膀胱癌组织中TopoⅡα表达水平及其对TURBT术后吡柔比星注射液膀胱灌注治疗的影响
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摘要
目的:探讨膀胱癌组织中DNA拓扑异构酶Ⅱα(TopoⅡα)表达水平及其对经尿道膀胱肿瘤切除术(TURBT)后吡柔比星注射液膀胱灌注治疗的影响。方法:本院泌尿外科确诊的膀胱癌患者49例,所有患者行TURBT,术后吡柔比星注射液膀胱灌注治疗,同时选取49例癌旁组织作为对照组,逆转录实时荧光PCR法、酶联免疫吸附法及免疫组化方法测定TopoⅡαmRNA、TopoⅡα蛋白表达水平,并对膀胱癌患者TURBT术后吡柔比星注射液灌注治疗进行随访。结果:膀胱癌组织TopoⅡαmRNA、TopoⅡα蛋白表达水平高于癌旁组织(t=42.867、92.026,P<0.01);膀胱癌组织TopoⅡα阳性率高于癌旁组织(χ~2=57.408,P<0.01);TopoⅡα蛋白表达与年龄、病理分型相关性不明显(χ~2=0.124、0.465,P>0.05);与浸润深度、病理学分级、TNM分期、淋巴结转移、淋巴血管间隙浸润相关性明显,且浸润深度越深、病理学分期越高、TNM分期越高、有淋巴结转移、有淋巴血管间隙浸润,TopoⅡα蛋白阳性表达率越高(χ~2=12.257、9.428、5.682、7.639、3.864,P<0.01或P<0.05);TURBT术后吡柔比星膀胱灌注未复发膀胱癌患者的TopoⅡα阳性表达水平明显高于TURBT术后吡柔比星膀胱灌注复发膀胱癌患者(χ~2=10.176,P<0.01);TURBT术后吡柔比星膀胱灌注TopoⅡα阳性组的不良反应发生率明显低于TopoⅡα阴性组(χ~2=20.862,P<0.01);TURBT术后吡柔比星膀胱灌TopoⅡα阳性组3年生存率及生存期均明显高于TopoⅡα阴性组(χ~2=5.267、Z=6.432,P<0.05)。结论:TopoⅡα在膀胱癌组织中高表达,TopoⅡα能促进膀胱癌的进展;TopoⅡα高表达能提高TURBT术后吡柔比星注射液膀胱灌注治疗效果,增加膀胱癌患者3年生存率及生存期,降低膀胱癌复发风险,其机制可能与吡柔比星结合TopoⅡα抑制癌细胞IL-8、VEGF的表达有关。
Objective:To investigate the effect of the TopoⅡαexpression level in bladder cancer tissue on the intravesical instillation of pirarubicin after transurethral resection of bladder tumor(TURBT).Method:Forty-nine patients diagnosed with urinary bladder cancer in our hospital were selected and received the intravesical instillation of pirarubicin after TURBT.And 49 normal adjacent bladder tissues were selected as controlled group.Reverse transcription real-time fluorescence PCR,enzyme-linked immunosorbent assay and immunohistochemistry were used to determine the expression of TopoⅡαmRNA and TopoⅡαprotein.Moreover,the patients were followed up.Result:The expression level of TopoⅡαmRNA and TopoⅡαprotein in bladder cancer tissues was higher than that in adjacent normal tissues(t=42.867,92.026,P<0.01).The positive rate of TopoⅡαin bladder cancer tissues was higher than that in adjacent normal tissues(χ~2=57.408,P<0.01).The expression of TopoⅡαprotein was not correlated with age or pathological type(χ~2=0.124,0.465,P>0.05),but was positively correlated with depth of invasion,pathological grade,TNM stage,lymph node metastasis and lymph vessel infiltration(χ~2=12.257,9.428,5.682,7.639,3.864,P<0.01/P<0.05).The positive expression level of TopoⅡαin patients without recurrent bladder cancer was significantly higher than that in patients with recurrent bladder cancer(χ~2=10.176,P<0.01).The incidence of adverse reactions in the TopoⅡαpositive group was significantly lower than that in the TopoⅡαnegative group(χ~2=20.862,P<0.01).The 3-year survival rate and survival time of the TopoⅡαpositive group were significantly higher than those of the TopoⅡαnegative group(χ~2=5.267,Z=6.432,P<0.05).Conclusion:TopoⅡαis highly expressed in bladder cancer tissue and can promote the progression of bladder cancer.High expression of TopoⅡαcan improve the therapeutic effect of intravesical instillation of pirarubicin after TURBT,increase the 3-year survival rate and survival time,and reduce recurrence rate.Its mechanism may be related to the inhibition of the expression of IL-8 and VEGF by the combination of pirarubicin with TopoⅡα.
Objective:To investigate the effect of the TopoⅡαexpression level in bladder cancer tissue on the intravesical instillation of pirarubicin after transurethral resection of bladder tumor(TURBT).Method:Forty-nine patients diagnosed with urinary bladder cancer in our hospital were selected and received the intravesical instillation of pirarubicin after TURBT.And 49 normal adjacent bladder tissues were selected as controlled group.Reverse transcription real-time fluorescence PCR,enzyme-linked immunosorbent assay and immunohistochemistry were used to determine the expression of TopoⅡαmRNA and TopoⅡαprotein.Moreover,the patients were followed up.Result:The expression level of TopoⅡαmRNA and TopoⅡαprotein in bladder cancer tissues was higher than that in adjacent normal tissues(t=42.867,92.026,P<0.01).The positive rate of TopoⅡαin bladder cancer tissues was higher than that in adjacent normal tissues(χ~2=57.408,P<0.01).The expression of TopoⅡαprotein was not correlated with age or pathological type(χ~2=0.124,0.465,P>0.05),but was positively correlated with depth of invasion,pathological grade,TNM stage,lymph node metastasis and lymph vessel infiltration(χ~2=12.257,9.428,5.682,7.639,3.864,P<0.01/P<0.05).The positive expression level of TopoⅡαin patients without recurrent bladder cancer was significantly higher than that in patients with recurrent bladder cancer(χ~2=10.176,P<0.01).The incidence of adverse reactions in the TopoⅡαpositive group was significantly lower than that in the TopoⅡαnegative group(χ~2=20.862,P<0.01).The 3-year survival rate and survival time of the TopoⅡαpositive group were significantly higher than those of the TopoⅡαnegative group(χ~2=5.267,Z=6.432,P<0.05).Conclusion:TopoⅡαis highly expressed in bladder cancer tissue and can promote the progression of bladder cancer.High expression of TopoⅡαcan improve the therapeutic effect of intravesical instillation of pirarubicin after TURBT,increase the 3-year survival rate and survival time,and reduce recurrence rate.Its mechanism may be related to the inhibition of the expression of IL-8 and VEGF by the combination of pirarubicin with TopoⅡα.
引文
1李吉,刘裔道,蚌凌青.肌层浸润性膀胱癌患者膀胱部分切除术结合放化疗的临床疗效及预后分析[J].临床泌尿外科杂志,2017,32(10):767-770.
2杨玉帛,刘振华,韩平.经尿道膀胱肿瘤整块切除术的研究进展[J].临床泌尿外科杂志,2017,32(10):775-778.
3 Grayson M.Bladder cancer[J].Nature,2017,551(7679):S33-S34.
4 Sanli O,Dobruch J,Knowles M A,et al.Bladder cancer[J].Nat Rev Dis Primers,2017,3(3):22-23.
5 Yoshida M M,Ting L,Gygi S P,et al.SUMOylation of DNA topoisomeraseⅡαregulates histone H3kinase Haspin and H3phosphorylation in mitosis[J].J Cell Biol,2016,213(6):665-678.
6 Guturi K K,Bohgaki M,Bohgaki T,et al.RNF168and USP10regulate topoisomerase IIαfunction via opposing effects on its ubiquitylation[J].Nat Commun,2016,7:12638.
7 Raspollini M R,Luque R J,Menendez C L.T1highgrade bladder carcinoma outcome:the role of p16,topoisomerase-Iiα,survivin,and E-cadherin[J].Hum Pathol,2016,57(3):78-84.
8 Farling K B.Bladder cancer:Risk factors,diagnosis,and management[J].Nurse Pract,2017,42(3):26-33.
9李文祥,魏瑾,胡森焱,等.乳腺癌患者新辅助化疗前后TopoⅡ蛋白变化及其对术后化疗方案的指导意义[J].实用癌症杂志,2017,32(12):1918-1921.
10董冰,汪洁.TUBB3和TopoⅡα表达与老年女性乳腺癌患者术后化疗临床预后的回顾性分析[J].老年医学与保健,2017,5(5):396-399.
11李先佳,任丽平,金少举.马鞭草总黄酮靶向拓扑异构酶Ⅱ诱导肝癌HepG-2细胞凋亡[J].中国药理学通报,2017,33(8):1147-1152.
12 Rao N,Qiu J,Wu J,et al.Significance of Tumor-Infiltrating Lymphocytes and the Expression of TopoisomeraseⅡαin the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy[J].Chemotherapy,2017,62(4):246-247.
13 Kozuki T,Chikamori K,Surleac M D,et al.Roles of the C-terminal domains of topoisomeraseⅡαand topoisomeraseⅡβin regulation of the decatenation checkpoint[J].Nucleic Acids Res,2017,45(10):5995-6010.
14 Ghosh S,Mukhopadhyay S,Sarkar M,et al.Biological evaluation of a halogenated triterpenoid,2α-bromo-dihydrobelulonic acid as inhibitor of human topoisomeraseⅡαand HeLa cell proliferation[J].Chem Biol Interact,2017,268:68-70.
15 Behnfeldt J H,Acharya S,Tangeman L,et al.A triserine cluster within the topoisomeraseⅡα-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells[J].Hum Mol Genet,2018,27(7):1241-1251.
16 Karelia D N,Sk U H,Singh P,et al.Design,synthesis,and identification of a novel napthalamide-isoselenocyanate compound NISC-6as a dual Topoisomerase-Ⅱαand Akt pathway inhibitor,and evaluation of its antimelanoma activity[J].Eur J Med Chem,2017,135:282-295.
17 Zoidis G,Sosic A,Da Ros S.et al.Indenocinnoline derivatives as G-quadruplex binders,topoisomeraseⅡαinhibitors and antiproliferative agents[J].Bioorg Med Chem,2017,25(9):2625-2634.
18 Kanagasabai R,Serdar L,Karmahapatra S,et al.Alternative RNA Processing of Topoisomerase IIαin Etoposide-Resistant Human Leukemia K562Cells:Intron Retention Results in a Novel C-Terminal Truncated 90-kDa Isoform[J].J Pharmacol Exp Ther,2017,360(1):152-163.
2杨玉帛,刘振华,韩平.经尿道膀胱肿瘤整块切除术的研究进展[J].临床泌尿外科杂志,2017,32(10):775-778.
3 Grayson M.Bladder cancer[J].Nature,2017,551(7679):S33-S34.
4 Sanli O,Dobruch J,Knowles M A,et al.Bladder cancer[J].Nat Rev Dis Primers,2017,3(3):22-23.
5 Yoshida M M,Ting L,Gygi S P,et al.SUMOylation of DNA topoisomeraseⅡαregulates histone H3kinase Haspin and H3phosphorylation in mitosis[J].J Cell Biol,2016,213(6):665-678.
6 Guturi K K,Bohgaki M,Bohgaki T,et al.RNF168and USP10regulate topoisomerase IIαfunction via opposing effects on its ubiquitylation[J].Nat Commun,2016,7:12638.
7 Raspollini M R,Luque R J,Menendez C L.T1highgrade bladder carcinoma outcome:the role of p16,topoisomerase-Iiα,survivin,and E-cadherin[J].Hum Pathol,2016,57(3):78-84.
8 Farling K B.Bladder cancer:Risk factors,diagnosis,and management[J].Nurse Pract,2017,42(3):26-33.
9李文祥,魏瑾,胡森焱,等.乳腺癌患者新辅助化疗前后TopoⅡ蛋白变化及其对术后化疗方案的指导意义[J].实用癌症杂志,2017,32(12):1918-1921.
10董冰,汪洁.TUBB3和TopoⅡα表达与老年女性乳腺癌患者术后化疗临床预后的回顾性分析[J].老年医学与保健,2017,5(5):396-399.
11李先佳,任丽平,金少举.马鞭草总黄酮靶向拓扑异构酶Ⅱ诱导肝癌HepG-2细胞凋亡[J].中国药理学通报,2017,33(8):1147-1152.
12 Rao N,Qiu J,Wu J,et al.Significance of Tumor-Infiltrating Lymphocytes and the Expression of TopoisomeraseⅡαin the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy[J].Chemotherapy,2017,62(4):246-247.
13 Kozuki T,Chikamori K,Surleac M D,et al.Roles of the C-terminal domains of topoisomeraseⅡαand topoisomeraseⅡβin regulation of the decatenation checkpoint[J].Nucleic Acids Res,2017,45(10):5995-6010.
14 Ghosh S,Mukhopadhyay S,Sarkar M,et al.Biological evaluation of a halogenated triterpenoid,2α-bromo-dihydrobelulonic acid as inhibitor of human topoisomeraseⅡαand HeLa cell proliferation[J].Chem Biol Interact,2017,268:68-70.
15 Behnfeldt J H,Acharya S,Tangeman L,et al.A triserine cluster within the topoisomeraseⅡα-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells[J].Hum Mol Genet,2018,27(7):1241-1251.
16 Karelia D N,Sk U H,Singh P,et al.Design,synthesis,and identification of a novel napthalamide-isoselenocyanate compound NISC-6as a dual Topoisomerase-Ⅱαand Akt pathway inhibitor,and evaluation of its antimelanoma activity[J].Eur J Med Chem,2017,135:282-295.
17 Zoidis G,Sosic A,Da Ros S.et al.Indenocinnoline derivatives as G-quadruplex binders,topoisomeraseⅡαinhibitors and antiproliferative agents[J].Bioorg Med Chem,2017,25(9):2625-2634.
18 Kanagasabai R,Serdar L,Karmahapatra S,et al.Alternative RNA Processing of Topoisomerase IIαin Etoposide-Resistant Human Leukemia K562Cells:Intron Retention Results in a Novel C-Terminal Truncated 90-kDa Isoform[J].J Pharmacol Exp Ther,2017,360(1):152-163.
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