TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance.
TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance.
复制标题
TAK1 是肝细胞癌的一个新靶点，有助于索拉非尼耐药。
DOI：
10.1016/j.jcmgh.2021.04.016
复制
发表时间：
2021
影响因子：
7.2
通讯作者：
Cai X
中科院分区：
文献类型：
--
作者：
Xia S;Ji L;Tao L;Pan Y;Lin Z;Wan Z;Pan H;Zhao J;Cai L;Xu J;Cai X
在肝细胞癌（HCC）中鉴定新的和可操作的靶标仍然是未满足的医疗需求。TAK 1最初被鉴定为转化生长因子-β激活的激酶，并被进一步证明磷酸化和激活许多下游靶点并促进癌症进展。然而，TAK 1在HCC进展和靶向治疗耐药中的作用知之甚少。TAK 1或MTDH在HCC细胞系、肿瘤组织和索拉非尼耐药模型中的表达通过计算机分析、定量实时聚合酶链反应、蛋白质印迹和免疫组织化学进行分析。采用小干扰RNA和药理学抑制剂联合或不联合索拉非尼的体内和体外实验，研究TAK 1或MTDH在HCC和索拉非尼耐药中的功能。采用免疫共沉淀和RNA免疫共沉淀法检测TAK 1与FBXW 2或MTDH与FBXW 2 mRNA的结合。进行蛋白半衰期和体外泛素化实验以验证FBXW 2是否调节TAK 1降解。我们的研究结果揭示了TAK 1在促进HCC和索拉非尼耐药方面的临床意义。我们鉴定了一种新的E3泛素连接酶FBXW 2，其靶向TAK 1进行K48连接的聚泛素化和随后的降解。我们还发现MTDH通过与FBXW 2 mRNA结合并加速其降解，有助于HCC和索拉非尼抗性中的TAK 1上调。此外，TAK 1抑制剂和索拉非尼的组合抑制了小鼠模型中索拉非尼抗性HCCLM 3异种移植物的生长。这些结果揭示了TAK 1蛋白降解的新机制，并强调了靶向TAK 1在抑制HCC和克服索拉非尼耐药方面的治疗价值。
Identifying novel and actionable targets in hepatocellular carcinoma (HCC) remains an unmet medical need. TAK1 was originally identified as a transforming growth factor-β–activated kinase and was further proved to phosphorylate and activate numerous downstream targets and promote cancer progression. However, the role of TAK1 in developed HCC progression and targeted therapy resistance is poorly understood. The expression of TAK1 or MTDH in HCC cell lines, tumor tissues, and sorafenib-resistant models was analyzed by in silico analysis, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. In vivo and in vitro experiments were introduced to examine the function of TAK1 or MTDH in HCC and sorafenib resistance using small interfering RNA and pharmacologic inhibitors in combination with or without sorafenib. Co-immunoprecipitation and RNA immunoprecipitation were carried out to determine the binding between TAK1 and FBXW2 or between MTDH and FBXW2 mRNA. Protein half-life and in vitro ubiquitination experiment was performed to validate whether FBXW2 regulates TAK1 degradation. Our findings unraveled the clinical significance of TAK1 in promoting HCC and sorafenib resistance. We identified a novel E3 ubiquitin ligase, FBXW2, targeting TAK1 for K48-linked polyubiquitylation and subsequent degradation. We also found that MTDH contributes to TAK1 up-regulation in HCC and sorafenib resistance through binding to FBXW2 mRNA and accelerates its degradation. Moreover, combination of TAK1 inhibitor and sorafenib suppressed the growth of sorafenib-resistant HCCLM3 xenograft in mouse models. These results revealed novel mechanism underlying TAK1 protein degradation and highlighted the therapeutic value of targeting TAK1 in suppressing HCC and overcoming sorafenib resistance.
登录
查看更多内容
EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
16.8
作者：
Luo EC;Nathanson JL;Tan FE;Schwartz JL;Schmok JC;Shankar A;Markmiller S;Yee BA;Sathe S;Pratt GA;Scaletta DB;Ha Y;Hill DE;Aigner S;Yeo GW
通讯作者：
Yeo GW
DOI：
10.1016/j.bbrc.2009.02.052
发表时间：
2009-04-10
影响因子：
3.1
作者：
Minoda, Yasumasa;Sakurai, Hiroaki;Takaesu, Giichi
通讯作者：
Takaesu, Giichi
LXR 激活通过激活 microRNA-378a 转录增强 HCC 中索拉非尼的敏感性
影响因子：
12.4
作者：
Lin, Zhongjie;Xia, Shunjie;Cai, Xiujun
通讯作者：
Cai, Xiujun
DOI：
10.1158/1078-0432.ccr-09-0049
发表时间：
2009-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hu G;Wei Y;Kang Y
通讯作者：
Kang Y