E2F1 通过转录调控 CCNA2 的表达来促进三阴性乳腺癌的致瘤性。

E2F1 transcriptionally regulates CCNA2 expression to promote triple negative breast cancer tumorigenicity.

机构信息

Scientific Development and Planing Department, The First Hospital of Lanzhou University, Lanzhou, Gansu, China.

College of Earth and Environmental Sciences, Lanzhou University, Lanzhou, Gansu, China.

出版信息

Cancer Biomark. 2022;33(1):57-70. doi: 10.3233/CBM-210149.

DOI:10.3233/CBM-210149

PMID:34366326

Abstract

BACKGROUND

Triple-negative breast cancer (TNBC) is a highly malignant breast cancer subtype with a poor prognosis. The cell cycle regulator cyclin A2 (CCNA2) plays a role in tumor development. Herein, we explored the role of CCNA2 in TNBC.

METHODS

We analyzed CCNA2 expression in 15 pairs of TNBC and adjacent tissues and assessed the relationship between CCNA2 expression using the tissue microarray cohort. Furthermore, we used two TNBC cohort datasets to analyze the correlation between CCNA2 and E2F transcription factor 1 (E2F1) and a luciferase reporter to explore their association. Through rescue experiments, we analyzed the effects of E2F1 knockdown on CCNA2 expression and cellular behavior.

RESULTS

We found that CCNA2 expression in TNBC was significantly higher than that in adjacent tissues with similar observations in MDA-MB-231 and MDA-MB-468 cells. E2F1 was highly correlated with CCNA2 as observed through bioinformatics analysis (R= 0.80, P< 0.001) and through TNBC tissue verification analysis (R= 0.53, P< 0.001). We determined that E2F1 binds the +677 position within the CCNA2 promoter. Moreover, CCNA2 overexpression increased cell proliferation, invasion, and migration owing to E2F1 upregulation in TNBC.

CONCLUSION

Our data indicate that E2F1 promotes TNBC proliferation and invasion by upregulating CCNA2 expression. E2F1 and CCNA2 are potential candidates that may be targeted for effective TNBC treatment.

摘要

背景

三阴性乳腺癌（TNBC）是一种预后较差的高度恶性乳腺癌亚型。细胞周期调节因子细胞周期蛋白 A2（CCNA2）在肿瘤发展中发挥作用。在此，我们探讨了 CCNA2 在 TNBC 中的作用。

方法

我们分析了 15 对 TNBC 和相邻组织中的 CCNA2 表达，并使用组织微阵列队列评估了 CCNA2 表达之间的关系。此外，我们使用两个 TNBC 队列数据集来分析 CCNA2 与 E2F 转录因子 1（E2F1）之间的相关性，并通过荧光素酶报告基因实验来探讨它们之间的关联。通过挽救实验，我们分析了 E2F1 敲低对 CCNA2 表达和细胞行为的影响。

结果

我们发现，TNBC 中 CCNA2 的表达明显高于相邻组织，在 MDA-MB-231 和 MDA-MB-468 细胞中也观察到类似的结果。通过生物信息学分析（R=0.80，P<0.001）和 TNBC 组织验证分析（R=0.53，P<0.001）发现，E2F1 与 CCNA2 高度相关。我们确定 E2F1 结合 CCNA2 启动子的+677 位。此外，由于 E2F1 的上调，CCNA2 的过表达增加了 TNBC 中的细胞增殖、侵袭和迁移。