叶酸结合蛋白与卵巢癌多药耐药关系的研究
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摘要
第一章卵巢癌多药耐药的研究进展
卵巢恶性肿瘤是女性生殖系统常见的肿瘤,它是妇科三大恶性肿瘤之一,仅次于宫颈癌,宫体癌,居第三位。卵巢癌约占卵巢恶性肿瘤的80%,目前主要的治疗手段是手术治疗和铂类为基础的联合化疗,患者5年生存率一直徘徊在20%-30%左右。大多数卵巢患者发现时已为中晚期,有的甚至已经失去了手术机会而给予非手术治疗,75%～80%的卵巢癌开始对化疗敏感,其余则表现为原发耐药,最终所有化疗患者至少80%出现耐药,而多药耐药机制极为复杂,目前还没完全清楚,卵巢癌多药耐药产生后治疗效果明显降低。预防和减少卵巢癌多药耐药的发生,以及对卵巢癌多药耐药的逆转治疗,是现阶段迫切需要解决的问题。国外有学者曾报道叶酸结合蛋白与卵巢癌的发生发展密切相关,在多药耐药中也扮演了重要的角色,具体机制暂未明确,需要我们进一步的研究探索。
第二章卵巢恶性肿瘤组织叶酸结合蛋白表达检测及其临床意义
目的：探讨卵巢恶性肿瘤组织中叶酸结合蛋白(FOLR1)的表达及其临床意义。方法：采用Western Blot检测80例卵巢恶性肿瘤组织、50例卵巢良性肿瘤组织及30例正常卵巢组织中的FOLR1表达情况,分析其与卵巢恶性肿瘤临床病理及多药耐药的相关性。结果：(1)FOLR1在正常卵巢组织,卵巢良性肿瘤和卵巢恶性肿瘤中的表达量依次增高(P<0.01)。(2)FOLR1在卵巢恶性肿瘤临床分期中Ⅰ～Ⅱ期的表达量低于Ⅲ～Ⅳ期,在组织分级高分化中的表达量低于中低分化(P<0.05)。(3)FOLR1在铂类药物耐药型卵巢恶性肿瘤中的表达量低于铂类药物敏感型(P<0.01)；其在治疗后仍进展肿瘤中的表达量低于缓解者(P<0.01)。(4)FOLR1在粘液性肿瘤中的表达量低于浆液性肿瘤(P<0.05),在有淋巴结和远处器官转移的卵巢恶性肿瘤中高于未有转移者(P<0.05),与患者的不同肿瘤病理分类、是否有大网膜转移和腹水量多少无明显相关(P>0.05)。(5)取FOLR1表达量界值为3.115时来判断卵巢肿瘤性质,ROC曲线的Youden指数最大,卵巢恶性肿瘤FOLR1表达量的高低与中位生存时间差别无明显相关(P>0.05),COX模型多因素分析显示FOLR1表达量不是影响患者生存预后的独立因素。结论：FOLR1在正常卵巢和卵巢良性肿瘤组织中的表达量低于卵巢恶性肿瘤,其可作为一种新型的卵巢恶性肿瘤早期诊断标志物。铂类药物耐药型卵巢恶性肿瘤中FOLR1呈低表达,在铂类药物敏感型卵巢恶性肿瘤中高表达,提示FOLR1与卵巢恶性肿瘤多药耐药相关,可作为判断卵巢恶性肿瘤多药耐药潜在标志物之一。
第三章FOLR1基因慢病毒表达载体的构建及鉴定
目的：构建携带叶酸结合蛋白基因(FOLR1)的慢病毒表达载体并进行表达鉴定。方法：PCR扩增FOLR1全长,克隆至pWPI载体质粒,重组阳性克隆行PCR和测序鉴定,重组质粒与其辅助质粒共同转染293T细胞包装病毒,病毒颗粒感染SKOV3细胞,流式分选,RT-PCR和Western Blot检测FOLR1的表达。结果：FOLR1正确克隆至pWPI载体质粒,PCR及测序证实重组表达载体构建成功,293T细胞成功包装慢病毒,pWPI-FOLR1慢病毒高效感染SKOV3细胞,RT-PCR和Western Blot检测出被感染后的SKOV3细胞中有FOLR1表达。结论：成功构建了FOLR1慢病毒表达载体,能高效感染SKOV3细胞,FOLR1基因转导后稳定表达,为下步探讨FOLR1在恶性卵巢肿瘤中的功能提供了实验基础。
第四章FOLR1基因对顺铂作用卵巢癌上皮细胞生物学影响的体外实验研究
目的：探索卵巢癌SKOV3细胞中FOLR1基因表达上调后对其生物学功能的影响以及作用途径。方法：MTT法测定三组细胞(SKOV3、pWPI-SKOV3、 pWPI-FOLR1-SKOV3)的生长增值情况、顺铂对三组细胞的IC50和不同顺铂浓度分别作用不同时间对三组细胞的抑制率；流式细胞术检测不同顺铂浓度分别作用不同时间诱导三组细胞的凋亡率；流式细胞术检测不同顺铂浓度作用48小时对三组细胞周期分布的影响；高效液相检测同浓度顺铂作用三组细胞48小时后细胞内顺铂的浓度。结果：实验组细胞(pWPI-FOLR1-SKOV3)与两组对照组相比较：(1)增殖速度明显升高、顺铂对其作用的IC50值降低。(2)顺铂对其生长抑制率增加(P<0.05),呈剂量-时间依赖关系,其对顺铂的敏感性增加。(3)顺铂更容易诱导其凋亡发生(P<0.05),呈时间-剂量依赖关系。(4)顺铂将其周期中的S期阻滞比例明显增加(P<0.05)。(5)细胞内的顺铂浓度增加近一倍。结论：FOLR1基因能增强卵巢癌SKOV3细胞的生长增殖能力；卵巢癌SKOV3细胞中FOLR1基因表达上调后顺铂对其抑制率增加,呈剂量-时间依赖关系,顺铂更容易诱导其凋亡发生,呈时间-剂量依赖关系,顺铂将其细胞周期中的S期阻滞明显增加,细胞内顺铂浓度升高。
Chapter1Research advance on multi-drug resistance in ovarian cancer
Malignant ovarian tumors are common in the female reproductive system,and second only to cervical cancer and endometrial cancer among the three gynecologic malignancies of highest incidence.Ovarian cancer.which consists of about80%of malignant ovarian tumors,is now mainly treated by surgery and platinum-based combination chemotherapy. However.most patients are diagnosed late and the chances of surgery for some of them are very little. While70-80%of all patients respond positively to chemotherapy at first,eventually drug resistance will emerge in at least80%of them who have been given the regimen.which leads to the overall5-year survival lower to be20-30%.Especially the efficacy significantly decreases as the result of multi-drug resistance(MDR),and the relative complex mechanisms remain unclear as now.So at this stage it is urgent to prevent and reduce the incidence of MDR as well as reverse it. It has been reported by foreign scholars that folate binding-protein is closely associated with the development of ovarian cancer and also plays an important role in MDR,but the specific mechanisms involved remain to be explored.
Chapter2Detection of folate binding protein expression and its clinical significance in ovarian carcinomas
Objective:To explore the expression level of folate binding protein (FOLR-1) and its clinical significance in ovarian carcinomas.
Methods:Western blot analysis was used to detect the expression levels of FOLR-1in80ovarian carcinomas,50benign ovarian tumors and30normal ovarian tissues, and its association with clinical pathology and multidrug resistance of ovarian carcinomas was analyzed.
Results:(1) The expression levels of FOLR-1increased orderly in normal ovarian tissues.benign ovarian tumors and ovarian carcinomas,and the difference was statistically significant (P<0.01).(2) For ovarian carcinomas,the expression levels of FOLR-1in clinical stage Ⅰ-Ⅱ were higher than that of stage Ⅲ-Ⅳ, and the levels of well-differentiated were lower than that of poorly differentiated.The differences were both statistically significant (P <0.05).(3) For ovarian carcinomas, the FOLR-1levels of the platinum-resistant were less than the platinum-sensitive,and the difference was statistically significant (P<0.01). After chemotherapy the FOLR-1levels of progressive ovarian carcinomas were lower than those in remission,and the difference was statistically significant (P<0.01).(4) For ovarian carcinomas,the FOLR-1levels of the mucinous type were lower than that of the serous,and the difference was statistically significant (P<0.05); The FOLR-1levels of ovarian carcinomas with metastasis to lymph nodes and distant organs were higher than those without metastasis, and the difference was statistically significant (P<0.05);However,the FOLR-1levels had no significant association with pathological classification, amounts of ascites and metastasis to the omentum (P>0.05).(5) ROC curve determining the FOLR-1levels associated nature of ovarian tumors demonstrated that the maximum Youden index was3.115.and the FOLR-1levels showed no obvious correlation with median survival time (P>0.05). COX multivariate analysis denied the FOLR-alevel as an independent prognostic factor.
Conclusions:The FOLR-1levels of normal ovarian tissues and benign ovarian tumors were lower than that of ovarian carcinomas,which suggested FOLR-1could be a new biomarker for early diagnosis of ovarian carcinomas.
Meanwhile,the FOLR-1levels in ovarian carcinomas were low for the platinum-resistant but high for the platinum-sensitive,which suggested that FOLR-1associated with multidrug resistance of ovarian carcinomas and could be a potential target for judging multidrug resistance.
Chapter3Construction and Identification of Lentiviral vector carrying FOLR1Gene
Objective:To construct a lentiviral vector expressing the gene of folate-binding protein (FOLR1) and identify its expression.
Methods:Full-length of FORL1gene was amplified by PCR,then cloned into the plasmid pWPI.and further confirmed by PCR and sequencing.After the recombinant pWPI and its helper plasmid co-transfected the virus packaging293T cells, SKOV3cells were infected with the virus particles and sorted by flow cytometry. Finally protein expression of FOLR1gene was detected by RT-PCR and Western Blotting.
Results:FOLR1gene was successfully cloned into the plasmid pWPl.The recombinant expression vector was successfully constructed,and lentiviruses were successfully packaged by the293T cells. SKOV3cells were effectively infected with the lentiviruses carrying pWPI-FOLR1gene. There's stable expression of FORL1in the infected SKOV3cells.
Conclusions:Lentiviral vector carrying FOLR1gene was constructed and could efficiently infect SKOV3cells,and stable expression of FOLR1gene laid foundation for exploring its function.
Chapter4Biological effect of the FORL1gene on epithelial ovarian cells acted by cisplatin in experimental study in vitro
Objective:To explore the biological effect of upregulated expression of the FORL gene on SKOV3cells and the functional patways.
Methods:MTT assay was used to measure the growth rate,the IC50values of cells with cisplatin and inhibition by different cisplatin concentrations at different times in the three groups of SKOV3cells,pWPI-SKOV3cells and pWPI-FOLR1-SKOV3cells.Meanwhile,flow cytometry was used to detect apoptosis and cell cycle distribution of the three groups acted by different cisplatin concentrations at different times.High Performance Liquid Chromatography (HPLC) was used to measure the cisplatin concentration in the three groups of cells acted by same concentration of cisplatin after48hours.
Results:Compared with the other two control groups,the experimental group of pWPI-FOLR1-SKOV3cells with cisplatin showed significantly increased growth rate as well as decreased IC50values.Meanwhile growth inhibition of the experimental group increased and was dose-time dependent.Cisplatin-induced apoptosis as the result of cell cycle arrest in S phase also increased in the time-dose dependent manner.The cisplatin concentration in cells was twice as much as before.
Conclusion:The FOLR1gene could enhance the growth ability of SKOV3cells,and its upregulated expression led to the increase of inhibition after cisplatin in a dose-time dependent manner.Meanwhile cisplatin-induced apoptosis through cell cycle arrest in S phase also increased significantly in the manner of time-dose dependence,and the cisplatin concentration in cells increased.
卵巢恶性肿瘤是女性生殖系统常见的肿瘤,它是妇科三大恶性肿瘤之一,仅次于宫颈癌,宫体癌,居第三位。卵巢癌约占卵巢恶性肿瘤的80%,目前主要的治疗手段是手术治疗和铂类为基础的联合化疗,患者5年生存率一直徘徊在20%-30%左右。大多数卵巢患者发现时已为中晚期,有的甚至已经失去了手术机会而给予非手术治疗,75%～80%的卵巢癌开始对化疗敏感,其余则表现为原发耐药,最终所有化疗患者至少80%出现耐药,而多药耐药机制极为复杂,目前还没完全清楚,卵巢癌多药耐药产生后治疗效果明显降低。预防和减少卵巢癌多药耐药的发生,以及对卵巢癌多药耐药的逆转治疗,是现阶段迫切需要解决的问题。国外有学者曾报道叶酸结合蛋白与卵巢癌的发生发展密切相关,在多药耐药中也扮演了重要的角色,具体机制暂未明确,需要我们进一步的研究探索。
第二章卵巢恶性肿瘤组织叶酸结合蛋白表达检测及其临床意义
目的：探讨卵巢恶性肿瘤组织中叶酸结合蛋白(FOLR1)的表达及其临床意义。方法：采用Western Blot检测80例卵巢恶性肿瘤组织、50例卵巢良性肿瘤组织及30例正常卵巢组织中的FOLR1表达情况,分析其与卵巢恶性肿瘤临床病理及多药耐药的相关性。结果：(1)FOLR1在正常卵巢组织,卵巢良性肿瘤和卵巢恶性肿瘤中的表达量依次增高(P<0.01)。(2)FOLR1在卵巢恶性肿瘤临床分期中Ⅰ～Ⅱ期的表达量低于Ⅲ～Ⅳ期,在组织分级高分化中的表达量低于中低分化(P<0.05)。(3)FOLR1在铂类药物耐药型卵巢恶性肿瘤中的表达量低于铂类药物敏感型(P<0.01)；其在治疗后仍进展肿瘤中的表达量低于缓解者(P<0.01)。(4)FOLR1在粘液性肿瘤中的表达量低于浆液性肿瘤(P<0.05),在有淋巴结和远处器官转移的卵巢恶性肿瘤中高于未有转移者(P<0.05),与患者的不同肿瘤病理分类、是否有大网膜转移和腹水量多少无明显相关(P>0.05)。(5)取FOLR1表达量界值为3.115时来判断卵巢肿瘤性质,ROC曲线的Youden指数最大,卵巢恶性肿瘤FOLR1表达量的高低与中位生存时间差别无明显相关(P>0.05),COX模型多因素分析显示FOLR1表达量不是影响患者生存预后的独立因素。结论：FOLR1在正常卵巢和卵巢良性肿瘤组织中的表达量低于卵巢恶性肿瘤,其可作为一种新型的卵巢恶性肿瘤早期诊断标志物。铂类药物耐药型卵巢恶性肿瘤中FOLR1呈低表达,在铂类药物敏感型卵巢恶性肿瘤中高表达,提示FOLR1与卵巢恶性肿瘤多药耐药相关,可作为判断卵巢恶性肿瘤多药耐药潜在标志物之一。
第三章FOLR1基因慢病毒表达载体的构建及鉴定
目的：构建携带叶酸结合蛋白基因(FOLR1)的慢病毒表达载体并进行表达鉴定。方法：PCR扩增FOLR1全长,克隆至pWPI载体质粒,重组阳性克隆行PCR和测序鉴定,重组质粒与其辅助质粒共同转染293T细胞包装病毒,病毒颗粒感染SKOV3细胞,流式分选,RT-PCR和Western Blot检测FOLR1的表达。结果：FOLR1正确克隆至pWPI载体质粒,PCR及测序证实重组表达载体构建成功,293T细胞成功包装慢病毒,pWPI-FOLR1慢病毒高效感染SKOV3细胞,RT-PCR和Western Blot检测出被感染后的SKOV3细胞中有FOLR1表达。结论：成功构建了FOLR1慢病毒表达载体,能高效感染SKOV3细胞,FOLR1基因转导后稳定表达,为下步探讨FOLR1在恶性卵巢肿瘤中的功能提供了实验基础。
第四章FOLR1基因对顺铂作用卵巢癌上皮细胞生物学影响的体外实验研究
目的：探索卵巢癌SKOV3细胞中FOLR1基因表达上调后对其生物学功能的影响以及作用途径。方法：MTT法测定三组细胞(SKOV3、pWPI-SKOV3、 pWPI-FOLR1-SKOV3)的生长增值情况、顺铂对三组细胞的IC50和不同顺铂浓度分别作用不同时间对三组细胞的抑制率；流式细胞术检测不同顺铂浓度分别作用不同时间诱导三组细胞的凋亡率；流式细胞术检测不同顺铂浓度作用48小时对三组细胞周期分布的影响；高效液相检测同浓度顺铂作用三组细胞48小时后细胞内顺铂的浓度。结果：实验组细胞(pWPI-FOLR1-SKOV3)与两组对照组相比较：(1)增殖速度明显升高、顺铂对其作用的IC50值降低。(2)顺铂对其生长抑制率增加(P<0.05),呈剂量-时间依赖关系,其对顺铂的敏感性增加。(3)顺铂更容易诱导其凋亡发生(P<0.05),呈时间-剂量依赖关系。(4)顺铂将其周期中的S期阻滞比例明显增加(P<0.05)。(5)细胞内的顺铂浓度增加近一倍。结论：FOLR1基因能增强卵巢癌SKOV3细胞的生长增殖能力；卵巢癌SKOV3细胞中FOLR1基因表达上调后顺铂对其抑制率增加,呈剂量-时间依赖关系,顺铂更容易诱导其凋亡发生,呈时间-剂量依赖关系,顺铂将其细胞周期中的S期阻滞明显增加,细胞内顺铂浓度升高。
Chapter1Research advance on multi-drug resistance in ovarian cancer
Malignant ovarian tumors are common in the female reproductive system,and second only to cervical cancer and endometrial cancer among the three gynecologic malignancies of highest incidence.Ovarian cancer.which consists of about80%of malignant ovarian tumors,is now mainly treated by surgery and platinum-based combination chemotherapy. However.most patients are diagnosed late and the chances of surgery for some of them are very little. While70-80%of all patients respond positively to chemotherapy at first,eventually drug resistance will emerge in at least80%of them who have been given the regimen.which leads to the overall5-year survival lower to be20-30%.Especially the efficacy significantly decreases as the result of multi-drug resistance(MDR),and the relative complex mechanisms remain unclear as now.So at this stage it is urgent to prevent and reduce the incidence of MDR as well as reverse it. It has been reported by foreign scholars that folate binding-protein is closely associated with the development of ovarian cancer and also plays an important role in MDR,but the specific mechanisms involved remain to be explored.
Chapter2Detection of folate binding protein expression and its clinical significance in ovarian carcinomas
Objective:To explore the expression level of folate binding protein (FOLR-1) and its clinical significance in ovarian carcinomas.
Methods:Western blot analysis was used to detect the expression levels of FOLR-1in80ovarian carcinomas,50benign ovarian tumors and30normal ovarian tissues, and its association with clinical pathology and multidrug resistance of ovarian carcinomas was analyzed.
Results:(1) The expression levels of FOLR-1increased orderly in normal ovarian tissues.benign ovarian tumors and ovarian carcinomas,and the difference was statistically significant (P<0.01).(2) For ovarian carcinomas,the expression levels of FOLR-1in clinical stage Ⅰ-Ⅱ were higher than that of stage Ⅲ-Ⅳ, and the levels of well-differentiated were lower than that of poorly differentiated.The differences were both statistically significant (P <0.05).(3) For ovarian carcinomas, the FOLR-1levels of the platinum-resistant were less than the platinum-sensitive,and the difference was statistically significant (P<0.01). After chemotherapy the FOLR-1levels of progressive ovarian carcinomas were lower than those in remission,and the difference was statistically significant (P<0.01).(4) For ovarian carcinomas,the FOLR-1levels of the mucinous type were lower than that of the serous,and the difference was statistically significant (P<0.05); The FOLR-1levels of ovarian carcinomas with metastasis to lymph nodes and distant organs were higher than those without metastasis, and the difference was statistically significant (P<0.05);However,the FOLR-1levels had no significant association with pathological classification, amounts of ascites and metastasis to the omentum (P>0.05).(5) ROC curve determining the FOLR-1levels associated nature of ovarian tumors demonstrated that the maximum Youden index was3.115.and the FOLR-1levels showed no obvious correlation with median survival time (P>0.05). COX multivariate analysis denied the FOLR-alevel as an independent prognostic factor.
Conclusions:The FOLR-1levels of normal ovarian tissues and benign ovarian tumors were lower than that of ovarian carcinomas,which suggested FOLR-1could be a new biomarker for early diagnosis of ovarian carcinomas.
Meanwhile,the FOLR-1levels in ovarian carcinomas were low for the platinum-resistant but high for the platinum-sensitive,which suggested that FOLR-1associated with multidrug resistance of ovarian carcinomas and could be a potential target for judging multidrug resistance.
Chapter3Construction and Identification of Lentiviral vector carrying FOLR1Gene
Objective:To construct a lentiviral vector expressing the gene of folate-binding protein (FOLR1) and identify its expression.
Methods:Full-length of FORL1gene was amplified by PCR,then cloned into the plasmid pWPI.and further confirmed by PCR and sequencing.After the recombinant pWPI and its helper plasmid co-transfected the virus packaging293T cells, SKOV3cells were infected with the virus particles and sorted by flow cytometry. Finally protein expression of FOLR1gene was detected by RT-PCR and Western Blotting.
Results:FOLR1gene was successfully cloned into the plasmid pWPl.The recombinant expression vector was successfully constructed,and lentiviruses were successfully packaged by the293T cells. SKOV3cells were effectively infected with the lentiviruses carrying pWPI-FOLR1gene. There's stable expression of FORL1in the infected SKOV3cells.
Conclusions:Lentiviral vector carrying FOLR1gene was constructed and could efficiently infect SKOV3cells,and stable expression of FOLR1gene laid foundation for exploring its function.
Chapter4Biological effect of the FORL1gene on epithelial ovarian cells acted by cisplatin in experimental study in vitro
Objective:To explore the biological effect of upregulated expression of the FORL gene on SKOV3cells and the functional patways.
Methods:MTT assay was used to measure the growth rate,the IC50values of cells with cisplatin and inhibition by different cisplatin concentrations at different times in the three groups of SKOV3cells,pWPI-SKOV3cells and pWPI-FOLR1-SKOV3cells.Meanwhile,flow cytometry was used to detect apoptosis and cell cycle distribution of the three groups acted by different cisplatin concentrations at different times.High Performance Liquid Chromatography (HPLC) was used to measure the cisplatin concentration in the three groups of cells acted by same concentration of cisplatin after48hours.
Results:Compared with the other two control groups,the experimental group of pWPI-FOLR1-SKOV3cells with cisplatin showed significantly increased growth rate as well as decreased IC50values.Meanwhile growth inhibition of the experimental group increased and was dose-time dependent.Cisplatin-induced apoptosis as the result of cell cycle arrest in S phase also increased in the time-dose dependent manner.The cisplatin concentration in cells was twice as much as before.
Conclusion:The FOLR1gene could enhance the growth ability of SKOV3cells,and its upregulated expression led to the increase of inhibition after cisplatin in a dose-time dependent manner.Meanwhile cisplatin-induced apoptosis through cell cycle arrest in S phase also increased significantly in the manner of time-dose dependence,and the cisplatin concentration in cells increased.
引文
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