Research Paper Volume 10, Issue 10 pp 2783—2799

Ubiquitin-specific protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition

Chan Qiu 1, *, , Yan Liu 2, *, , Ying Mei 3, , Min Zou 1, , Zhibo Zhao 3, , Mingxin Ye 4, , Xiaoling Wu 1, ,

  • 1 Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
  • 2 Department of Gastroenterology, the Fifth People’s Hospital of Chengdu, Chengdu, Sichuan, 611130, P.R. China
  • 3 Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
  • 4 Department of Hepatobiliary Surgery, the Affiliated Hospital of Southwest Medical University, Lu zhou, Sichuan, 646000, P.R. China
* Equal contribution

received: July 12, 2018 ; accepted: October 4, 2018 ; published: October 18, 2018 ;

https://doi.org/10.18632/aging.101587
How to Cite
This article has been corrected. See Correction. Aging (Albany NY). 2019; 11:3408-3409. https://doi.org/10.18632/aging.102010

Copyright: Qiu et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Invasion and metastasis are the main cause of recurrence and death in advanced hepatocellular carcinoma (HCC). Revealing the mechanisms of HCC metastasis is important for developing new therapeutic approaches and reducing patient mortality. Ubiquitin specific protease 4 (USP4), is involved in tumorigenesis by deubiquitinating some important oncogenic proteins and impacting their degradation. In the present study, we found that USP4 was significantly upregulated in HCC tumor tissues and the high expression of USP4 was associated with distant metastasis and poor survival in patients. Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results. In vivo, we also found that USP4 knockdown obviously blocked HCC cell metastasis. Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-β receptor type I (TGFR-1) to activate the TGF-β signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells. Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-β signaling-Induced EMT. These results could provide a new therapeutic target for the treatment of HCC.

Abbreviations

HCC: hepatocellular carcinoma; USP4: Ubiquitin specific protease 4; TGF-β: transforming growth factor-β; TGFR-1: TGF-β receptor type I; EMT: epithelial-mesenchyme transition; DUBs: deubiquitinating enzymes; USPs: Ubiquitin-specific proteases; CO-IP: Co-immunoprecipitation; CHX: Cycloheximide; H&E: Hematoxylin and eosin; IHC: Immunohistochemical; MDM2: murine double minute2; HNSCC: head and neck squamous cell carcinoma; HRP: horse radish peroxidase; DAB: diaminobenzidine.