细胞周期蛋白E、细胞核增殖抗原、基质金属蛋白酶-9在大肠癌组织的表达及临床意义

Expression of Cyclin E, proliferation cell nuclear antigen and matrix metalloproteinase -9 in color- ectal carcinoma cells and the significance

目的观察细胞周期调控因子蛋白表达在大肠癌发生、发展中的作用及对预后的影响。方法收集手术切除的大肠癌128例，采用免疫组织化学染色，对128例大肠癌和24例正常大肠黏膜细胞周期蛋白E（Cyclin E）、细胞核增殖抗原（Ki-67）、基质金属蛋白酶（MMP）-9进行检测。采用χ2检验、单因素方差分析和Kaplan-Meier生存率曲线分析及Log-rank检验。结果大肠癌与正常大肠黏膜比较Cyclin E、Ki-67阳性表达率明显增高，MMP-9阳性表达率明显降低（χ2＝5.203，P＝0.013）。Duke’s A期Cyclin E阳性表达率明显高于Duke’s B、C、D期（χ2＝10.331，P＝0.001），无淋巴结转移明显高于有淋巴结转移者（χ2＝6.732，P＝0.005）；Cyclin E的表达与大肠癌患者的预后无明显相关。MMP-9表达下降或缺乏。与大肠癌的Duke’s分期、淋巴结转移有关（χ2＝7.201，P＝0.003），且其5年生存率显著降低（χ2＝12.072，P＝0.000）。Ki-67表达与大肠癌部位、Duke’s分期及患者预后无明显相关。128例患者中因本病死亡者44例，占39.29%，包括Cyclin E、Ki-67、MMP-9阳性表达各24、14、36例，阴性表达各20、30、8例。Cyclin E阳性、阴性表达组5年生存率较接近，分别为63.64%、56.52%，差异无统计学意义（χ2＝0.958，P＝0.273）。MMP-9阳性表达组5年生存率为73.33%，明显高于MMP-9阴性组的46.15%（χ2＝3.143，P＝0.035）。Ki-67阳性表达组5年生存率（61.70%）与阴性表达组（55.56%）较接近，两组间差异无统计学意义（χ2＝0.827，P＝0.419），128例患者中，Cyclin E与Ki-67的表达呈正相关（r＝0.391，P＝0.019），MMP-9与Ki-67表达无相关（r＝－0.109，P＝0.387），MMP-9与Cyclin E表达无明显相关（r＝－0.168，P＝0.183）。结论Cyclin E过表达及MMP-9蛋白表达下降或缺失可能会加速细胞周期的转化，并参与大肠癌的发生；Cyclin E过表达可能是大肠癌形成过程中较早的分子事件。MMP-9蛋白表达下降或缺失可能促进了大肠癌的发展及转移，且提示为患者预后不良的危险因素。

Objective To explore the effect of the expression of cell cycle regulators on the development and prognosis of colorectal carcinoma.Methods The surgicall resected tissues from 128 cases of colorectal cancer were collected in our hospital from June 2012-December 2015 December. The expression levels of Cyclin E, proliferation cell nuclear antigen （Ki-67） and matrix metalloproteinase （MMP）-9 were detected by immunohistochemieal staining in the large intestine mucosa from 128 cases of carcinoma and 24 samples of normal mucosa.χ2 test, single factor analysis of variance, Kaplan-Meier survival rate curve analysis and Log-rank test were applied.P〈0.05 was considered to be statistically significant difference.Results The positive rate of Cyclin E, Ki-67 and MMP-9 was significalntly higher in colorectal carcinoma than in normal mucosa （χ2=5.203, P=0.013）. The expression of Cyclin E in Duke’s stage A was markedly higher than in Duke’s stages B, C and D （χ2=10.331, P=0.001）, and it was higher in cases with negative lymph node metastasis than in those with positive lymph node metastasis （χ2=6.732, P=0.005）. The expression of Cyclin E was not correlated with the prognosis of the cases with lymph node metastasis. The down-regulated expression or deficiency of MMP-9 was related to advanced Duke’s stages （χ2=7.201, P=0.003） and lymph node metastasis （χ2=12.072, P=0.000）. The Ki-67 expression was not associated with the carcinoma localization, advanced Duke’s stages and prognosis. There were 44 deaths from 128 patients, accounting for 39.29%, with 24, 14 and 36 cases positive for, and 20, 30 and 8 cases negative for Cyclin E, Ki-67 and MMP-9 expression, respectively. The 5-year survival rate in Cyclin E positive and negative expression groups was 63.64% and 56.52% respectively, with no significant difference （χ2=0.958, P=0.273）. The 5-year survival rate in MMP-9 positive expression group was 73.33%, significantly higher than that in MMP-9 negative group （46.15%, χ2=3.143, P=0.035）. The 5-year surfival rate in Ki-67 positive group （61.70%） and negative group （55.56%） showed no significant difference （χ2=0.827, P=0.419）. The expression of Cyclin E was positively correlated with Ki-67 （r=0.391, P=0.019）, MMP-9 and Ki-67 showed no significant correlation （r= -0.109, P=0.387）, and MMP-9 and Cyclin E expression had no significant correlation （r=-0.168, P=0.183）. Conclusion The overexpression of Cyclin E and decline or deficiency of MMP-9 expression might accelerate the progression of the cell cycle and promote the carcinogenesis of colorectal carcinoma. The overexpression of Cyclin E might be a relatively early event in initiation of colorectal carcinoma. The decline or deficiency of MMP-9 expression might promote the development and metastasis of colorectal carcinoma, and it could be an indicator for unfavorable prognosis.