The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy.
The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy.
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Aurora A/B 和 BRCA1/2 之间的负相互作用通过细胞周期进程、胞质分裂和四倍体的不同调节来控制癌细胞生长和肿瘤发生
DOI：
10.1186/1476-4598-13-94
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发表时间：
2014-04-28
期刊：
影响因子：
37.3
通讯作者：
Yang G
中科院分区：
文献类型：
--
作者：
Wang Y;Wang Z;Qi Z;Yin S;Zhang N;Liu Y;Liu M;Meng J;Zang R;Zhang Z;Yang G
众所周知，Aurora A/B（Aur A/B）的激活或BRCA 1/2的失活诱导肿瘤形成。我们和其他研究者报道Aur A/B和BRCA 1/2之间的相互抑制作用可能调控癌细胞的生长和肿瘤的发生，但这两种分子之间的相互调控和作用机制尚不清楚。在这项研究中，通过连续沉默Aur A/B或/和BRCA 1/2与特定的shRNAs，我们发现，在BRCA 2缺陷的胰腺癌细胞系Capan-1和卵巢癌细胞系OVCA 433，Aur A/B和BRCA 1/2的表达可能是通过蛋白酶体介导的蛋白水解，而不是通过基因转录的反向调节对方。Aur A/B和BRCA 1/2主要通过调控p53和cyclin A来调控细胞周期进程。Aur A/B缺失可阻断异常胞质分裂，降低细胞多核性和染色体四倍体，而BRCA 1/2缺失可促进异常胞质分裂，增加细胞多核性和染色体四倍体。此外，我们通过动物实验表明，Aur A/B的缺失抑制了两种细胞系的肿瘤生长，而BRCA 1/2的敲除促进了肿瘤生长。然而，Aur A/B和BRCA 1/2的同时沉默减弱了这些分子对细胞周期、胞质分裂和四倍体调节的作用，导致负荷肿瘤大小与乱序shRNA处理的对照细胞诱导的肿瘤大小相似。综上所述，我们的研究揭示了Aur A/B和BRCA 1/2之间的负相互作用反向控制细胞增殖、细胞周期进展、细胞多核化和四倍体化以调节肿瘤发生。
It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis.
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