南方医科大学学报

南方医科大学学报 ›› 2020, Vol. 40 ›› Issue (11): 1593-1600.doi: 10.12122/j.issn.1673-4254.2020.11.09

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乳腺浸润性导管癌中JMJD3、 MMP-2和VEGF的表达及其与临床病理特征的关系

徐小艳，王建君，闫 琛，门颖丽，姜 黄，方会娟，徐宪伟，杨金花   

  • 出版日期:2020-11-20 发布日期:2020-11-23

Association of JMJD3, MMP-2 and VEGF expressions with clinicopathological features of invasive ductal breast carcinoma

  • Online:2020-11-20 Published:2020-11-23

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摘要： 目的 观察乳腺浸润性导管癌中JMJD3、MMP-2和VEGF蛋白水平的表达，研究过表达JMJD3对乳腺癌细胞增殖以及MMP-2 和 VEGF 表达的影响。方法 用免疫组织化法和 RT-PCR 检测乳腺浸润性导管癌及相对应的癌旁组织中 JMJD3、MMP-2和VEGF蛋白和mRNA的表达情况，分析蛋白表达与乳腺癌患者临床病理特征的关系及上述蛋白的相关性，采用Kaplan-Meier法来评估JMJD3、MMP-2和VEGF蛋白的异常表达与乳腺癌患者生存期之间的关系。通过重组质粒在乳腺癌MDA-MB-231细胞中过表达JMJD3，用CCK-8和免疫组化检测Ki67表达分析其对增殖的影响，用RT-PCR方法检测MMP-2和VEGFmRNA水平表达的变化。结果 免疫组化结果显示，乳腺癌组织中JMJD3阳性强度低于相应癌旁组织（P<0.05），乳腺癌组织中MMP-2和VEGF阳性强度高于相应癌旁组织（P<0.05）；RT-PCR结果显示，乳腺癌JMJD3 mRNA水平低于癌旁组织，MMP-2和VEGF mRNA水平高于癌旁组织（P<0.05）。JMJD3的表达在乳腺癌直径较小、高分化、TNMⅠ+Ⅱ期、淋巴结无转移及分子分型Luminal A型和Luminal B型表达率较高（P<0.05），MMP-2和VEGF的表达在乳腺癌肿瘤直径较大、低分化、TNM Ⅲ+Ⅳ期、淋巴结有转移、Luminal B 型和 Her-2 过表达型表达率较高（P<0.05）。Kaplan-Meier 分析结果显示，JMJD3蛋白表达水平较高者的无病生存期高于低表达者（P<0.05），MMP-2和VEGF蛋白表达水平较高者的无病生存期低于低表达表达者（P<0.05）。Cox 回归模型分析显示，JMJD3、MMP-2 和 VEGF、分化程度是乳腺癌预后的独立危险因素。Spearman 相关分析结果显示，JMJD3与MMP2和VEGF均呈负相关（r=-0.569，-0.533，P<0.05），MMP2和VEGF呈正相关（r=0.923，P<0.05）。过表达JMJD3能够抑制乳腺癌MDA-MB-231细胞的增殖、MMP-2和VEGF的表达。结论 JMJD3、MMP-2和VEGF在乳腺浸润性导管癌中的异常表达与肿瘤的增殖、浸润、转移及预后密切相关，三者可作为判断乳腺癌预后不良的重要指标之一。

关键词: 乳腺浸润性导管癌, JMJD3, MMP-2, VEGF, 临床病理特征

Abstract: Objective To examine the expressions of JMJD3, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in invasive ductal breast carcinoma, their association with the clinicopathological features of the patients and the effect of JMJD3 overexpression on proliferation and MMP-2 and VEGF expressions in breast cancer cells. Methods The protein and mRNA expressions of JMJD3, MMP-2, and VEGF in invasive ductal breast carcinoma and paired adjacent tissues were detected by immunohistochemistry and RT-PCR, respectively, and their correlation with the clinicopathological characteristics of the patients was analyzed. Kaplan-Meier survival analysis was used to evaluate the correlation of JMJD3, MMP-2 and VEGF expression levels with the survival of the patients. In breast cancer MDA-MB-231 cells transfected with a JMJD3-expression plasmid, the expression of Ki67 was examined immunohistochemically, the cell proliferation was assessed with CCK8 assay, and the mRNA expressions of MMP-2 and VEGF were detected with RT-PCR. Results Breast cancer tissues had significantly lower JMJD3 expression and higher MMP-2 and VEGF expressions at both the mRNA and protein levels than the adjacent tissue (P<0.05). The positivity rates of JMJD3, MMP-2 and VEGF in breast cancer tissues were significantly correlated with tumor diameter, differentiation, TNM stage, lymph node metastasis, and molecular subtypes (P<0.05). KaplanMeier analysis showed that JMJD3 expression level was positively while MMP-2 and VEGF were inversely correlated with the disease-free survival time of the patients (P<0.05). Cox regression analysis identified JMJD3, MMP-2, VEGF and tumor differentiation as independent prognostic factors of breast cancer. Spearman correlation analysis suggested a negative correlation of JMJD3 with MMP2 (r=-0.569, P<0.05) and VEGF (r=-0.533, P<0.05) and a positive correlation between MMP2 and VEGF (r=0.923, P<0.05). In MDA-MB-231 cells, overexpression of JMJD3 inhibited the proliferation of MDA-MB-231 cells and
the expression of MMP-2 and VEGF. Conclusion The expressions of JMJD3, MMP-2 and VEGF in invasive ductal breast carcinoma are closely correlated to tumor proliferation, invasion, metastasis and prognosis and can be used for prognostic evaluation of breast cancer.

Key words: invasive ductal carcinoma of breast, JMJD3, matrix metalloproteinase-2, vascular endothelial growth factor, clinicopathological features