细胞周期蛋白D3可预测乳腺癌的无病生存期。
Cyclin D3 predicts disease-free survival in breast cancer.
作者信息
Chi Yayun, Huang Sheng, Liu Mengying, Guo Liang, Shen Xuxia, Wu Jiong
机构信息
Department of Breast Surgery, Breast Cancer Institute, Fudan University Shanghai Cancer Center, Building 7, No. 270 Dong An Road, Shanghai, 200032 China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China.
出版信息
Cancer Cell Int. 2015 Sep 26;15:89. doi: 10.1186/s12935-015-0245-6. eCollection 2015.
BACKGROUND
Cyclin D3, which induces progression through the G1 phase of the cell cycle, is a regulator of Cyclin-dependent kinases 4 and 6. Previous studies revealed that abnormal expression of Cyclin D3 was found in many different cancers. However, the role of Cyclin D3 in breast cancer (BC) remains unknown. The aim of this study is to examine the expression pattern of Cyclin D3 in BC and to evaluate its biological role and clinical significance in prognosis prediction. The mechanism involved is also evaluated.
METHODS
Immunohistochemical staining was used to detect the expression of Cyclin D3. qRT-PCR was used to detect the mRNA level of Cyclin D3 in BC tissues and BC cell lines. Transwell assay was used to examine the role of Cyclin D3 in the migration and invasion of BC cells. Mass Spectrometry was used to search for the interacting protein with Cyclin D3. Co-Immunoprecipitation assay and GST-Pull Down assay were used to validate the interaction of Cyclin D3 and its interaction protein.
RESULTS
Through detecting Cyclin D3 expression in 243 breast cancer patients' tissue array, we found Cyclin D3 expression was correlated with ER status (p = 0.000), PR status (p = 0.001), HER2 status (p = 0.002) and tumor differentiation (p = 0.045). The Kaplan-Meier survival curves indicated that the disease free survival (DFS) was significantly poor in high Cyclin D3 expression BC patients (p = 0.004). Furthermore, expression of Cyclin D3 was significantly associated with BC prognosis and was shown to be an independent prognostic marker in breast cancer (p = 0.028). By IHC staining and qPCR detection, Cyclin D3 expression was found to be down-regulated both in BC tissues and in BC cell lines compared with the corresponding normal controls. Further investigation showed Cyclin D3 was involved in the metastasis of BC cells and physically interacted with actin in vivo and in vitro.
CONCLUSION
Our studies revealed that Cyclin D3 was upregulated in breast cancer and represented a novel predictor of BC prognosis.
背景
细胞周期蛋白D3可诱导细胞通过细胞周期的G1期，是细胞周期蛋白依赖性激酶4和6的调节因子。先前的研究表明，在许多不同的癌症中都发现了细胞周期蛋白D3的异常表达。然而，细胞周期蛋白D3在乳腺癌（BC）中的作用仍不清楚。本研究的目的是检测细胞周期蛋白D3在乳腺癌中的表达模式，并评估其在预后预测中的生物学作用和临床意义。同时也评估其中涉及的机制。
方法
采用免疫组织化学染色检测细胞周期蛋白D3的表达。采用qRT-PCR检测乳腺癌组织和乳腺癌细胞系中细胞周期蛋白D3的mRNA水平。采用Transwell实验检测细胞周期蛋白D3在乳腺癌细胞迁移和侵袭中的作用。采用质谱法寻找与细胞周期蛋白D3相互作用的蛋白。采用免疫共沉淀实验和GST-Pull Down实验验证细胞周期蛋白D3与其相互作用蛋白的相互作用。
结果
通过检测243例乳腺癌患者组织芯片中细胞周期蛋白D3的表达，我们发现细胞周期蛋白D3的表达与雌激素受体（ER）状态（p = 0.000）、孕激素受体（PR）状态（p = 0.001）、人表皮生长因子受体2（HER2）状态（p = 0.002）和肿瘤分化（p = 0.045）相关。Kaplan-Meier生存曲线表明，细胞周期蛋白D3高表达的乳腺癌患者无病生存期（DFS）显著较差（p = 0.004）。此外，细胞周期蛋白D3的表达与乳腺癌预后显著相关，并且是乳腺癌的一个独立预后标志物（p = 0.028）。通过免疫组织化学染色和qPCR检测发现，与相应的正常对照相比，乳腺癌组织和乳腺癌细胞系中细胞周期蛋白D3的表达均下调。进一步研究表明，细胞周期蛋白D3参与乳腺癌细胞的转移，并在体内和体外与肌动蛋白发生物理相互作用。
结论
我们的研究表明，细胞周期蛋白D3在乳腺癌中上调，是乳腺癌预后的一个新的预测指标。
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