急性髓系白血病患者PD-L1和MicroRNA-138-5p的表达及其临床意义
|
摘要
目的:探讨PD-L1和MicroRNA-138-5p(miR-138)在急性髓系白血病(AML)患者外周血单个核细胞(PBMNCs)中的表达特点及其临床意义。方法:应用SYBR GreenⅠreal-time PCR方法分别检测20例初治AML患者、9例复发/难治AML患者和8例完全缓解患者PBMNCs中PD-L1 mRNA和miR-138的表达水平,并选择20例健康体检者外周血样本作为对照组。结果:初治AML组和复发/难治AML组患者PD-L1的表达水平均显著高于健康对照组(P<0.01),而且复发/难治AML组患者PD-L1的表达水平显著高于初治AML组患者(P<0.01);初治AML组和复发/难治AML组患者miR-138的表达水平均显著低于健康对照组(P<0.01);在20例初治AML患者中共收集了8例完全缓解期标本,完全缓解组mi R-138的表达水平高于初治AML组(P<0.05),而缓解组PD-L1的表达水平与初治AML组差异无统计学意义(P>0.05);初治AML患者中PD-L1 mRNA与mi R-138表达呈负相关(P<0.05)。结论:AML患者PBMC中PD-L1表达增加、miR-138表达下调,且两者间有相关性。
Objective: To investigate the expression and clinical significance of PD-L1 and microRNA-138-5 p in the peripheral blood mononuclear cells of patients with acute myeloid leukemia. Methods: The SYBR Green Ⅰ real-time PCR was used to detect the expression levels of PD-L1 mRNA and miR-138 in 20 cases of primary AML, 9 cases of relapsed/refractory AML and 8 cases of complete remission. The samples of peripheral blood of 20 healthy peoples were used as controls. Results: The expression levels of PD-L1 in both the primary AML and the relapsed/refractory AML groups were significantly higher than those in the healthy control group(P<0.01), and the expression level of PD-L1 in the relapsed/refractory AML group was significantly higher than that in the primary AML group(P<0.01).The expression level of miR-138 in both the primary AML and the relapsed/refractory AML groups were significantly lower than that in the healthy control group(P<0.01). The 8 sampes out of 20 cases of primary AML patients achieved complete remission(CR) were collected and detected. The results showed that the expression level of miR-138 in the complete remission group was higher than that in the primary AML group(P<0.05), but the expression level of PDL1 mRNA in the CR group was not significantly different from that in the primary AML group(P>0.05). and there was a negative correlation between PD-L1 mRNA and miR-138 in primary AML patients(P<0.05). Conclusion: The expression of PD-L1 increases and the expression of miR-138 down-regulates in PBMNCs of AML patients, furthermore,both correlate each other.
Objective: To investigate the expression and clinical significance of PD-L1 and microRNA-138-5 p in the peripheral blood mononuclear cells of patients with acute myeloid leukemia. Methods: The SYBR Green Ⅰ real-time PCR was used to detect the expression levels of PD-L1 mRNA and miR-138 in 20 cases of primary AML, 9 cases of relapsed/refractory AML and 8 cases of complete remission. The samples of peripheral blood of 20 healthy peoples were used as controls. Results: The expression levels of PD-L1 in both the primary AML and the relapsed/refractory AML groups were significantly higher than those in the healthy control group(P<0.01), and the expression level of PD-L1 in the relapsed/refractory AML group was significantly higher than that in the primary AML group(P<0.01).The expression level of miR-138 in both the primary AML and the relapsed/refractory AML groups were significantly lower than that in the healthy control group(P<0.01). The 8 sampes out of 20 cases of primary AML patients achieved complete remission(CR) were collected and detected. The results showed that the expression level of miR-138 in the complete remission group was higher than that in the primary AML group(P<0.05), but the expression level of PDL1 mRNA in the CR group was not significantly different from that in the primary AML group(P>0.05). and there was a negative correlation between PD-L1 mRNA and miR-138 in primary AML patients(P<0.05). Conclusion: The expression of PD-L1 increases and the expression of miR-138 down-regulates in PBMNCs of AML patients, furthermore,both correlate each other.
引文
1Lee J, Kefford R, Carlino M. PD-1 and PD-L1 inhibitors in melanoma treatment:past success, present application and future challenges. Immunotherapy, 2016; 8(6):733-746.
2 Tanaka Y, Maeshima AM, Nomoto J, et al. Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol, 2018; 100(5):511-517.
3 陈泽,蔡志梅,赵利东,等. BCL-2与PD-L1联合检测在预测初治急性白血病预后中的价值分析.中国实验血液学杂志,2017;25(6):1636-1640.
4 Wang X, Li JG, Dong K, et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal, 2015; 27(3):443-452.
5 McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an antiprogrammed death-ligand 1 antibody, in metastatic renal cell carcinoma:long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol, 2016; 34(8):833-842.
6 Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer(POPLAR):a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016; 387(10030):1837-1846.
7 Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med, 2015; 372(4):311-319.
8 Zhao L, Yu HB, Yi SJ, et al. The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer. Oncotarget, 2016; 7(29):45370-45384.
9 张之南,沈悌.血液病诊断及疗效标准(第三版).北京:科学出版社, 2007:103-121.
10 马新建,张付华,孙莉. PD-L1、HSP90及HSP90α在急性白血病患者中表达及其意义.中国实验血液学杂志, 2017; 25(5):1384-1389.
11 Rom-Jurek EM, Kirchhammer N, Ugocsai P, et al. Regulation of programmed death ligand 1(PD-L1)expression in breast cancer cell lines in vitro and in immunodeficient and humanized tumor mice.Int J Mol Sci, 2018; 19(2):doi:10.3390/ijms19020563.
12 Jia L, Xi Q, Wang HF, et al. MiR-142-5p regulates tumor cell PDL1 expression and enhances anti-tumor immunity. Biochem Biophys Res Commun, 2017; 488(2):425-431.
13 Cortez MA, Ivan C, Valdecanas D, et al. PDL1 regulation by p53via miR-34. J Natl Cancer Inst, 2016; 108(1):djv303.
14 Xu SH, Tao Z, Hai B, et al. MiR-424(322)reverses chemoresistance via T-cell immune response activation by blocking the PD-L1immune checkpoint. Nat Commun, 2016; 7:11406.
15 Liu CZ, Zhu JK, Liu FY, et al. MicroRNA-138 targets SP1 to inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells. Oncol Lett, 2018; 15(1):1279-1286.
16 Zhou Z, Li ZH, Shen Y, et al. MicroRNA-138 directly targets TNFAIP8 and acts as a tumor suppressor in osteosarcoma. Exp Ther Med, 2017; 14(4):3665-3673.
17 Li HQ, Sheng Y, Zhang Y, et al. MicroRNA-138 is a potential biomarker and tumor suppressor in human cervical carcinoma by reversely correlated with TCF3 gene. Gynecol Oncol, 2017; 145(3):569-576.
18 Zhao XH, Yang L, Hu JG, et al. MiR-138 might reverse multidrug resistance of leukemia cells. Leuk Res, 2010; 34(8):1078-1082.
19 Rupaimoole R, Slack FJ. MicroRNA therapeutics:towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov, 2017; 16(3):203-222.
20 Catela Ivkovic T, Voss G, Cornella H, et al. MicroRNAs as cancer therapeutics:a step closer to clinical application. Cancer Lett,2017; 407:113-122.
21 Chakraborty C, Sharma AR, Sharma G, et al. Therapeutic miRNA and siRNA:moving from bench to clinic as next generation medicine. Mol Ther Nucleic Acids, 2017; 8:132-143.
2 Tanaka Y, Maeshima AM, Nomoto J, et al. Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol, 2018; 100(5):511-517.
3 陈泽,蔡志梅,赵利东,等. BCL-2与PD-L1联合检测在预测初治急性白血病预后中的价值分析.中国实验血液学杂志,2017;25(6):1636-1640.
4 Wang X, Li JG, Dong K, et al. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal, 2015; 27(3):443-452.
5 McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an antiprogrammed death-ligand 1 antibody, in metastatic renal cell carcinoma:long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol, 2016; 34(8):833-842.
6 Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer(POPLAR):a multicentre, open-label, phase 2 randomised controlled trial. Lancet, 2016; 387(10030):1837-1846.
7 Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med, 2015; 372(4):311-319.
8 Zhao L, Yu HB, Yi SJ, et al. The tumor suppressor miR-138-5p targets PD-L1 in colorectal cancer. Oncotarget, 2016; 7(29):45370-45384.
9 张之南,沈悌.血液病诊断及疗效标准(第三版).北京:科学出版社, 2007:103-121.
10 马新建,张付华,孙莉. PD-L1、HSP90及HSP90α在急性白血病患者中表达及其意义.中国实验血液学杂志, 2017; 25(5):1384-1389.
11 Rom-Jurek EM, Kirchhammer N, Ugocsai P, et al. Regulation of programmed death ligand 1(PD-L1)expression in breast cancer cell lines in vitro and in immunodeficient and humanized tumor mice.Int J Mol Sci, 2018; 19(2):doi:10.3390/ijms19020563.
12 Jia L, Xi Q, Wang HF, et al. MiR-142-5p regulates tumor cell PDL1 expression and enhances anti-tumor immunity. Biochem Biophys Res Commun, 2017; 488(2):425-431.
13 Cortez MA, Ivan C, Valdecanas D, et al. PDL1 regulation by p53via miR-34. J Natl Cancer Inst, 2016; 108(1):djv303.
14 Xu SH, Tao Z, Hai B, et al. MiR-424(322)reverses chemoresistance via T-cell immune response activation by blocking the PD-L1immune checkpoint. Nat Commun, 2016; 7:11406.
15 Liu CZ, Zhu JK, Liu FY, et al. MicroRNA-138 targets SP1 to inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells. Oncol Lett, 2018; 15(1):1279-1286.
16 Zhou Z, Li ZH, Shen Y, et al. MicroRNA-138 directly targets TNFAIP8 and acts as a tumor suppressor in osteosarcoma. Exp Ther Med, 2017; 14(4):3665-3673.
17 Li HQ, Sheng Y, Zhang Y, et al. MicroRNA-138 is a potential biomarker and tumor suppressor in human cervical carcinoma by reversely correlated with TCF3 gene. Gynecol Oncol, 2017; 145(3):569-576.
18 Zhao XH, Yang L, Hu JG, et al. MiR-138 might reverse multidrug resistance of leukemia cells. Leuk Res, 2010; 34(8):1078-1082.
19 Rupaimoole R, Slack FJ. MicroRNA therapeutics:towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov, 2017; 16(3):203-222.
20 Catela Ivkovic T, Voss G, Cornella H, et al. MicroRNAs as cancer therapeutics:a step closer to clinical application. Cancer Lett,2017; 407:113-122.
21 Chakraborty C, Sharma AR, Sharma G, et al. Therapeutic miRNA and siRNA:moving from bench to clinic as next generation medicine. Mol Ther Nucleic Acids, 2017; 8:132-143.