Targeted TPX2 increases chromosome missegregation and suppresses tumor cell growth in human prostate cancer.
Targeted TPX2 increases chromosome missegregation and suppresses tumor cell growth in human prostate cancer.
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DOI：
10.2147/ott.s136491
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发表时间：
2017
影响因子：
4
通讯作者：
Wu TT
中科院分区：
文献类型：
--
作者：
Pan HW;Su HH;Hsu CW;Huang GJ;Wu TT
前列腺癌是一种复杂的疾病，可能相对无害或极具侵略性。虽然雄激素剥夺疗法是前列腺癌患者常用的治疗方法，但其不良反应可能对患者的健康和生活质量有害。因此，识别肿瘤生长的新靶基因将能够开发新的治疗干预。TPX 2在有丝分裂期间的染色体分离机制中起关键作用。低比率的染色体错误分离可以促进肿瘤的发展，而较高的水平可能会促进细胞死亡并抑制肿瘤发生。因此，通过诱导大量染色体错误分离来促进细胞死亡的策略已经成为选择性消除高度增殖的肿瘤细胞的治疗应用。采用RNAi技术敲低TPX 2蛋白表达，克隆形成实验、免疫组化染色、双胸苷阻断、图像细胞分析和肿瘤球体实验分别分析TPX 2在肿瘤细胞生长、细胞周期进程、多核性、倍性和致瘤性中的作用;最后采用Western blotting分析TPX 2靶向的抗癌机制。我们证明，靶向TPX 2减少了细胞周期调节因子和染色体分离基因，导致细胞微核增加。此外，TPX 2耗尽导致前列腺癌细胞生长抑制，增加细胞凋亡，并减少肿瘤发生。这些结果证实了靶向TPX 2在前列腺癌治疗中的治疗潜力。此外，我们发现TPX 2沉默导致CDK 1，细胞周期蛋白B，securin，分离酶和极光A蛋白的失调;相比之下，p21 mRNA上调。我们还确定了TPX 2靶向前列腺癌细胞的分子机制。总之，我们的研究说明TPX 2作为前列腺癌治疗的潜在新靶基因的能力。
Prostate cancer is a complex disease that can be relatively harmless or extremely aggressive. Although androgen-deprivation therapy is a commonly used treatment for men with prostate cancer, the adverse effects can be detrimental to patient health and quality of life. Therefore, identifying new target genes for tumor growth will enable the development of novel therapeutic intervention. TPX2 plays a critical role in chromosome segregation machinery during mitosis. Low rates of chromosome missegregation can promote tumor development, whereas higher levels might promote cell death and suppress tumorigenesis. Hence, the strategy of promoting cell death by inducing massive chromosome missegregation has been a therapeutic application for selectively eliminating highly proliferating tumor cells. RNAi was used for TPX2 protein expression knockdown, and a clonogenic assay, immunostaining, double thymidine block, image-cytometry analysis, and tumor spheroid assay were used to analyze the role of TPX2 in tumor cell growth, cell cycle progression, multinuclearity, ploidy, and tumorigenicity, respectively; finally, Western blotting was used to analyze anticancer mechanisms in TPX2 targeting. We demonstrated that targeting TPX2 reduced cell cycle regulators and chromosome segregation genes, resulting in increased cell micronucleation. Moreover, TPX2 depletion led to prostate cancer cell growth inhibition, increased apoptosis, and reduced tumorigenesis. These results confirmed the therapeutic potential of targeting TPX2 in prostate cancer treatment. Moreover, we found that TPX2 silencing led to deregulation of CDK1, cyclin B, securin, separase, and aurora A proteins; by contrast, p21 mRNA was upregulated. We also determined the molecular mechanisms for TPX2 targeting in prostate cancer cells. In conclusion, our study illustrates the power of TPX2 as a potential novel target gene for prostate cancer treatment.