Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer.
Utility of the dual-specificity protein kinase TTK as a therapeutic target for intrahepatic spread of liver cancer.
复制标题
DOI：
10.1038/srep33121
复制
发表时间：
2016-09-13
影响因子：
4.6
通讯作者：
Zhao H
中科院分区：
文献类型：
--
作者：
Miao R;Wu Y;Zhang H;Zhou H;Sun X;Csizmadia E;He L;Zhao Y;Jiang C;Miksad RA;Ghaziani T;Robson SC;Zhao H
原发性肝癌是全球癌症相关死亡的第三大原因，其治疗方法仍然有限。经过多组学分析（包括全基因组和转录组测序），我们能够将双特异性蛋白激酶 TTK 鉴定为假定的肝癌新预后生物标志物。在此，我们发现，与邻近的肝组织相比，一组肝癌患者的肿瘤组织中 TTK 蛋白的水平显着升高。我们还测试了 TTK 靶向抑制的效用，并在体内肝癌实验模型中展示了治疗潜力。在几种人肝癌细胞系中进行慢病毒 shRNA 敲除后，我们证明 TTK 可以促进细胞生长并促进细胞扩散；以及防止衰老和减少自噬。在实验动物模型中，我们发现 TTK 的体外敲低可有效阻止人 HCC 异种移植物的肝内生长。此外，我们注意到，通过将 TTK siRNA 系统性地递送至已经患有肿瘤的肝脏，TTK 的体内沉默可限制肝癌细胞的肝内扩散。这种干预与肿瘤侵袭性降低以及衰老和自噬增加相关。综上所述，我们的数据表明，靶向 TTK 抑制可能具有临床实用性，可作为肝癌治疗的辅助疗法。
Therapies for primary liver cancer, the third leading cause of cancer-related death worldwide, remain limited. Following multi-omics analysis (including whole genome and transcriptome sequencing), we were able to identify the dual-specific protein kinase TTK as a putative new prognostic biomarker for liver cancer. Herein, we show that levels of TTK protein are significantly elevated in neoplastic tissues from a cohort of liver cancer patients, when compared with adjacent hepatic tissues. We also tested the utility of TTK targeted inhibition and have demonstrated therapeutic potential in an experimental model of liver cancer in vivo. Following lentiviral shRNA knockdown in several human liver cancer cell lines, we demonstrated that TTK boosts cell growth and promotes cell spreading; as well as protects against senescence and decreases autophagy. In an experimental animal model, we show that in vitro knockdown of TTK effectively blocks intrahepatic growth of human HCC xenografts. Furthermore, we note that, in vivo silencing of TTK, by systemically delivering TTK siRNAs to already tumor-bearing liver, limits intrahepatic spread of liver cancer cells. This intervention is associated with decreased tumor aggressiveness, as well as increased senescence and autophagy. Taken together, our data suggest that targeted TTK inhibition might have clinical utility as an adjunct therapy in management of liver cancer.
登录
查看更多内容
影响因子：
13.5
作者：
Llovet, Josep M.;Bruix, Jordi
通讯作者：
Bruix, Jordi
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
2.7
作者：
Kumar, D. Vijay;Hoarau, Christophe;Carlson, Robert O.
通讯作者：
Carlson, Robert O.
影响因子：
2.7
作者：
Bursavich, Matthew G.;Dastrup, David;Kumar, D. Vijay
通讯作者：
Kumar, D. Vijay