BAG3 regulates epithelial-mesenchymal transition and angiogenesis in human hepatocellular carcinoma

Heng Xiao; Shaobing Cheng; Rongliang Tong; Zheng Lv; Chaofeng Ding; Chengli Du; Haiyang Xie; Lin Zhou; Jian Wu; Shusen Zheng

doi:10.1038/labinvest.2013.151

BAG3 regulates epithelial-mesenchymal transition and angiogenesis in human hepatocellular carcinoma

Lab Invest. 2014 Mar;94(3):252-61. doi: 10.1038/labinvest.2013.151. Epub 2013 Dec 23.

Authors

Affiliations

¹ 1] Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China [2] Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
² Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.

PMID: 24365746
DOI: 10.1038/labinvest.2013.151

Abstract

Bcl2-associated athanogene 3 (BAG3) protein is a co-chaperone of heat-shock protein (Hsp) 70 and may regulate major physiological and pathophysiological processes. However, few reports have examined the role of BAG3 in human hepatocellular carcinoma (HCC). In this study, we show that BAG3 regulates epithelial-mesenchymal transition (EMT) and angiogenesis in HCC. BAG3 was overexpressed in HCC tissues and cell lines. BAG3 knockdown resulted in reduction in migration and invasion of HCC cells, which was linked to reversion of EMT by increasing E-cadherin expression and decreasing N-cadherin, vimentin and slug expression, as well as suppressing matrix metalloproteinase 2 (MMP-2) expression. In a xenograft tumorigenicity model, BAG3 knockdown effectively inhibited tumor growth and metastasis through reduction in CD34 and VEGF expression and reversal of the EMT pathway. In conclusion, BAG3 is associated with the invasiveness and angiogenesis in HCC, and the BAG3 gene may be a novel therapeutic approach against HCC.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / physiology*
Aged
Animals
Antigens, CD34 / metabolism
Apoptosis
Apoptosis Regulatory Proteins
Carcinoma, Hepatocellular / blood supply*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cell Movement
Cell Proliferation
Epithelial-Mesenchymal Transition / genetics
Epithelial-Mesenchymal Transition / physiology
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Gene Knockdown Techniques
Heterografts
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Liver Neoplasms / blood supply*
Liver Neoplasms / genetics
Liver Neoplasms / pathology*
Male
Matrix Metalloproteinase 2 / metabolism
Mice
Middle Aged
Neoplasm Invasiveness
Neovascularization, Pathologic
Signal Transduction
Vascular Endothelial Growth Factor A / metabolism

Substances

Adaptor Proteins, Signal Transducing
Antigens, CD34
Apoptosis Regulatory Proteins
BAG3 protein, human
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
VEGFA protein, human
Vascular Endothelial Growth Factor A
Extracellular Signal-Regulated MAP Kinases
MMP2 protein, human
Matrix Metalloproteinase 2