缺氧诱导因子1α和CD133预测直肠癌患者新辅助放化疗疗效的临床研究

doi:10.3785/j.issn.1008-9292.2017.02.06

浙江大学学报（医学版）

2017, Vol. 46

Issue (1): 36-43 DOI: 10.3785/j.issn.1008-9292.2017.02.06

原著

缺氧诱导因子1α和CD133预测直肠癌患者新辅助放化疗疗效的临床研究

蔡成¹(

),王建平¹,钟志凤¹,戴志慧¹,王庆华¹,董武真¹,施红旗²,刘庆伟²,杜金林^1,^*(

)

⁽¹⁾ 浙江省金华市中心医院结直肠肛门外科, 浙江金华 321099
⁽²⁾ 浙江省金华市中心医院病理科, 浙江金华 321099

Hypoxia-inducible factor-1α and CD133 predicts pathological complete response and survival for locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy

CAI Cheng¹(

),WANG Jianping¹,ZHONG Zhifeng¹,DAI Zhihui¹,WANG Qinghua¹,DONG Wuzhen¹,SHI Hongqi²,LIU Qingwei²,DU Jinlin^1,^*(

)

⁽¹⁾ Department of Colorectal and Anal Surgery, Jinhua Municipal Central Hospital, Jinhua 321000, China
⁽²⁾ Department of Pathology, Jinhua Municipal Central Hospital, Zhejiang University, Jinhua 321000, China

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摘要： 目的

评估缺氧诱导因子1α（HIF-1α）和CD133在接受新辅助放化疗的直肠癌患者病理缓解及预后中的意义。

方法

选取2010年1月至2015年12月浙江省金华市中心医院收治的114例病理学检查结果证实为直肠癌的患者，获取放疗前后肿瘤组织标本，RT-PCR检测放化疗前后肿瘤组织HIF-1α和CD133 mRNA表达，免疫组织化学方法检测放疗后肿瘤组织HIF-1α和CD133蛋白的表达。Spearman秩相关方法分析HIF-1α与CD133 mRNA表达相关性，单因素及多因素方法分析与直肠癌患者病理学缓解相关的因素，Logistic和Cox回归方法分析与患者总存活率及无病存活率相关的临床病理因素。

结果

HIF-1α和CD133 mRNA的表达与临床T分期、新辅助放化疗后TNM分期、病理学完全缓解、复发及转移相关，与性别、年龄、体质指数等其他临床因素无关。新辅助放化疗后，HIF-1α与CD133 mRNA表达呈显著正相关（α=0.579，P=0.000）。免疫组织化学检测显示，CD133高表达肿瘤细胞中HIF-1α也呈高表达。单因素分析发现，HIF-1α mRNA（P=0.001）和CD133 mRNA表达（P=0.022）与病理学完全缓解相关；多因素分析发现，HIF-1α mRNA（P=0.012）和CD133 mRNA（P=0.047）表达是患者病理学完全缓解的独立预测因子。Cox多因素回归分析发现，HIF-1α mRNA表达（P=0.025）与CD133 mRNA表达（P=0.033）是患者无复发存活的独立预测因子，HIF-1α mRNA表达是患者总存活的独立预测因子（P=0.046）。

结论

HIF-1α和CD133与接受新辅助放化疗的直肠癌患者病理学完全缓解及存活显著相关，对两者的研究可能在新辅助放化疗患者的选择及改善患者预后方面具有意义。

关键词： 直肠肿瘤/药物疗法; 直肠肿瘤/放射疗法; 直肠肿瘤/病理学; 缺氧诱导因子1, α亚基/代谢; 抗原, CD/代谢; 存活率; 预后; 免疫组织化学

Abstract: Objective

To investigate the expression of hypoxia-inducible factor 1α (HIF-1α) and CD133 in predicting pathologic remission and survival of patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

Methods

One hundred and fourteen patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy from January 2010 to December 2015 in Jinhua Municipal Central Hospital were enrolled in the study. RT-PCR and immunohistochemistry methods were used to detect the mRNA and protein expression of HIF-1α and CD133 before and after chemoradiotherapy. Spearman rank correlation was used to analyze the correlation between HIF-1α and CD133 mRNA expression. Univariate and logistic multivariate analyses were used to determine the factors related to pathological complete response (pCR). Logistic regression analysis and Cox's proportional hazard model were used to determine factors related to overall survival and recurrence-free survival.

Results

The expression of HIF-1α and CD133 mRNA was correlated with pT, ypTNM, pCR, recurrence and metastasis of rectal cancer, while not correlated with sex, age and BMI of patients. HIF-1α mRNA expression was positively correlated with CD133 mRNA expression (α=0.579, P=0.000). Immunohistochemistry analysis showed that residual cancer cells strongly expressing HIF-1α also expressed CD133 strongly. Univariate analysis showed that HIF-1α mRNA and CD133 mRNA were significantly correlated with pCR (P=0.001, P=0.022, respectively). Multivariate analysis showed that HIF-1α and CD133 mRNA expression were independent prognostic factors of pCR (P=0.012, P=0.047, respectively). Cox regression analysis showed that the expression of HIF-1α mRNA and CD133 mRNA were independent predictors of recurrence-free survival and overall survival (P=0.025, P=0.033, respectively).

Conclusion

The study indicates that HIF-1α and CD133 can predict pathological complete remission and survival of patients with locally advanced rectal cancer.

Key words: Rectal neoplasms/drugtherapy Rectal neoplasms/radiotherapy Rectal neoplasms/pathology Hypoxia-inducible factor 1, alpha subunit/metabolism Antigens, CD/metabolism Survival rate Prognosis Immunohistochemistry

收稿日期: 2016-12-10 出版日期: 2017-07-07

CLC:

R735.3

基金资助: 浙江省金华市社会发展类重点项目(2014-3-010)

通讯作者: 杜金林 E-mail: csj_198@126.com;djl9090@163.com

作者简介: 蔡成 (1987-), 男, 硕士研究生, 主要从事结直肠肿瘤的基础和临床研究, E-mail: csj_198@126.com|杜金林 (1965-), 男, 硕士, 主任医师, 硕士生导师, 主要从事结直肠肛门相关疾病的临床和基础研究. E-mail: djl9090@163.com

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引用本文:

蔡成,王建平,钟志凤,戴志慧,王庆华,董武真,施红旗,刘庆伟,杜金林. 缺氧诱导因子1α和CD133预测直肠癌患者新辅助放化疗疗效的临床研究[J]. 浙江大学学报（医学版）, 2017, 46(1): 36-43.

CAI Cheng,WANG Jianping,ZHONG Zhifeng,DAI Zhihui,WANG Qinghua,DONG Wuzhen,SHI Hongqi,LIU Qingwei,DU Jinlin. Hypoxia-inducible factor-1α and CD133 predicts pathological complete response and survival for locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy. J Zhejiang Univ (Med Sci), 2017, 46(1): 36-43.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2017.02.06 或 http://www.zjujournals.com/med/CN/Y2017/V46/I1/36

表1 不同临床病理特征患者HIF-1α mRNA、CD133 mRNA的表达比较

图1 新辅助放化疗前后HIF-1α mRNA与CD133 mRNA表达相关关系

图2 免疫组织化学检测HIF-1α和CD133表达 A：HIF-1α在直肠腺癌细胞核中染色成棕黄色颗粒状，呈高表达；B：CD133在同一切片直肠腺癌细胞质中染色成棕黄色颗粒状，呈高表达；C：HIF-1α在直肠腺癌细胞核中未见明显染色，呈低表达；D：CD133在同一切片组织细胞质中未见明显着色，呈低表达.标尺=500 μm.

表2 病理学完全缓解相关预测因素单因素分析

图3 HIF-1α mRNA和CD133 mRNA预测病理学完全缓解的受试者工作特征曲线

表3 患者无复发存活率相关预测因素单因素分析

表4 患者总存活率相关预测因素单因素分析

图4 不同HIF-1α、CD133表达水平患者生存曲线比较

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