Targeting anillin inhibits tumorigenesis and tumor growth in hepatocellular carcinoma via impairing cytokinesis fidelity
Targeting anillin inhibits tumorigenesis and tumor growth in hepatocellular carcinoma via impairing cytokinesis fidelity
复制标题
靶向苯尼林通过损害胞质分裂保真度抑制肝细胞癌的肿瘤发生和肿瘤生长
DOI：
10.1038/s41388-022-02274-1
复制
发表时间：
2022-04-27
期刊：
影响因子：
8
通讯作者：
Song, Penghong
中科院分区：
文献类型：
--
作者：
Chen, Jian;Li, Zequn;Song, Penghong
靶向胞质分裂可以通过阻断细胞分裂和促进细胞凋亡来抑制肿瘤生长。我们的目的是描述肝细胞癌（HCC）进展中的关键胞质分裂调节因子，为确定有前途的HCC治疗靶点提供见解。无偏的生物信息学筛选确定了苯胺肌动蛋白结合蛋白（ANLN）作为一个关键的胞质分裂调节剂参与肝癌的发展。功能分析表明，敲低ANLN可通过诱导胞质分裂失败和DNA损伤，导致多核化和有丝分裂灾难，从而抑制肝癌的生长。从机制上讲，ANLN作为一个支架，以加强RACGAP 1和PLK 1之间的相互作用。ANLN促进PLK 1介导的RACGAP 1磷酸化和RhoA激活，以确保胞质分裂保真度。为了探索ANLN在HCC肿瘤发生中的功能，我们通过尾静脉注射将c-Myc和NRAS质粒水动力学转染到Anln+/+、Anln+/−和Anln−/−小鼠中。HepaticAnlnablation显著损害c-Myc/NRAS驱动的肝癌发生。此外，在Anlnablation小鼠中观察到增强的肝脏多倍化，表现为细胞和核多倍化比例增加。临床上，ANLN在人HCC组织中上调，并且高水平的ANLN与不良患者预后相关。此外，细胞多倍体比例在HCC进展过程中降低，并且ANLN水平与人HCC样品中的细胞多倍体比例显著相关。总之，ANLN被确定为一个关键的胞质分裂调节因子，有助于肝癌的发生和发展。我们的研究结果揭示了ANLN在调节胞质分裂以促进HCC肿瘤发生和生长中的新机制，表明靶向ANLN抑制胞质分裂可能是HCC的有希望的治疗策略。
Targeting cytokinesis can suppress tumor growth by blocking cell division and promoting apoptosis. We aimed to characterize key cytokinesis regulator in hepatocellular carcinoma (HCC) progression, providing insights into identifying promising HCC therapeutic targets. The unbiased bioinformatic screening identified Anillin actin binding protein (ANLN) as a critical cytokinesis regulator involved in HCC development. Functional assay demonstrated that knockdown of ANLN inhibited HCC growth by inducing cytokinesis failure and DNA damage, leading to multinucleation and mitotic catastrophe. Mechanistically, ANLN acts as a scaffold to strengthen interaction between RACGAP1 and PLK1. ANLN promotes PLK1-mediated RACGAP1 phosphorylation and RhoA activation to ensure cytokinesis fidelity. To explore the function of ANLN in HCC tumorigenesis, we hydrodynamically transfected c-Myc and NRAS plasmids into Anln+/+, Anln+/−, and Anln−/−mice through tail vein injection. HepaticAnlnablation significantly impaired c-Myc/NRAS-driven hepatocarcinogenesis. Moreover, enhanced hepatic polyploidization was observed inAnlnablation mice, manifesting as increasing proportion of cellular and nuclear polyploidy. Clinically, ANLN is upregulated in human HCC tissues and high level of ANLN is correlated with poor patients’ prognosis. Additionally, the proportion of cellular polyploidy decreases during HCC progression and ANLN level is significantly correlated with cellular polyploidy proportion in human HCC samples. In conclusion, ANLN is identified as a key cytokinesis regulator contributing to HCC initiation and progression. Our findings revealed a novel mechanism of ANLN in the regulation of cytokinesis to promote HCC tumorigenesis and growth, suggesting targeting ANLN to inhibit cytokinesis may be a promising therapeutic strategy for HCC.