Deubiquitinase PSMD14 enhances hepatocellular carcinoma growth and metastasis by stabilizing GRB2

Autor: Huita Wu, Jing Lu, Qinliang Fang, Ping Zhan, Wenxiu Zhao, Sheng Zhang, Jie Lv, Yuyan Lu, Zhenyu Yin, Chengrong Xie, Junjiang Lu, Fuqiang Wang
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Cancer Research
Proteasome Endopeptidase Complex
Carcinoma
Hepatocellular
Disease-Free Survival
Deubiquitinating enzyme
Metastasis
03 medical and health sciences
0302 clinical medicine
In vivo
Cell Movement
Cell Line
Tumor
medicine
Animals
Humans
Cell Proliferation
GRB2 Adaptor Protein
Gene knockdown
Oncogene
biology
business.industry
PSMD14
Liver Neoplasms
Ubiquitination
Middle Aged
medicine.disease
Prognosis
Xenograft Model Antitumor Assays
digestive system diseases
Up-Regulation
Gene Expression Regulation
Neoplastic
030104 developmental biology
HEK293 Cells
Oncology
Proteasome
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Gene Knockdown Techniques
Proteolysis
Cancer research
biology.protein
Trans-Activators
Female
Neoplasm Recurrence
Local
business
Protein Processing
Post-Translational
Zdroj: Cancer letters. 469
ISSN: 1872-7980
Popis: Hepatocellular carcinoma (HCC) has emerged as one of the most common malignancies worldwide. It is associated with a high mortality rate, as evident from its increasing incidence and extremely poor prognosis. The deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) has been reported to act as an oncogene in several human cancers. The present study aimed to reveal the functional significance of PSMD14 in HCC progression and the underlying mechanisms. We found that PSMD14 was significantly upregulated in HCC tissues. Overexpression of PSMD14 correlated with vascular invasion, tumor number, tumor recurrence, and poor tumor-free and overall survival of patients with HCC. Knockdown and overexpression experiments demonstrated that PSMD14 promoted proliferation, migration, and invasion in HCC cells in vitro, and facilitated tumor growth and metastasis in vivo. Mechanistically, we identified PSMD14 as a novel post-translational regulator of GRB2. PSMD14 inhibits degradation of GRB2 via deubiquitinating this oncoprotein in HCC cells. Furthermore, pharmacological inhibition of PSMD14 with O-phenanthroline (OPA) suppressed the malignant behavior of HCC cells in vitro and in vivo. In conclusion, our findings suggest that PSMD14 could serve as a novel promising therapeutic candidate for HCC.
Databáze: OpenAIRE
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