HOOK1 Inhibits the Progression of Renal Cell Carcinoma via TGF-β and TNFSF13B/VEGF-A Axis

Lei Yin; Wenjia Li; Xuxiao Chen; Ronghao Wang; Tao Zhang; Jialin Meng; Zhao Li; Li Xu; Rui Yin; Bo Cheng; Huan Yang

doi:10.1002/advs.202206955

HOOK1 Inhibits the Progression of Renal Cell Carcinoma via TGF-β and TNFSF13B/VEGF-A Axis

Adv Sci (Weinh). 2023 Jun;10(17):e2206955. doi: 10.1002/advs.202206955. Epub 2023 Apr 21.

Authors

Lei Yin^{1

2}, Wenjia Li³, Xuxiao Chen⁴, Ronghao Wang⁵, Tao Zhang¹, Jialin Meng⁶, Zhao Li⁷, Li Xu⁸, Rui Yin⁹, Bo Cheng¹⁰, Huan Yang¹¹

Affiliations

¹ Department of Urology, Putuo People's Hospital, Tongji University, Shanghai, 200060, P. R. China.
² Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
³ Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
⁴ Department of General Surgery, Hepatobiliary Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
⁵ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, P. R. China.
⁶ Department of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei, 230032, P. R. China.
⁷ Department of Anesthesiology, Xiangya Hospital Central South University, Changsha, 410008, P. R. China.
⁸ Department of Anesthesiology, The First People's Hospital of Changde, Changde, 415000, P. R. China.
⁹ Center for Reproductive Medicine, Shandong University, Jinan, 250012, P. R. China.
¹⁰ Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, P. R. China.
¹¹ Department of Urology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, P. R. China.

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.

Keywords: HOOK1; TGF-Î2 signaling; TNFSF13B; renal cell carcinoma; tumor metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B-Cell Activating Factor / therapeutic use
Carcinoma, Renal Cell* / drug therapy
Carcinoma, Renal Cell* / metabolism
Carcinoma, Renal Cell* / pathology
Humans
Kidney Neoplasms* / drug therapy
Sunitinib
Transforming Growth Factor beta
Vascular Endothelial Growth Factor A

Substances

Vascular Endothelial Growth Factor A
Sunitinib
Transforming Growth Factor beta
TNFSF13B protein, human
B-Cell Activating Factor

Abstract

Publication types

MeSH terms

Substances

Grants and funding