Oncotarget

Research Papers:

Suppression of ATAD2 inhibits hepatocellular carcinoma progression through activation of p53- and p38-mediated apoptotic signaling

Wen-Jing Lu, Mei-Sze Chua _ and Samuel K. So

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Oncotarget. 2015; 6:41722-41735. https://doi.org/10.18632/oncotarget.6152

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Abstract

Wen-Jing Lu1, Mei-Sze Chua1 and Samuel K. So1

1 Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA

Correspondence to:

Mei-Sze Chua, email:

Keywords: ATAD2, apoptosis, mutant p53, liver cancer, targeted therapy

Received: July 07, 2015 Accepted: September 30, 2015 Published: October 19, 2015

Abstract

The ATPase family, AAA domain containing 2 (ATAD2) is highly expressed in multiple cancers. We aim to understand the clinical and biological significance of ATAD2 over-expression in hepatocellular carcinoma (HCC), as a means to validate it as a therapeutic target in HCC. We demonstrated that ATAD2 was over-expressed in HCC patients, where high ATAD2 levels were significantly correlated with aggressive phenotypes such as high AFP levels, advanced tumor stages, and vascular invasion. Using RNA interference, suppression of ATAD2 in HCC cell lines decreased cell viability, migration, and invasion, and induced apoptosis in vitro. Furthermore, we identified p53 and p38 as key proteins that mediate apoptosis induced by ATAD2 suppression. In HCC cells, we demonstrated that ATAD2 directly interacted with MKK3/6, which prevented p38 activation and therefore inhibited p38-mediated apoptosis. In vivo, suppression of ATAD2 impaired the growth of HepG2 and Hep3B subcutaneous xenografts, accompanied by enhanced apoptosis and p-p53 and p-p38 levels. Our results validate that ATAD2 is an important negative regulator of apoptosis, and that neutralizing its activity has promising anti-tumor effects in HCC cells.


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