人磷脂酰乙醇胺结合蛋白4在多发性骨髓瘤中的表达及其意义

Expression of human phosphatidylethanolamine-binding protein 4 in patients with multiple myeloma and its significance

目的探讨多发性骨髓瘤(MM)患者血清人磷脂酰乙醇胺结合蛋白4(hPEBP4)等因子的表达情况及其临床意义。方法以2016年9月至2018年9月北京朝阳医院西院收治的59例症状性MM患者作为研究对象。根据血钙升高、肾损害、贫血和骨损害(CRAB症状)将患者分为两组,其中具有活动性CRAB症状的44例为活动组,化疗后至少达到部分缓解且CRAB症状缓解的15例为反应组。活动组患者中,严重骨损害(SBL)组30例,非严重骨损害(NSBL)组14例;修订的国际预后分期系统(R-ISS)Ⅰ、Ⅱ和Ⅲ期分别为26、11、7例。选取与患者年龄及性别匹配的健康体检者15名作为健康对照组。用酶联免疫吸附试验(ELISA)检测hPEBP4、肿瘤坏死因子配体超家族成员14(LIGHT/TNFSF14)和激活素A在受试者中的表达水平。采用Pearson法分析活动组中各因子表达间的关系,依据受试者工作特征(ROC)曲线确定各因子诊断MM的最佳截断值,并依此分层,比较各分层患者间总生存(OS)差异。结果活动组、反应组、健康对照组hPEBP4水平分别为(1.48±0.64)μg/L、(1.49±0.75)μg/L、(0.31±0.10)μg/L,LIGHT/TNFSF14分别为(169±112)ng/L、(256±132)ng/L、(44±27)ng/L,激活素A分别为(383±266)ng/L、(223±79)ng/L、(234±85)ng/L,差异均有统计学意义(均P<0.05)。活动组中,R-ISSⅠ、Ⅱ、Ⅲ期患者hPEBP4水平分别为(1.06±0.60)μg/L、(1.15±0.50)μg/L、(1.73±0.68)μg/L,差异有统计学意义(F=3.287,P=0.032);激活素A水平分别为(219±55)ng/L、(247±117)ng/L、(450±215)ng/L,Ⅲ期患者均高于Ⅰ、Ⅱ期(均P<0.05)。活动组中,SBL患者的LIGHT/TNFSF14和激活素A水平均高于NSBL患者[(174±101)ng/L比(98±53)ng/L,(467±238)ng/L比(189±71)ng/L],差异均有统计学意义(均P<0.05)。IgG型活动组患者hPEBP4水平与M蛋白水平(r=0.694,P<0.01)和激活素A水平(r=0.252,P<0.01)均呈正相关。经ROC曲线分析,hPEBP4、LIGHT/TNFSF14、激活素A诊断MM的最佳截断值分别为1.04μg/L、97.0 ng/L、156.2 ng/L。hPEBP4>1.04μg/L和≤1.04μg/L患者中位OS时间分别为57个月(95%CI 22~92个月)和未达到,差异有统计学意义(P<0.05);激活素A≥156.2 ng/L和<156.2 ng/L患者的中位OS时间分别为61个月(95%CI 24~98个月)和未达到,差异有统计学意义(P<0.05)。结论hPEBP4高表达与MM进展有关,与M蛋白水平呈正相关,与OS呈负相关;其可能成为判断病情进展和肿瘤负荷的重要标志物。LIGHT/TNFSF14和激活素A协同hPEBP4可能参与MM肿瘤微环境的病理过程。

Objective To investigate the expression of serum human phosphatidylethanolamine-binding protein 4(hPEBP4)in patients with multiple myeloma(MM)and its clinical significance.Methods A total of 59 symptomatic MM patients admitted to West Branch of Beijing Chaoyang Hospital from September 2016 to September 2018 were selected as the research objects.According to the CRAB symptoms[elevated serum calcium(C),kidney injury(R),anemia(A),bone lesions(B)],all patients were divided into 2 groups,including the active group of 44 patients with CRAB symptoms,and the response group of 15 patients who achieved at least partial remission after chemotherapy and symptom relief of CRAB.According to the degree of bone lesions(BL),30 patients with severe bone-related events were grouped as the severe bone lesions(SBL)group,and 14 patients were grouped as the non-severe bone lesions(NSBL)group.According to the revised international prognostic staging system(R-ISS),patients in the active group were divided into three subgroups:stageⅠ,stageⅡ,and stageⅢ,including 26,11 and 7 patients,respectively.A total of 15 healthy examination people whose gender and age matched those of the patients were treated as the healthy control group.Enzyme-linked immunosorbent assay(ELISA)was used to detect the expression levels of hPEBP4,tumor necrosis factor ligand superfamily member 14(LIGHT/TNFSF14)and activin A of patients in different groups.Pearson was used to analyze the relationship of the expressions of multiple factors in the active group.The optimal cut-off value of multiple factors diagnosing MM was determined by using receiver operating characteristic(ROC)curve,and according to the cut-off value,the differences in overall survival(OS)of patients with different stratification were compared.Results In the active group,the respond group,the healthy control group,the level of hPEBP4 was(1.48±0.64)μg/L,(1.49±0.75)μg/L,(0.31±0.10)μg/L,respectively;the level of LIGHT/TNFSF14 was(169±112)ng/L,(256±132)ng/L,(44±27)ng/L,respectively;the level of activin A was(383±266)ng/L,(223±79)ng/L,(234±85)ng/L,respectively;and the differences were statistically significant(all P<0.05).In the active group,the level of hPEBP4 was(1.06±0.60)μg/L,(1.15±0.50)μg/L,(1.73±0.68)μg/L,respectively in patients with stage R-ISSⅠ,R-ISSⅡand R-ISSⅢ,and the difference was statistically significant(F=3.287,P=0.032).The level of activin A was(219±55)ng/L,(247±117)ng/L,(450±215)ng/L,respectively among patients in stage R-ISSⅠ,R-ISSⅡ,R-ISSⅢ,and the level of activin A in stage R-ISSⅢwas higher than that in stage R-ISSⅠand R-ISSⅡ(all P<0.05).The levels of LIGHT/TNFSF14 and activin A of SBL patients were higher than those of NSBL patients[(174±101)ng/L vs.(98±53)ng/L;(467±238)ng/L vs.(189±71)ng/L,all P<0.05].The level of hPEBP4 was positively correlated with the levels of M protein(r=0.694,P<0.01)and activin A(r=0.252,P<0.01)of IgG patients in the active group.ROC curve analysis showed that the optimal cut-off value of hPEBP4,LIGHT/TNFSF14,activin A diagnosing MM was 1.04μg/L,97.0μg/L,156.2 ng/L.The median overall survival(OS)time of patients with hPEBP4>1.04μg/L and hPEBP4≤1.04μg/L was 57 months(95%CI 22-92 months)and not reached,respectively,and the difference was statistically significant(P<0.05);while the median OS time of patients with activin A≥156.2 ng/L and activin A<156.2 ng/L was 61 months(95%CI 24-98 months)and not reached,respectively,and the difference was statistically significant(P<0.05).Conclusions High expression level of hPEBP4 is related with the progression of MM.It is positively related with the level of M protein and negatively with the OS of MM patients.It is suggested that hPEBP4 may be used as an important marker to judge disease progression and tumor burden in MM.LIGHT/TNFSF14 and activin A cooperate with hPEBP4 to participate in the pathological processes of tumor microenvironment of MM.