舒尼替尼
肾细胞癌
癌症研究
转移
血管生成
肾透明细胞癌
转化生长因子
MAPK/ERK通路
癌症
医学
内科学
化学
信号转导
生物
细胞生物学
作者
Lei Yin,Wenjia Li,Xuxiao Chen,Ronghao Wang,Tao Zhang,Jialin Meng,Li Zhao,Xu Li,Rui Yin,Bo Cheng,Huan Yang
标识
DOI:10.1002/advs.202206955
摘要
Abstract Accumulating evidence shows HOOK1 disordered in human malignancies. However, the clinicopathological and biological significance of HOOK1 in renal cell carcinoma (RCC) remains rarely studied. In this study, the authors demonstrate that HOOK1 is downregulated in RCC samples with predicted poorer clinical prognosis. Mechanistically, HOOK1 inhibits tumor growth and metastasis via canonical TGF‐ β /ALK5/p‐Smad3 and non‐canonical TGF‐ β /MEK/ERK/c‐Myc pathway. At the same time, HOOK1 inhibits RCC angiogenesis and sunitinib resistance by promoting degradation of TNFSF13B through the ubiquitin‐proteasome pathway. In addition, HOOK1 is transcriptionally regulated by nuclear factor E2F3 in VHL dependent manner. Notably, an agonist of HOOK1, meletin, is screened and it shows antitumor activity more effectively when combined with sunitinib or nivolumab than it is used alone. The findings reveal a pivotal role of HOOK1 in anti‐cancer treatment, and identify a novel therapeutic strategy for renal cell carcinoma.
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