显的自我更新、分化、抵抗化疗药物及高成瘤性。EMT参与胃癌细胞向胃癌干样细胞的转化，具有EMT表型的胃癌细胞有干细胞样特性，胃癌细胞可能通过EMT逆分化为胃癌干样细胞。
With the research going further, people have realized that the properties of malignanttumor, such as genesis, development, metastasis and recurrence were amazingly similar towhat of the normal stem cell.Stem cells are identified as a class of immatureundifferentiated cell populations with self-renewal and differentiation capacity, andreserve the asymmetric replication phenotype. There is now compelling evidence that thebulk of the malignant cells, terned cancer stem-like cells (CSCs). The last decade haswitnessed a transition from a state of assumptions of stem cells in the onset andprogression of cancer to the establishment of actual experimental proof of the isolationand identification of CSCs in most kinds of tumors, including leukemia and solid tumors,such as in gatric cancer. The CSCs are usually associated with the development of drugresistance, tumor dormancy, minimal residual disease, and disease relapse. However, thebehind mechanisms how these peoperties maintained in CSCs are need to be furtherelucidated, especially in gastric cancer.
The epithelial-mesenchymal transition (EMT) facilitates cancer metastasis andsurvival by transdifferentiation, in which a tumor loses epithelial characteristics andacquires a mesenchymal phenotype. This phenotype transition enriches the subpopulationof CSCs, which have proven tumor seeding, sphere formation and invasive properties.High-throughput experimental methods have thus been adopted to screen for drugs thatkill the rare epithelial cancer stem cells enriched by EMT. The advantages of obtainingCSCs by inducing the EMT are the easy enrichment of CSCs and the relative stability inculture of these cell lines. Because CSCs are generally only small populations withincancer cells,standard high-throughput screening cannot be applied to identify drugs withCSC-specific toxicity invivo. Furthermore, searching for agents that effectively kill CSCsdepends on propagation stability invitro. However, identifying and developing newmethods to induce the EMT for enriching gastric cancer stem cells(GCSCs) is one of thebetter choices for the study of CSC target therapy. Therefore, it is an urgent challenge tounderstand the detail molecular events of these cells from a developmental andevolutionary aspect, and that may be crucial in identifying the aberrant events leadinggastric cancer.
【Aims】
1. To isolate and identificate GCSCs in the floatingspheres culture ofchemotherapeutics-preconditioning gatric cancer cells.
2. To study the function and molecular mechanism of EMT during the transformationof gastric cancer cells into gastric cancer stem cells.
【Methods】
1. Isolation and identification of GCSCs.
SGC7901cells were treated with vincristine for72hours (VCR-induced cancer cells).Toisolate and identificate GCSCs in the floatingspheres culture of VCR-induced cancercells. To investigate co-expression of the embryonic proteins OCT4A, SOX2and OCT4by immunofluorescence in CSLCs. Gastric CSLCs exhibited differentiation ability andself-Renewal ability in Vitro. To study the differentiation of CSLCs of gastric cells, we first used transmission electron microscopy to examine the morphological changes. Thedifferentiation ability of VCR-induced CSLCs was explored in a2D and3D Matrigeldifferentiation assay. To identify the self-renewal property in CSLCs, we employed alipophilic fluorescent dye, PKH-26, which stains the rare quiescent subpopulations, andexamined the asymmetric and symmetric division to identify cancer-initiating cells by theamount of retained dye. Tumorigenicity in vivo was assessed by inoculating CSLCs ortheir parental cells subcutaneously into nude mice.
2. The study on function and molecular mechanism of EMT during thetransformation of gastric cancer cells into gastric cancer stem cells.
To identify EMT markers, we examined the expression of Snail、Twist、Vimentin andE-cadherin by real-time PCR. After baeteria transformation，use restrietion enzymetechnique, gel electro phoresis technique and gene sequencing identifieation the Twistsense Plasmid. The SGC7901cells were transfeeted with pcDNA3.I(+)-Twist sensePlasmid by lipofectamine technique，and gained the stable Twist-SGC7901cell modelwith high expression of Twist protein. Serum free culture was used to earn CLSCsTwist+with high expression of Twist protein. Consistency among CLSCsTwist+and VCR-inducedCSLCs for stem cell markers, clone formation, EMT markers and multi-drug resistancewere evaluated.
3. Screening of different proteins which involved in the transformation of gastriccancer cells into gastric cancer stem cells by iTRAQ.
Highthroughout techniques can be used to screen the diference relatedproteins andexplore the mechanisms of the transformation of gastric cancer cells into gastric cancerstem cells. After cell lysis, acetone precipitation, denaturation and protein digestion ofSGC7901and CLSCs, the peptide was labeled with iTRAQ reagents and subjected tomass spectrometry.
【Results】
1. The were successfully isolated and identificated.
The GCLSCs were successfully isolated and cultured from Vincristine preconditioned SGC7901cell line. The CSLCs displayed stem cell characteristics,including the up-regulated stem cell markers OCT4A, OCT4and SOX2. Using aMatrigel-based differentiation assay, CSLCs formed2D tube-like and3D complexlumen-like structures, which resembled differentiated gastric crypts. We further showedthat CSLCs could self-renew through significant asymmetric division compared withparent cells by tracing PKH-26label-retaining cells. Drug sensitivity assays and xenograftexperiments demonstrated that the cells developed multi-drug resistance (MDR) andsignificant tumorigenicity in vivo.
2. The study on function and molecular mechanism of EMT during thetransformation of gastric cancer cells into gastric cancer stem cells.
The CSLCs displayed mesenchymal characteristics, including the up-regulatedmesenchymal markers Snail, Twist and vimentin, and the down-regulated epithelialmarker E-cadherin. The cell models (Twist-SGC7901) steadily expressing high Twistprotein were obtained. Compared with CLSCs, CLSCsTwist+and SGC7901cells，CLSCsand CLSCsTwist+have the similar characteristics including the up-regulated mesenchymalmarkers Snail, Twist and vimentin, the down-regulated epithelial marker E-cadherin,remarkable Clone Formation and the up-regulated stem cell makers SOX2, OCT4,BMI-1.EMT is an important role playing in the transformation of gastric cancer cells into gastriccancer stem cells.
4. iTRAQ based screening is useful in discovering different proteins betweenCLSCs and SGC7901.
【Conclusion】
The GCLSCs were successfully isolated and cultured from Vincristinepreconditioned SGC7901cell line. Drug sensitivity assays and xenograft experimentsdemonstrated that the cells developed multi-drug resistance (MDR) and significanttumorigenicity in vivo. EMT is an important role playing in the transformation of gastriccancer cells into gastric cancer stem cells.
胃癌是世界上第四高发的肿瘤,在每年因癌症死亡的100万人口中,胃癌致死率位列第二。近年来的研究阐明了肿瘤干细胞(cancer stem cell,CSC)的存在，CSC具有再生肿瘤及自我更新和分化的特殊能力，与组织干细胞具有很多相似的特性，其与肿瘤发生、复发和转移有着重要关系。近些年的研究发现在胃癌细胞中存在有胃癌干细胞。但是由于缺乏特异性标志，不了解调节胃干细胞增殖分化的分子通路，目前还没有理想的分离纯化出人类胃干细胞的技术及其具体作用机制目前尚不完全明确。
上皮间质转化（epithelial-mesenchymal transition，EMT）赋予上皮细胞间质特征，与肿瘤细胞获取侵犯特征密切相关，是上皮细胞来源肿瘤局部浸润和远处转移的一个重要途径。EMT发生及调控机制对于寻找恶性肿瘤浸润转移的靶点，进行临床干预有重要意义。这种转分化现象同时会伴有干细胞样特性，这说明有一部分不具有分化能力的肿瘤细胞可以通过EMT逆分化为肿瘤干细胞。然而在胃癌中，胃癌干细胞是否能通过EMT对胃癌发生、转移及多药耐药性起关键作用，其中的具体机制尚不清楚，这些问题的研究对我们揭示胃癌干细胞的来源，明确胃癌发生、转移、多药耐药的机制以及胃癌的潜在治疗靶点有着重要意义。
【目的】
1．通过化疗药物诱导再经无血清培养法分离鉴定胃癌干样细胞。
2．研究EMT在胃癌细胞向胃癌干样细胞转化过程中的作用及其分子机制。
【方法】
1．胃癌干样细胞的培养及鉴定
长春新碱体外诱导胃癌SGC7901细胞72小时后无血清培养法分离胃癌干样细胞。对成功分离出的胃癌干样细胞的干细胞特性进行鉴定，包括干细胞表面标记物SOX2、OCT4a、OCT4b，BMI-1检测，通过Matrigel细胞群落外观区分实验及透射电镜观察胃癌干样细胞的分化能力，通过PKH-26标记细胞，观察其增殖、分化情况。通过药物敏感试验和体外成瘤实验验证肿瘤干样细胞耐药性及成瘤能力。
2．EMT在胃癌细胞向胃癌干样细胞转化过程中的作用研究
通过实时定量PCR技术分别在蛋白水平和mRNA水平检测胃癌干样细胞中间质标志物Snail、Twist、Vimentin和上皮细胞标志物E-cadherin表达改变。构建Twist重组质粒，转染SGC7901细胞，筛选获得稳定转染株，Western-Blot证实载体的有效性。通过诱导稳定高表答Twist的SGC7901细胞获得新的高表达Twist的肿瘤干样细胞，比较其与化疗药物诱导而来的胃癌干样细胞的干细胞标志物的表达、克隆形成能力、EMT表型、耐药性是否一致。
3．用ITRAQ技术高通量筛选参与胃癌细胞向胃癌干样细胞转化过程的分子靶点。
【结果】
1．成功培养并鉴定胃癌干样细胞
长春新碱体外诱导胃癌SGC7901细胞并通过无血清培养法成功分离胃癌干样细胞。Western Blot实验显示肿瘤干样细胞较亲本细胞SGC7901其干细胞表面标记物SOX2、OCT4a、OCT4b、BMI-1表达明显升高。用matrigel细胞群落外观区分实验观察到肿瘤干样细胞可以形成二维的管样结构及三维的管腔样结构，其与胃隐窝的分化形式十分相似，通过透射电镜也可观察到的胃癌干样细胞出现干细胞特征。使用PKH-26标记细胞，可以观察到肿瘤干样细胞具有明显的不对称分裂能力。平板克隆实验证明胃癌干样细胞较其亲本细胞有更强的克隆形成能力。药物敏感性实验和异种移植实验证明这种细胞具有多药耐药性和显著地体内致瘤性。.
2．EMT参与胃癌细胞向胃癌干样细胞的转化
实时定量PCR实验显示肿瘤干样细胞与亲本细胞SGC7901相比，其间质标志物Snail、Twist、Vimentin表达增强，上皮细胞标志物E-cadherin表达降低。成功构建Twist重组质粒，并通过质粒转染技术获得稳定的Twist高表达的胃癌干样细胞系CSLCsTwist+，实时定量PCR显示CSLCsTwist+较亲本细胞SGC7901高表达间质标志物Snail、Twist、Vimentin，而上皮细胞标志物E-cadherin表达降低，其耐药性，克隆形成能力及干细胞标志物SOX2、OCT4、BMI-1表达均明显增强，结果与化疗药物诱导而来的胃癌干样细胞特征一致。
3．用iTRAQ高通量技术筛选出了一批胃癌细胞向胃癌干样细胞转化过程中的差异蛋白
【结论】
在胃癌SGC7901细胞系中成功用化疗药物诱导获得胃癌干样细胞，此肿瘤干细胞具有明显的自我更新、分化、抵抗化疗药物及高成瘤性。EMT参与胃癌细胞向胃癌干样细胞的转化，具有EMT表型的胃癌细胞有干细胞样特性，胃癌细胞可能通过EMT逆分化为胃癌干样细胞。
With the research going further, people have realized that the properties of malignanttumor, such as genesis, development, metastasis and recurrence were amazingly similar towhat of the normal stem cell.Stem cells are identified as a class of immatureundifferentiated cell populations with self-renewal and differentiation capacity, andreserve the asymmetric replication phenotype. There is now compelling evidence that thebulk of the malignant cells, terned cancer stem-like cells (CSCs). The last decade haswitnessed a transition from a state of assumptions of stem cells in the onset andprogression of cancer to the establishment of actual experimental proof of the isolationand identification of CSCs in most kinds of tumors, including leukemia and solid tumors,such as in gatric cancer. The CSCs are usually associated with the development of drugresistance, tumor dormancy, minimal residual disease, and disease relapse. However, thebehind mechanisms how these peoperties maintained in CSCs are need to be furtherelucidated, especially in gastric cancer.
The epithelial-mesenchymal transition (EMT) facilitates cancer metastasis andsurvival by transdifferentiation, in which a tumor loses epithelial characteristics andacquires a mesenchymal phenotype. This phenotype transition enriches the subpopulationof CSCs, which have proven tumor seeding, sphere formation and invasive properties.High-throughput experimental methods have thus been adopted to screen for drugs thatkill the rare epithelial cancer stem cells enriched by EMT. The advantages of obtainingCSCs by inducing the EMT are the easy enrichment of CSCs and the relative stability inculture of these cell lines. Because CSCs are generally only small populations withincancer cells,standard high-throughput screening cannot be applied to identify drugs withCSC-specific toxicity invivo. Furthermore, searching for agents that effectively kill CSCsdepends on propagation stability invitro. However, identifying and developing newmethods to induce the EMT for enriching gastric cancer stem cells(GCSCs) is one of thebetter choices for the study of CSC target therapy. Therefore, it is an urgent challenge tounderstand the detail molecular events of these cells from a developmental andevolutionary aspect, and that may be crucial in identifying the aberrant events leadinggastric cancer.
【Aims】
1. To isolate and identificate GCSCs in the floatingspheres culture ofchemotherapeutics-preconditioning gatric cancer cells.
2. To study the function and molecular mechanism of EMT during the transformationof gastric cancer cells into gastric cancer stem cells.
【Methods】
1. Isolation and identification of GCSCs.
SGC7901cells were treated with vincristine for72hours (VCR-induced cancer cells).Toisolate and identificate GCSCs in the floatingspheres culture of VCR-induced cancercells. To investigate co-expression of the embryonic proteins OCT4A, SOX2and OCT4by immunofluorescence in CSLCs. Gastric CSLCs exhibited differentiation ability andself-Renewal ability in Vitro. To study the differentiation of CSLCs of gastric cells, we first used transmission electron microscopy to examine the morphological changes. Thedifferentiation ability of VCR-induced CSLCs was explored in a2D and3D Matrigeldifferentiation assay. To identify the self-renewal property in CSLCs, we employed alipophilic fluorescent dye, PKH-26, which stains the rare quiescent subpopulations, andexamined the asymmetric and symmetric division to identify cancer-initiating cells by theamount of retained dye. Tumorigenicity in vivo was assessed by inoculating CSLCs ortheir parental cells subcutaneously into nude mice.
2. The study on function and molecular mechanism of EMT during thetransformation of gastric cancer cells into gastric cancer stem cells.
To identify EMT markers, we examined the expression of Snail、Twist、Vimentin andE-cadherin by real-time PCR. After baeteria transformation，use restrietion enzymetechnique, gel electro phoresis technique and gene sequencing identifieation the Twistsense Plasmid. The SGC7901cells were transfeeted with pcDNA3.I(+)-Twist sensePlasmid by lipofectamine technique，and gained the stable Twist-SGC7901cell modelwith high expression of Twist protein. Serum free culture was used to earn CLSCsTwist+with high expression of Twist protein. Consistency among CLSCsTwist+and VCR-inducedCSLCs for stem cell markers, clone formation, EMT markers and multi-drug resistancewere evaluated.
3. Screening of different proteins which involved in the transformation of gastriccancer cells into gastric cancer stem cells by iTRAQ.
Highthroughout techniques can be used to screen the diference relatedproteins andexplore the mechanisms of the transformation of gastric cancer cells into gastric cancerstem cells. After cell lysis, acetone precipitation, denaturation and protein digestion ofSGC7901and CLSCs, the peptide was labeled with iTRAQ reagents and subjected tomass spectrometry.
【Results】
1. The were successfully isolated and identificated.
The GCLSCs were successfully isolated and cultured from Vincristine preconditioned SGC7901cell line. The CSLCs displayed stem cell characteristics,including the up-regulated stem cell markers OCT4A, OCT4and SOX2. Using aMatrigel-based differentiation assay, CSLCs formed2D tube-like and3D complexlumen-like structures, which resembled differentiated gastric crypts. We further showedthat CSLCs could self-renew through significant asymmetric division compared withparent cells by tracing PKH-26label-retaining cells. Drug sensitivity assays and xenograftexperiments demonstrated that the cells developed multi-drug resistance (MDR) andsignificant tumorigenicity in vivo.
2. The study on function and molecular mechanism of EMT during thetransformation of gastric cancer cells into gastric cancer stem cells.
The CSLCs displayed mesenchymal characteristics, including the up-regulatedmesenchymal markers Snail, Twist and vimentin, and the down-regulated epithelialmarker E-cadherin. The cell models (Twist-SGC7901) steadily expressing high Twistprotein were obtained. Compared with CLSCs, CLSCsTwist+and SGC7901cells，CLSCsand CLSCsTwist+have the similar characteristics including the up-regulated mesenchymalmarkers Snail, Twist and vimentin, the down-regulated epithelial marker E-cadherin,remarkable Clone Formation and the up-regulated stem cell makers SOX2, OCT4,BMI-1.EMT is an important role playing in the transformation of gastric cancer cells into gastriccancer stem cells.
4. iTRAQ based screening is useful in discovering different proteins betweenCLSCs and SGC7901.
【Conclusion】
The GCLSCs were successfully isolated and cultured from Vincristinepreconditioned SGC7901cell line. Drug sensitivity assays and xenograft experimentsdemonstrated that the cells developed multi-drug resistance (MDR) and significanttumorigenicity in vivo. EMT is an important role playing in the transformation of gastriccancer cells into gastric cancer stem cells.
引文
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