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中华关节外科杂志(电子版) ›› 2018, Vol. 12 ›› Issue (01) : 52 -57. doi: 10.3877/cma.j.issn.1674-134X.2018.01.010

所属专题： 文献；

基础论著

吲哚胺2，3-双加氧酶和叉状头转录因子3在骨肉瘤中表达与预后的关系
郑传禧1, 张世权2,†(), 万鹏2, 郑建荣2, 关弘3   
  1. 1. 518035　深圳市第二人民医院骨关节骨肿瘤科
    3. 518035　深圳市第二人民医院病理科
  • 收稿日期:2016-12-15 出版日期:2018-02-01
  • 通信作者: 张世权
  • 基金资助:
    深圳市卫生计生系统科研项目(201501014)

Expression and significance of indoleamine 2, 3-dioxygenase and forkhead box P3 in osteosarcoma

Chuanxi Zheng1, Shiquan Zhang2,†(), Peng Wan2, Jianrong Zheng2, Hong Guan3   

  1. 1. Department of joint and musculoskeletal tumor, the Second People Hospital of Shenzhen University, Shenzhen 518035, China; Department of pathology, the Second People Hospital of Shenzhen University, Shenzhen 518035, China
    2. Department of joint and musculoskeletal tumor, the Second People Hospital of Shenzhen University, Shenzhen 518035, China
  • Received:2016-12-15 Published:2018-02-01
  • Corresponding author: Shiquan Zhang
  • About author:
    Corresponding author: Zhang Shiquan, Email:
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引用本文：

郑传禧, 张世权, 万鹏, 郑建荣, 关弘. 吲哚胺2，3-双加氧酶和叉状头转录因子3在骨肉瘤中表达与预后的关系[J]. 中华关节外科杂志(电子版), 2018, 12(01): 52-57.

Chuanxi Zheng, Shiquan Zhang, Peng Wan, Jianrong Zheng, Hong Guan. Expression and significance of indoleamine 2, 3-dioxygenase and forkhead box P3 in osteosarcoma[J]. Chinese Journal of Joint Surgery(Electronic Edition), 2018, 12(01): 52-57.

目的

检测骨肉瘤组织中吲哚胺2，3-双加氧酶(IDO)及叉状头转录因子3(FOXP3)的表达水平，并分析IDO与FOXP3的表达与患者预后的关系。

方法

2005年5月至2014年9月，选取在深圳市第二人民医院确诊且有完整临床资料的骨肉瘤患者标本39例，骨巨细胞瘤患者标本20例，骨软骨瘤患者20例。骨肉瘤患者标本来自于患者术后大体标本。骨巨细胞瘤标本均取自四肢骨巨细胞瘤患者；骨软骨瘤标本均取自单发四肢骨软骨瘤患者，多发骨软骨瘤和骨软骨瘤病标本不纳入本实验。应用免疫组织化学法测定IDO及FOXP3在39例骨肉瘤和20例骨巨细胞瘤，20例骨软骨瘤中的表达情况。应用SPSS 19.0软件进行统计学分析。卡方检验分析各样本组间的差异，生存分析采用Kaplan-Meier法和log-rank检验；Cox比例风险模型进行单因素，多因素生存分析。

结果

IDO，FOXP3在骨肉瘤组中阳性率分别为69.2%(27/39)，53.8%(21/39)，在骨巨细胞瘤组中阳性率分别为15%(3/20)，0%，骨软骨瘤组中无阳性表达，各组间IDO，FOXP3表达差异具有统计学意义(IDO: χ2＝6.201，P<0.05；FOXP3：χ2＝5.834，P<0.05)。IDO高表达(评分≥5分)在Enneking分期，肺部转移亚组间有差异(χ2＝6.594，P<0.05；χ2＝8.770，P<0.05)而FOXP3在各亚组表达差异无统计学意义。通过Kaplan-Meier生存分析发现IDO，FOXP3高表达患者各时点总体生存时间均短于低表达者，差异具有统计学意义(χ2＝8.905，P<0.05；χ2＝4.573，P<0.05)。单因素分析表明，肺转移及IDO，FOXP3表达水平是影响骨肉瘤患者预后的因素而多因素分析显示，肺转移(HR＝6.053，95% CI：13～34，P＝0.040)是影响骨肉瘤预后的相关独立因素。

结论

IDO，FOXP3在骨良恶性肿瘤中的表达具有显著差异；IDO、FOXP3的高表达可作为评判骨肉瘤不良预后的指标。

关键词: 骨肉瘤, 免疫组织化学, 吲哚胺－吡咯2，3-双加氧酶, 叉头转录因子类
Objective

To investigate the expression of indoleamine 2, 3-dioxygenase (IDO) and forkhead box P3(FOXP3) in the osteosarcoma, and evaluate the correlation between the expressions of IDO and FOXP3 protein and prognosis.

Methods

Cancer tissue samples were obtained from the patients (39 cases of osteosarcoma, 20 cases of giant cell tumor, 20 cases of osteochondroma) who were pathological diagnosed between May 2005 and September 2014 at the Second People Hospital of Shenzhen in China. Cancer tissue samples of osteosarcoma were obtained from postoperative tissue, giant cell tumor(GCT) tissue was obtained from the patients extremities with GCT, osteochondroma tissue was obtained from the patients extremities with osteochondroma; multiple lesions and hereditary multiple exostoses were excluded. The expressions of IDO and FOXP3 in osteosarcoma, osteochondroma and giant cell tumor tissues were studied by immunohistochemical staining. The statistical analysis was performed by using SPSS 19.0 software. Chi-square was used to analyze association between clinical parameters with IDO, FOXP3 expression subgroups. Kaplan-Meier and log-rank test were used for survival analysis. Cox analysis was performed to estimate univariate and multivariate analysis.

Results

IDO was expressed in 69.2% (27/39) and FOXP3 was expressed in 53.8% (21/39) of osteosarcoma. IDO was expressed in 15.0% (3/20) of giant cell tumor, but positive expression of FOXP3 was not found in giant cell tumor. Neither of them were found in osteochondroma, there were significant differences among the three groups in IDO and FOXP3 expressions(IDO: χ2=6.201, P<0.05; FOXP3: χ2=5.834, P<0.05). High expression of IDO (score≥5) was correlated with aggressive clinicopathologic features, such as lung metastasis, high surgical stage (Enneking stage)(χ2=6.594, P<0.05; χ2=8.770, P<0.05). Kaplan Meier-survival analysis showed that high expressions of IDO and FOXP3 were significantly associated with poor overall survival rates(χ2=8.905, P<0.05; χ2=4.573, P<0.05). Single factor variance analysis of overall survival rate showed that lung metastasis and high expression of IDO and FOXP3 were predicative factors of poor prognosis. However, only the lung metastasis was found to be an independent prognostic factor in multivariate analysis (HR=6.053, 95% CI: 13-34, P=0.040). There was no significant correlation between high the expression of IDO, FOXP3 and overall survival in multivariate analysis.

Conclusion

The expression of IDO, FOXP3 shows significant difference between benign and malignant tumors; thus high expression of IDO and FOXP3 is likely to be an effective predicative factor of poor prognosis for patients with osteosarcoma.

Key words: Osteosarcoma, Immunohistochemistry, Indoleamine-pyrrole 2, 3, -dioxygenase, Forkhead transcription factors
图1 骨肉瘤细胞IDO(吲哚胺2，3双加氧酶)免疫组化染色。图A　为强阳性表达，×200；图B　为阳性表达，×200
图2 骨巨细胞瘤和骨软骨瘤IDO(吲哚胺2，3双加氧酶)免疫组化染色。图A 　为骨巨细胞瘤IDO阳性表达，×200；图B　为骨软骨瘤阴性表达，×100
图3 骨肉瘤细胞FOXP3(叉状头转录因子3)免疫组化染色。图A　强阳性表达，×200；图B　阳性表达，×200
图4 骨巨细胞瘤和骨软骨瘤FOXP3(叉状头转录因子3)免疫组化染色。图A　骨巨细胞瘤中FOXP3阴性表达，×100；图B　骨软骨瘤中FOXP3阴性表达，×100
表1 骨肉瘤组织中IDO及FOXP3表达与临床病理参数之间的关系(例)
临床参数分组 例数 IDO (高表达/低表达) F值 P值 临床参数分组 FOXP3(高表达/低表达) F值 P值
性别 男 24 76.5%(13)/50.0%(11) 2.839 0.092 性别 男 66.7%(12)/57.1%(12) 0.371 0.542
? 女 15 23.5%(4)/50.0%(11) ? ? ? 女 33.3%(6)/42.9%(9) ? ?
年龄(岁) <20 12 47.0%(8)/18.2%(4) 3.754 0.053 年龄(岁) <20 22.2%(4)/38.1%(8) 1.146 0.284
? ≥20 27 52.9%(9)/81.8%(18) ? ? ? ≥20 77.8%(14)/61.9%(13) ? ?
肿瘤部位 中轴骨 2 11.8%(2)/0(0) 2.728 0.251 肿瘤部位 中轴骨 5.6%(1)/4.8%(1) 0.013 0.909
? 四肢 37 88.2%(15)/100%(22) ? ? ? 四肢 94.4%(17)/95.2%(20) ? ?
外科分期b ⅡA 14 47.0%(8)/27.3%(6) 6.594 0.037a 外科分期b ⅡA 44.4%(8)/28.6%(6) 2.211 0.331
? ⅡB 18 23.5%(4)/63.6%(14) ? ? ? ⅡB 33.3%(6)/57.1%？(12) ? ?
? ⅢA-B 7 29.4%(5)/9.1%(2) ? ? ? ⅢA-B 22.2%(4)/14.3%(3) ? ?
病理性骨折 是 3 5.9%(1)/9.1%(2) 0.139 0.709 病理性骨折 是 5.6%(1)/9.5%(2) 0.215 0.643
? 否 36 94.1%(16)/90.9%(20) ? ? ? 否 94.4%(17)/90.5%(19) ? ?
碱性磷酸酶 升高 9 35.3%(6)/13.6%(3) 2.534 0.111 碱性磷酸酶 升高 33.3%(6)/14.3%(3) 1.981 0.159
? 正常 30 64.7%(11)/86.4%(19) ? ? ? 正常 66.7%(12)/85.7%(18) ? ?
肺部转移 是 15 64.7%(11)/18.2%(4) 8.77 0.003a 肺部转移 是 50.0%(9)/28.6%(6) 1.88 0.17
? 否 24 35.3%(6)/81.8%(18) ? ? ? 否 50.0%(9)/71.4%(15) ? ?
组织类型 骨母细胞性 35 88.2%(15)/90.9%(20) 4.141 0.126 组织类型 骨母细胞性 94.4%(17)/85.7%(18) 1.809 0.405
? 软骨母细胞性 2 11.8%(2)/0(0) ? ? ? 软骨母细胞性 5.56%(1)/4.8%(1) ? ?
? 纤维母细胞性 2 0(0)/9.1%(2) ? ? ? 纤维母细胞性 0(0)/9.5%(2) ? ?
复发 是 6 23.5%(4)/9.1%(2) 1.536 0.215 复发 是 11.1%(2)/19.0%(4) 0.469 0.493
? 否 33 76.5%(13)/90.9%(20) ? ? ? 否 88.9%(16)/80.1%(17) ? ?
图5 骨肉瘤患者Kaplan-Meier总体生存函数曲线　图A IDO(吲哚胺2，3双加氧酶)高表达组，IDO低表达组生存函数；图B FOXP3(叉状头转录因子3)高表达组，FOXP3低表达组生存函数
表2 骨肉瘤总体生存率的单因素、多因素COX回归分析
因素 单因素分析 P值 多因素分析 P值
HR 95%CI HR 95%CI
肺部转移情况 8.149 2.005～42.301 0.004 6.053 1.088～33.665 0.040
IDO表达水平 4.032 1.091～14.905 0.037 1.515 0.325～7.057 0.597
FOXP3表达水平 3.966 1.052～14.955 0.042 2.1621 0.519～9.009 0.290
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