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J Cell Mol Med. 2019 Apr;23(4):2399-2409. doi: 10.1111/jcmm.14055. Epub 2019 Jan 24.

Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase-2 in hepatocellular carcinoma cells and inhibits cell invasion.

Author information

1
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2
Department of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou, China.
3
Department of Pathology and Pathophysiology Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
4
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
5
Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Department of Clinical Laboratory, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Golgi phosphoprotein 73 (GP73) has been regarded as a novel serum biomarker for the diagnosis of hepatocellular carcinoma (HCC) in recent years. It has been reported that the upregulation of GP73 may promote the carcinogenesis and metastasis of HCC; however, the mechanisms remain poorly understood. In this study, GP73 correlates positively with matrix metalloproteinase-2 (MMP-2) in HCC-related cells and tissues. Further studies indicate that the knockdown of GP73 blocks MMP-2 trafficking and secretion, resulting in cell invasion inhibition. Additionally, the knockdown of GP73 induces the accumulation of intracellular MMP-2, which inhibits the phosphorylation of Src at Y416 and triggers the inhibition of SAPK/JNK and p53-p21 signalling pathways through a negative feedback loop. Finally, the transactivation of MMP2 was inhibited by the reduction in E2F1. This study reveals that GP73 plays functional roles in the trafficking and equilibrium of epithelial-mesenchymal transition (EMT)-related secretory proteins and that GP73 serves as a new potential target for combating the metastasis of HCC.

KEYWORDS:

GP73; MMP-2; hepatocellular carcinoma; intrahepatic metastasis; negative feedback loop; protein trafficking

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