PO.CL01.19 · 临床研究
与良性结肠疾病患者相比，结直肠癌患者血浆中Serpin-E1（PAI-1）水平显著升高
Plasma levels of Serphin-E1 (PAI-1) are significantly increased in patients with colorectal cancer compared to patients with benign colonic disease
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：纤溶酶原激活物抑制剂-1（PAI-1）是尿激酶型纤溶酶原激活物（uPA）和组织型纤溶酶原激活物（tPA）的抑制剂。PAI-1具有促血管生成作用，并在上皮-间质转化和转移中发挥作用。PAI-1在体外是内皮细胞增殖和迁移的调节因子，在体内是血管生成和肿瘤生长的调节因子。PAI-1通过调节细胞外基质蛋白水解、细胞黏附与脱附来促进肿瘤进展；它还促进癌细胞的侵袭/迁移。已有报道称PAI-1在乳腺癌和结直肠癌（CRC）中过表达。CRC患者（pts）血浆中PAI-1水平尚未得到充分研究。本研究的目的是比较CRC患者与良性结肠病变（BCP）患者术前（PreOp）血浆PAI-1水平。
方法：因BCP或CRC而接受结直肠切除术的患者（pts）被前瞻性纳入一个经IRB批准的组织和数据库。前瞻性收集术前血样、人口学与临床数据以及病理结果。使用ELISA双孔测定血浆PAI-1水平（ng/ml），结果以中位数±95% CI表示。还对部分患者采用QRT-PCR评估配对肿瘤/正常组织中PAI-1的表达水平；并对CRC和正常组织样本进行了免疫组织化学（IHC）检测。采用ROC曲线和AUC评估血浆PAI-1作为CRC诊断标志物的价值。采用Mann-Whitney检验进行统计学分析（显著性p<0.05）。
结果：共研究了156例CRC（71%结肠癌，29%直肠癌）和101例BCP患者（腺瘤57%，憩室炎32%，其他11%）。CRC组的分期（S）分布为：S 1，29%；S 2，29%；S 3，36%；S 4，6%。CRC患者血浆PAI-1中位水平显著高于BCP患者（11.75，CI：9.06，15.32 对 2.95，CI：2.33，3.49；P<0.0001）。与S.I相比，II、III、IV期患者的平均PAI-1水平呈非显著性升高（12%-33%，p=无显著性）。在所检测的CRC组织样本中，50%（9/18）的mRNA PAI-1表达水平高于配对正常组织（p<0.05）。IHC证实CRC组织中存在PAI-1蛋白，而正常结肠组织中则无。ROC曲线的AUC值为0.759（敏感性68%，特异性77%）。
结论：CRC组术前血浆PAI-1中位水平比BCP组高3.9倍。尽管尚未证实，但CRC患者血浆中增加的PAI-1可能由肿瘤细胞及周围炎症细胞产生。PAI-1水平升高可能与肿瘤部位的新生血管形成和炎症诱导的组织重塑有关。AUC结果提示PAI-1在蛋白检测组合中可能具有作为CRC预后标志物的价值。需要在更大规模的对照组和CRC患者人群中开展进一步研究，以更好地确定血浆PAI-1水平与癌症分期或进展之间是否存在相关性。
查看英文原文 English abstract
Introduction: Plasminogen activator inhibitor-1 (PAI-1), is an inhibitor for urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). PAI-1 has proangiogenic effects and plays a role in epithelial-mesenchymal transition and metastasis. PAI-1 is a modulator of endothelial cell proliferation and migration in vitro and of angiogenesis and tumor growth in vivo. PAI-1 promotes tumor progression by modulating extracellular matrix proteolysis, cellular adhesion, and detachment; it also facilitates invasion/migration of cancer cells. PAI-1 overexpression has been reported in breast and colorectal cancer(CRC). Plasma levels of PAI-1 in CRC patients (pts) have not been well studied. This study's purpose was to compare preoperative (PreOp) plasmaPAI-1 levels in CRC and benign colonic pathology (BCP) patients.
Methods: Patients (pts) who underwent colorectal resection for BCP or CRC were prospectively enrolled in an IRB-approved tissue and data bank. Preop blood samples, demographic and clinical data, and pathology results were collected prospectively. Plasma PAI-1 levels were measured in duplicate (ng/ml) using ELISA, with results presented as median ± 95% CI. PAI-1 expression levels were also assessed in paired tumor/normal tissues for a subset of pts using QRT-PCR; immunohistochemistry (IHC) was also carried out on CRC and normal tissue samples. The ROC curve and AUC were used to assess plasma PAI-1 as a CRC diagnostic marker. The Mann-Whitney test was used for statistical analysis (significance p<0.05.)
Results: A total of 156 CRC (71%colon, 29%rectal) and 101 BCP pts (adenoma 57%, diverticulitis 32%, other11%) were studied. The Stage (S) breakdown for the CRC group was: S 1, 29%; S 2, 29%; S 3, 36%; and S 4, 6%. The median CRC plasma PAI-1 levels were significantly higher (11.75, CI: 9.06, 15.32) vs. BCP pts (2.95, CI: 2.33, 3.49; P< 0.0001). A non-significant rise in mean PAI-1 levels was observed in Stage II, III, and IV pts compared to S.I (12% - 33%, p=ns). mRNA PAI-1 expression levels were higher (p<0.05) in 50% (9/18) of the CRC tissue samples tested vs. paired normal tissues. IHC confirmed the presence of PAI-1 protein in CRC vs. normal colon tissue. The AUC value for the ROC curve was 0.759 (sensitivity 68%, specificity 77%).
Conclusion: The median Preop plasma PAI-1 was 3.9 X higher in the CRC vs. the BCP group. Although not proven, the added PAI-1 found in the plasma of CRC pts is likely produced by tumor cells and the surrounding inflammatory cells. Elevated PAI-1 levels may be related to neovascularization and inflammation-induced tissue remodeling at tumor sites. The AUC results suggest PAI-1 may have value as a CRC prognostic marker in a panel of proteins. Further studies with a larger population of controls and CRC pts are needed to better determine if there is a correlation between plasma PAI-1 levels and cancer stage or progression.
利益披露 Disclosure
C. S. Herath Mudiyanselage, None..
Y. Chen, None..
H. Miyagaki, None..
N. Mitra, None..
M. S. Naparst,, None..
V. Cekic, None.
R. L. Whelan,
Applied Medical Company ).
ERBE Other, Education Grant.