盐霉素抗膀胱癌T24细胞作用机制及对Mta-1基因及Smad4基因表达的影响
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摘要
目的：膀胱癌是我国泌尿外科最常见的恶性肿瘤。是一种严重威胁患者生命安全的疾病。目前对非浸润性膀胱癌最主要的治疗手段是经尿道膀胱肿瘤电切手术加术后灌注化疗。术后灌注化疗可以有效的降低膀胱癌的复发率,但是目前膀胱灌注化疗的药物毒性较大,副作用多,很多患者无法耐受而导致终止灌注化疗。盐霉素是一种典型的具有特殊环状结构的离子载体抗生素,属于聚醚类一元羧酸。本身是一种具有低毒、低残留特性的抗球虫剂及促生长素。然而2009年美国科研人员发现其是一种可以直接瞄准杀死肿瘤干细胞的的化合物,其不但可以直接杀灭肿瘤干细胞,还可以抑制肿瘤干细胞分化出新生的肿瘤细胞及减缓肿瘤的生长速度。本实验通过研究盐霉素对膀胱癌T24细胞的体外抗肿瘤作用及从分子生物学角度阐述盐霉素对膀胱癌T24细胞基因的影响,力图揭示盐霉素对膀胱癌的抗肿瘤作用机制,对将盐霉素应用于临床膀胱癌术后灌注化疗提供理论依据。
方法：(1)体外传代培养人类膀胱癌T24细胞系；(2)应用四氮噻唑蓝(MTT)法测定盐霉素对膀胱癌T24细胞增殖的影响；(3)应用光镜及流式细胞仪观察测定盐霉素对膀胱癌T24细胞凋亡的影响；(4)应用RT-PCR, Western-blot方法探讨盐霉素对癌基因Mta-1及抗癌基因Smad-4基因表达的影响。
结果及讨论：(1)盐霉素能诱导人膀胱癌T24细胞凋亡,随着盐霉素作用时间和浓度的增加,T24细胞的凋亡明显增加,统计学分析表明药物浓度和作用时间与细胞凋亡率呈正相关；盐霉素抑制人膀胱癌T24细胞增殖,随着盐霉素作用时间和浓度的增加,T24细胞的增殖明显受到抑制,统计学分析表明药物浓度和作用时间与细胞凋亡率呈负相关；(2)盐霉素作用于膀胱癌T24细胞,可以抑制膀胱癌T24细胞Mta-1基因的表达,通过这种抑制作用可能降低膀胱癌T24细胞的侵袭力及转移力,从而降低膀胱癌术后复发率；(3)盐霉素作用于膀胱癌T24细胞,可以增加膀胱癌T24细胞Smad4基因的表达,通过这种作用机制可以抑制膀胱癌细胞增殖及促进凋亡,可能是盐霉素抗膀胱癌的作用机制之一。
Purpose:Bladder cancer is the most common malignancy of Urology.,Which seriously threat the safety of patients.The most important treatment for non-invasive bladder cancer is transurethral resection of bladder tumor cut surgery plus postoperative infusion chemotherapy. Postoperative infusion chemotherapy can effectively reduce the rate of recurrence of bladder cancer. Because of bladder instillation chemotherapy drug with toxicity and side effects, many patients can not tolerate a result of the termination of infusion chemotherapy. Salinomycin is a typical example having a cyclic structure in special ionophore antibiotics belonging to the polyether monocarboxylic acid. Salinomycin is a kind of low toxicity and residue characteristics of anticoccidial agents and somatotropin. In2009, U.S. researchers found a aimed directly kill tumor stem cell compounds, not only can directly kill tumor stem cells can also inhibit cancer stem cell differentiation nascent tumor cells and slow tumor growth rate. In this study, the research salinomycin T24bladder cancer cells in vitro anti-tumor effect and salinomycin T24cells gene described from the perspective of molecular biology, trying to reveal salinomycin antitumor mechanism of bladder cancer, salinomycin used in clinical bladder cancer infusion chemotherapy provide a theoretical basis.
Methods:(1) In vitro cultured human T24bladder cancer cell lines;(2) Application of nitrogen thiazole blue (MTT) method for the determination of salinomycin proliferation of T24cells;(3) Light microscopy and flow cytometryDetermination of salinomycin apoptosis in T24cells;(4) RT-PCR, Western-blot method of salinomycin oncogene Mta-1and the anticancer genes Smad-4gene expression.
Result and Conclusion:(1)Salinomycin can induce apoptosis in human bladder carcinoma T24, T24cell apoptosis increased significantly with increasing duration of action and concentration of salinomycin, statistical analysis showed that the drug concentration and the duration of action and the rate of apoptosiswas positively correlated; salinomycin inhibits the proliferation of T24cells, the as salinomycin role of time and the increasing concentration of the proliferation of T24cells was significantly inhibited, statistical analysis showed that the drug concentration and duration of action and the rate of apoptosis was negativelyRelevance;(2) Salinomycin role in bladder cancer T24cells, bladder cancer T24cells MTA-1gene expression can be inhibited by this inhibition may reduce the invasiveness and metastasis of bladder cancer T24cells, thereby reducing bladder cancerrecurrence rate;(3) Salinomycin role in bladder cancer T24cells can be increased bladder cancer T24cells Smad4gene expression in bladder cancer cell proliferation and promote apoptosis can be suppressed by this mechanism, it may be salinomycinone of the mechanisms of the anti-bladder cancer.
方法：(1)体外传代培养人类膀胱癌T24细胞系；(2)应用四氮噻唑蓝(MTT)法测定盐霉素对膀胱癌T24细胞增殖的影响；(3)应用光镜及流式细胞仪观察测定盐霉素对膀胱癌T24细胞凋亡的影响；(4)应用RT-PCR, Western-blot方法探讨盐霉素对癌基因Mta-1及抗癌基因Smad-4基因表达的影响。
结果及讨论：(1)盐霉素能诱导人膀胱癌T24细胞凋亡,随着盐霉素作用时间和浓度的增加,T24细胞的凋亡明显增加,统计学分析表明药物浓度和作用时间与细胞凋亡率呈正相关；盐霉素抑制人膀胱癌T24细胞增殖,随着盐霉素作用时间和浓度的增加,T24细胞的增殖明显受到抑制,统计学分析表明药物浓度和作用时间与细胞凋亡率呈负相关；(2)盐霉素作用于膀胱癌T24细胞,可以抑制膀胱癌T24细胞Mta-1基因的表达,通过这种抑制作用可能降低膀胱癌T24细胞的侵袭力及转移力,从而降低膀胱癌术后复发率；(3)盐霉素作用于膀胱癌T24细胞,可以增加膀胱癌T24细胞Smad4基因的表达,通过这种作用机制可以抑制膀胱癌细胞增殖及促进凋亡,可能是盐霉素抗膀胱癌的作用机制之一。
Purpose:Bladder cancer is the most common malignancy of Urology.,Which seriously threat the safety of patients.The most important treatment for non-invasive bladder cancer is transurethral resection of bladder tumor cut surgery plus postoperative infusion chemotherapy. Postoperative infusion chemotherapy can effectively reduce the rate of recurrence of bladder cancer. Because of bladder instillation chemotherapy drug with toxicity and side effects, many patients can not tolerate a result of the termination of infusion chemotherapy. Salinomycin is a typical example having a cyclic structure in special ionophore antibiotics belonging to the polyether monocarboxylic acid. Salinomycin is a kind of low toxicity and residue characteristics of anticoccidial agents and somatotropin. In2009, U.S. researchers found a aimed directly kill tumor stem cell compounds, not only can directly kill tumor stem cells can also inhibit cancer stem cell differentiation nascent tumor cells and slow tumor growth rate. In this study, the research salinomycin T24bladder cancer cells in vitro anti-tumor effect and salinomycin T24cells gene described from the perspective of molecular biology, trying to reveal salinomycin antitumor mechanism of bladder cancer, salinomycin used in clinical bladder cancer infusion chemotherapy provide a theoretical basis.
Methods:(1) In vitro cultured human T24bladder cancer cell lines;(2) Application of nitrogen thiazole blue (MTT) method for the determination of salinomycin proliferation of T24cells;(3) Light microscopy and flow cytometryDetermination of salinomycin apoptosis in T24cells;(4) RT-PCR, Western-blot method of salinomycin oncogene Mta-1and the anticancer genes Smad-4gene expression.
Result and Conclusion:(1)Salinomycin can induce apoptosis in human bladder carcinoma T24, T24cell apoptosis increased significantly with increasing duration of action and concentration of salinomycin, statistical analysis showed that the drug concentration and the duration of action and the rate of apoptosiswas positively correlated; salinomycin inhibits the proliferation of T24cells, the as salinomycin role of time and the increasing concentration of the proliferation of T24cells was significantly inhibited, statistical analysis showed that the drug concentration and duration of action and the rate of apoptosis was negativelyRelevance;(2) Salinomycin role in bladder cancer T24cells, bladder cancer T24cells MTA-1gene expression can be inhibited by this inhibition may reduce the invasiveness and metastasis of bladder cancer T24cells, thereby reducing bladder cancerrecurrence rate;(3) Salinomycin role in bladder cancer T24cells can be increased bladder cancer T24cells Smad4gene expression in bladder cancer cell proliferation and promote apoptosis can be suppressed by this mechanism, it may be salinomycinone of the mechanisms of the anti-bladder cancer.
引文
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