肝细胞癌中性肽链内切酶和二肽基肽酶IV表达水平对手术切除术后患者预后的影响

doi:10.3969/j.issn.1672-5069.2017.05.013

摘要/Abstract

摘要： 目的探讨肝癌组织中性肽链内切酶（NEP）和二肽基肽酶IV（DPP Ⅳ）表达水平对肝细胞癌（HCC）患者肝癌切除术后预后的影响。方法选择2008年1月～2013年7月北京第301医院肝胆外科行肝癌切除治疗的HCC患者42例，选择同时期检查的42例肝良性肿瘤患者肝组织作为对照。采用免疫组化法检测NEP和DPP Ⅳ。采用 Kaplan-Meier 法进行无复发生存（RFS）曲线和总生存（OS）曲线绘制，采用 Cox 比例风险回归模型进行多因素分析，确定影响RFS和OS的因素。结果 NEP和DPP Ⅳ蛋白均定位于HCC细胞胞浆；HCC组织NEP蛋白阳性率为78.6%（33/42），DPP Ⅳ蛋白阳性率为71.4%（30/42），NEP和PP Ⅳ蛋白双阳性率为54.8%（23/42），均显著高于正常组织【2.4%（1/42）、4.8%（2/42）和0.0%（0/42），P＜0.05】；经单因素和多因素分析显示，肿瘤分化、NEP表达、DPP Ⅳ表达、NEP和DPP Ⅳ共表达、复发、癌细胞远处转移是影响HCC患者RFS和OS的独立危险因素；生存曲线显示，HCC组织NEP阳性、DPP Ⅳ阳性和NEP/DPP Ⅳ均阳性表达者RFS和OS显著缩短，预后差。结论 NEP和DPP Ⅳ表达水平是HCC患者预后不良的危险因素。

关键词: 肝细胞癌, 中性肽链内切酶, 二肽基肽酶IV, 免疫组化, 预后

Abstract: Objective To investigate the implication of neutral endopeptidase （NEP） and dipeptidyl peptidase（DPP） Ⅳ in hepatocellular carcinoma tissues. Methods Cancerous tissues were obtained from 42 patients with hepatocellular carcinoma （HCC） after hepatectomy，and 42 benign liver tissues at the same time were also obtained for control in the Department of Hepatobiliary Surgery，Beijing 301st Hospital between January 2008 and July 2013. The expression of NEP and DPP Ⅳin cancerous tissues were detected by immunohistochemical staining. Patients were checked-up every 3 months after operation. Kaplan-Meier method was used to draw the recurrence-free survival （RFS） curves and overall survival （OS） curves. Cox proportional hazards regression multivariate analysis was performed to determine the influencing factors of RFS and OS. Results NEP and DPP Ⅳ proteins were both located in the cytoplasm of hepatocellular carcinoma cells；The positive rates of NEP protein，DPP Ⅳ protein and double NEP and DPP Ⅳ protein in patients with hepatocellular carcinoma were 78.6%（33/42），71.4%（30/42） and 54.8%（23/42），respectively，all significantly higher than in normal liver tissues[2.4%（1/42），4.8%（2/42） and 0.0%（0/42），P<0.05]；Multivariate analysis demonstrated that tumor differentiation，NEP expression，DPP Ⅳ expression，NEP and DPPⅣ co-expression，recurrence and metastasis of cancer were the prognostic factors of RFS and OS in patients with HCC；The survival curves showed that RFS and OS were significantly shortened and the prognosis was poorer in patients with NEP or DPP Ⅳ or both of them positive in cancerous tissues. Conclusion The expression of NEP and DPP Ⅳ might be the risk factors for the poor prognosis in patients with HCC.

Key words: Hepatocellular caicinoma, Neutral endopeptidase, Dipeptidyl peptidase Ⅳ, Immunohistochemical staining, Prognosis

牛福勇，李福荣. 肝细胞癌中性肽链内切酶和二肽基肽酶IV表达水平对手术切除术后患者预后的影响[J]. 实用肝脏病杂志, 2017, 20(5): 559-562.

Niu Fuyong，Li Furong.. Implication of neutral endopeptidase and dipeptidyl peptidase Ⅳ expression in hepatocellular carcinoma tissues[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2017, 20(5): 559-562.

参考文献

[1] Okuda K. Epidemiology of primary liver cancer. Springer Netherlands，2008:161-195.
[2] 李永胜，孙保君. HCC手术治疗的预后影响因素分析. 实用癌症杂志，2016，31（4）:610-612.
[3] 陆凯，张博，董立巍，等. 中下段胆管癌的预后影响因素分析. 现代生物医学进展，2012，12（26）:5068-5071.
[4] 王捷. 对“1370例HCC肝切除术的疗效及预后因素分析”和“肝门部胆管癌手术切除的远期疗效及预后因素分析”的点评. 中华消化外科杂志，2016，12（4）:334-334.
[5] 刘婷婷，葛漫丽，王继红，等. 中性肽链内切酶（CD10）生理功能研究进展. 现代生物医学进展，2014，14（9）:1766-1768.
[6] 叶蕴瑶，韩高华，卢开进，等. APE1单核苷酸多态性与食管小细胞癌预后的关系研究. 中国综合临床，2016，32（1）:64-68.
[7] Clifton P. Do dipeptidyl peptidase IV （DPP-IV） inhibitors cause heart failure Clin Therapeut，2014，36（12）:2072-2079.
[8] 李汝懿. 基因表达谱在甲状腺乳头状癌的诊断与鉴别诊断中的应用. 昆明医科大学，2015.
[9] Kshirsagar AD，Aggarwal AS，Harle UN，et al. DPP IV inhibitors:Successes，failures and future prospects. Diabet Metab Syndr Clin Res Rev，2011，5（2）:105-112.
[10] 董辉，丛文铭. 提高肝癌规范化病理诊断水平，为临床精细化治疗保驾护航-《原发性肝癌规范化病理诊断指南（2015年版）》解读. 中国普通外科杂志，2016，25（7）:44-49.
[11] 李玉博，高雪梅，程敬亮，等. 体素内不相干运动扩散加权成像在HCC术前分级中的应用. 中国医学影像技术，2014，34（11）:1669-1673.
[12] 权继传，解亦斌，田艳涛. 国际抗癌联盟胃癌TN M分期系统第七版解读. 中华诊断学电子杂志，2014，2（1）:59-61.
[13] Nagata S，Tomoeda M，Kubo C，et al. Intraductal polypoid growth variant of pancreatic acinar cell carcinoma metastasizing to the intrahepatic bile duct 6 years after surgery:A case report and literature review. Pancreatology，2012 12（1）:23-26.
[14] Veronique Maguer-Satta CR，Besancon R，Bachelard-Cascales E. Concise review:Neutral endopeptidase （CD10）:A multifaceted environment actor in stem cells，physiological mechanisms and cancer. Stem Cells，2011，29（3）:389-396.
[15] Zhu J，Guo X，Qiu B，et al. Prognostic significance of the combined expression of neutral endopeptidase and dipeptidyl peptidase IV in intrahepatic cholangiocarcinoma patients after surgery resection. Oncotarg Ther，2014，7（1）:297-304.
[16] 孙发政，种晓迪. 肺癌组织中NEP、APN的表达变化及意义. 山东医药，2013，53（24）:66-67.
[17] 张梦真，乔玉环，索振河. 二肽基肽酶Ⅳ与卵巢上皮性癌临床病理特征和预后的关系. 中华肿瘤杂志，2008，30（11）:848-852.[18] Griggs D W，Prinsen M J，Campbell M，et al. Mo1233 pharmacologic evaluation of clinical neutral endopeptidase inhibitors in a rat model of acute secretory diarrhea. J Pharmacol Experiment Ther，2016，148（4）:644-645.
[19] Jiang F，Yang J，Zhang Y，et al. Angiotensin-converting enzyme 2 and angiotensin 1-7:novel therapeutic targets. Nat Rev Cardiol，2014，11（7）:413-426.
[20] Kim H，Lee H，Shin KS. Intestinal immunostimulatory activity of neutral polysaccharide isolated from traditionally fermented Korean brown rice vinegar. Biosci Biotech Biochem，2016，8（17）:1-8.