Stabilization of TGF-β Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-β Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance,Advanced Science

当前位置： X-MOL 学术 › Adv. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Stabilization of TGF-β Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-β Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance
Advanced Science ( IF 14.3 ) Pub Date : 2024-07-09 , DOI: 10.1002/advs.202402327
Kewei Liu _{1,

2} , Fanxuan Tian ₂ , Xu Chen _{2,

3} , Biyin Liu ₂ , Shuoran Tian ₂ , Yongying Hou _{2,

4} , Lei Wang ₂ , Mengyi Han ₂ , Shiying Peng _{2,

3} , Yuting Tan _{2,

3} , Yuwei Pan _{2,

3} , Zhaole Chu ₂ , Jinyang Li ₂ , Linrong Che ₂ , Dongfeng Chen ₂ , Liangzhi Wen ₂ , Zhongyi Qin ₂ , Xianfeng Li ₂ , Junyu Xiang ₂ , Xiu-Wu Bian ₅ , Qin Liu _{2,

3,

5} , Xiaoli Ye ₁ , Tao Wang ₂ , Bin Wang _{2,

5,

6}

Affiliation

Dysregulation of the transforming growth factor-β (TGF-β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-β receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-β-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-β signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

中文翻译：

受体相关接头对 TGF-β 受体 1 的稳定作用要求反馈激活 TGF-β 信号通路以维持肝癌干性和耐药性

转化生长因子-β (TGF-β) 信号通路的失调可调节癌症干细胞 (CSC) 和药物敏感性，但目前仍不清楚反馈调节机制是如何被劫持以促进耐药 CSC 的。通过利用茎样耐药特性作为读数的全基因组 CRISPR 激活筛选，TGF-β 受体相关结合蛋白 1 (TGFBRAP1) 被鉴定为 TGF-β 诱导的正反馈调节因子，可控制对酪氨酸的敏感性激酶抑制剂（TKI）并促进肝癌干细胞。通过与 1 型 TGF-β 受体 (TGFBR1) 相互作用并使其稳定，TGFBRAP1 在增强 TGF-β 信号转导方面发挥着重要作用。从机制上讲，TGFBRAP1 与 E3 泛素连接酶 Smurf1/2 竞争与 TGFBR1 的结合，导致受体多泛素化和蛋白酶体降解受损。此外，过度活跃的 TGF-β 信号传导反过来又上调耐药 CSC 样细胞中 TGFBRAP1 的表达，从而构成了一种以前未表征的反馈机制来放大 TGF-β 信号传导。因此，TGFBRAP1 表达与肝细胞癌 (HCC) 组织中的 TGFβR1 水平和 TGF-β 信号传导活性以及多个 HCC 队列中的总体生存率和疾病复发相关。在治疗上，通过选择性抑制剂阻断 TGFBRAP1 介导的 TGFBR1 稳定作用，可通过减少 CSC 来减轻瑞戈非尼耐药性。总的来说，靶向 TGF-β 信号通路的反馈机制可能是减轻耐药性和肝癌干细胞性的可行方法。

更新日期：2024-07-09

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南