Wnt/β-catenin信号通路对套细胞淋巴瘤中细胞增殖、侵袭性生长的影响
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摘要
目的:研究Wnt/β-catenin信号通路对套细胞淋巴瘤中细胞增殖、侵袭性生长的影响。方法:选择2015年3月~2017年5月期间华中科技大学同济医学院附属同济医院经淋巴结活检诊断为套细胞淋巴瘤的患者作为研究的淋巴瘤组,同期经淋巴结活检诊断为反应性增生的患者作为对照组。采用酶联免疫吸附试剂盒测定淋巴结组织中Wnt/β-catenin信号通路分子的蛋白表达量,采用荧光定量PCR试剂盒测定增殖基因、侵袭基因的mRNA表达量。结果:淋巴瘤组患者淋巴结组织中β-catenin、pGSK-3β、Tcf/Lef的蛋白含量以及C-myc、CyclinD1、Est-1、MMP9、MMP26的mRNA表达量显著高于对照组,DKK1、WIF-1的蛋白含量以及Bax、Apaf1、Caspase-3、TNFAIP3、TIMP2、TIMP4的mRNA表达量显著低于对照组。淋巴瘤组织中C-myc、CyclinD1、Est-1、MMP9、MMP26的mRNA表达量与β-catenin、p-GSK-3β、Tcf/Lef的蛋白含量呈正相关,与DKK1、WIF-1的蛋白含量呈负相关;Bax、Apaf1、Caspase-3、TNFAIP3、TIMP2、TIMP4的mRNA表达量与β-catenin、p-GSK-3β、Tcf/Lef的蛋白含量呈负相关,与DKK1、WIF-1的蛋白含量呈正相关。结论:Wnt/β-catenin信号通路的激活能够促进套细胞淋巴瘤中细胞的增殖及侵袭性生长。
Objective:To study the effects of Wnt/β-catenin signaling pathway on the proliferation and invasive growth of cells in mantle cell lymphoma.Methods:Patients who were diagnosed with mantle cell lymphoma by lymph node biopsy in Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology between March 2015 and May 2017 were selected as lymphoma group of the research,and patients who were diagnosed with reactive hyperplasia by lymph node biopsy during the same period were selected as the control group.The protein expression of Wnt/β-catenin signaling pathway molecules in lymph node tissues were determined by enzyme-linked immunosorbent assay kit,and the mRNA expression of proliferation genes and invasion genes were determined by fluorescence quantitative PCR kit.Results:β-catenin,pGSK-3βand Tcf/Lef protein levels as well as C-myc,CyclinD1,Est-1,MMP9 and MMP26 mRNA expression in lymph node tissues of lymphoma group were significantly higher than those of control group whereas DKK1 and WIF-1 protein levels as well as Bax,Apaf1,Caspase-3,TNFAIP3,TIMP2 and TIMP4 mRNA expression were significantly lower than those of control group(P<0.05).C-myc,CyclinD1,Est-1,MMP9 and MMP26 mRNA expression in lymphoma tissues were positively correlated withβ-catenin,p-GSK-3βand Tcf/Lef protein levels,and negatively correlated with DKK1 and WIF-1 protein levels;Bax,Apaf1,Caspase-3,TNFAIP3,TIMP2 and TIMP4 mRNA expression were negatively correlated withβ-catenin,pGSK-3βand Tcf/Lef protein levels,and positively correlated with DKK1 and WIF-1 protein levels.Conclusion:The activation of Wnt/β-catenin signaling pathway can promote the proliferation and invasive growth of cells in mantle cell lymphoma.
Objective:To study the effects of Wnt/β-catenin signaling pathway on the proliferation and invasive growth of cells in mantle cell lymphoma.Methods:Patients who were diagnosed with mantle cell lymphoma by lymph node biopsy in Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology between March 2015 and May 2017 were selected as lymphoma group of the research,and patients who were diagnosed with reactive hyperplasia by lymph node biopsy during the same period were selected as the control group.The protein expression of Wnt/β-catenin signaling pathway molecules in lymph node tissues were determined by enzyme-linked immunosorbent assay kit,and the mRNA expression of proliferation genes and invasion genes were determined by fluorescence quantitative PCR kit.Results:β-catenin,pGSK-3βand Tcf/Lef protein levels as well as C-myc,CyclinD1,Est-1,MMP9 and MMP26 mRNA expression in lymph node tissues of lymphoma group were significantly higher than those of control group whereas DKK1 and WIF-1 protein levels as well as Bax,Apaf1,Caspase-3,TNFAIP3,TIMP2 and TIMP4 mRNA expression were significantly lower than those of control group(P<0.05).C-myc,CyclinD1,Est-1,MMP9 and MMP26 mRNA expression in lymphoma tissues were positively correlated withβ-catenin,p-GSK-3βand Tcf/Lef protein levels,and negatively correlated with DKK1 and WIF-1 protein levels;Bax,Apaf1,Caspase-3,TNFAIP3,TIMP2 and TIMP4 mRNA expression were negatively correlated withβ-catenin,pGSK-3βand Tcf/Lef protein levels,and positively correlated with DKK1 and WIF-1 protein levels.Conclusion:The activation of Wnt/β-catenin signaling pathway can promote the proliferation and invasive growth of cells in mantle cell lymphoma.
引文
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4 秦贝贝,李亚青,李小丽,等.Wnt/β-catenin通路关键分子在NK/T细胞淋巴瘤组织中的表达及其临床意义[J].吉林大学学报(医学版),2015,41(2):230-234.
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9 Linke F,Harenberg M,Nietert MM,et al.Microenvironmental interactions between endothelial and lymphoma cells:a role for the canonical WNT pathway in Hodgkin lymphoma[J].Leukemia,2017,31(2):361-372.
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11 Verras M,Papandreou I,Denko NC.WNT16-expressing Acute Lymphoblastic Leukemia Cells are Sensitive to Autophagy Inhibitors after ER Stress Induction[J].Anticancer Res,2015m35(9):4625-4631.
12 Ptrascu AM,Rotaru I,Olar L,et al.The prognostic role of Bcl-2,Ki67,c-MYC and p53in diffuse large B-cell lymphoma[J].Rom J Morphol Embryol,2017,58(3):837-843.
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14 Hirsch B,Grünbaum M,Wagner F,et al.A novel A20(TNFAIP3)antibody(Ber-A20)can be used to detect unmutated A20by immunohistology[J].Histopathology,2012,60(6B):19-27.
15 Malaponte G,Hafsi S,Polesel J,et al.Tumor microenvironment in diffuse large B-cell lymphoma:Matrixmetalloproteinases activation is mediated by osteopontin overexpression[J].Biochim Biophys Acta,2016,1863(3):483-489.
16 PrvnescuV,Georgescu M,Georgescu I,et al.The Role of Matrix Metalloproteinase-9(MMP-9)as a Prognostic Factor in Epithelial and Lymphatic Neoplasia[J].Chirurgia(Bucur),2015,110(6):506-510.
17 Guo F,Tian J,Cui M,et al.Downregulation of matrix metalloproteinase 9by small interfering RNA inhibits the tumor growth of ovarian epithelial carcinoma in vitro and in vivo[J].Mol Med Rep,2015,12(1):753-759.
2 Vergote V,Janssens A,AndréM,et al.Results from the Belgian mantle cell lymphoma registry[J].Acta Clin Belg,2017,72(3):172-178.
3 Santiago L,Daniels G,Wang D,et al.Wnt signaling pathway protein LEF1in cancer,as a biomarker for prognosis and a target for treatment[J].Am J Cancer Res,2017,7(6):1389-1406.
4 秦贝贝,李亚青,李小丽,等.Wnt/β-catenin通路关键分子在NK/T细胞淋巴瘤组织中的表达及其临床意义[J].吉林大学学报(医学版),2015,41(2):230-234.
5 Martin P,Ghione P,Dreyling M.Mantle cell lymphoma-Current standards of care and future directions[J].Cancer Treat Rev,2017,58:51-60.
6 Cohen JB,Zain JM,Kahl BS.Current Approaches to Mantle Cell Lymphoma:Diagnosis,Prognosis,and Therapies[J].Am Soc Clin Oncol Educ Book,2017,37:512-525.
7 JanovskP,Bryja V.Wnt signalling pathways in chronic lymphocytic leukaemia and B-cell lymphomas[J].Br J Pharmacol,2017,174(24):4701-4715.
8 Wu C,Zhang HF,Gupta N,et al.A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma[J].J Hematol Oncol,2016,9(1):120.
9 Linke F,Harenberg M,Nietert MM,et al.Microenvironmental interactions between endothelial and lymphoma cells:a role for the canonical WNT pathway in Hodgkin lymphoma[J].Leukemia,2017,31(2):361-372.
10 Pamuk GE,Uyanik MS,Pamuk ON,et al.Decreased dickkopf-1 levels in chronic lymphocytic leukemia and increased osteopontin levels in non-Hodgkin's lymphoma at initial diagnosis:Could they be playing roles in pathogenesis?[J].Hematology,2015,20(5):267-271.
11 Verras M,Papandreou I,Denko NC.WNT16-expressing Acute Lymphoblastic Leukemia Cells are Sensitive to Autophagy Inhibitors after ER Stress Induction[J].Anticancer Res,2015m35(9):4625-4631.
12 Ptrascu AM,Rotaru I,Olar L,et al.The prognostic role of Bcl-2,Ki67,c-MYC and p53in diffuse large B-cell lymphoma[J].Rom J Morphol Embryol,2017,58(3):837-843.
13 Jiang C,Shi X,Fan C.A cyclin D1-positive diffuse large B-cell lymphoma of germinal center B-cell-like subtype in the right tonsil:A rare case report[J].Medicine(Baltimore),2017,96(11):e6311.
14 Hirsch B,Grünbaum M,Wagner F,et al.A novel A20(TNFAIP3)antibody(Ber-A20)can be used to detect unmutated A20by immunohistology[J].Histopathology,2012,60(6B):19-27.
15 Malaponte G,Hafsi S,Polesel J,et al.Tumor microenvironment in diffuse large B-cell lymphoma:Matrixmetalloproteinases activation is mediated by osteopontin overexpression[J].Biochim Biophys Acta,2016,1863(3):483-489.
16 PrvnescuV,Georgescu M,Georgescu I,et al.The Role of Matrix Metalloproteinase-9(MMP-9)as a Prognostic Factor in Epithelial and Lymphatic Neoplasia[J].Chirurgia(Bucur),2015,110(6):506-510.
17 Guo F,Tian J,Cui M,et al.Downregulation of matrix metalloproteinase 9by small interfering RNA inhibits the tumor growth of ovarian epithelial carcinoma in vitro and in vivo[J].Mol Med Rep,2015,12(1):753-759.