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.
Highlights
Hepatocellualr carcinoma (HCC), the primary malignancy of the adult liver, is a global health problem with unmet medical needs
Correlation analysis of ATAD2 transcript expression level www.impactjournals.com/oncotarget with clinical pathological data of these 75 hepatocellular carcinoma (HCC) patients suggested that ATAD2 expression was significantly associated with high AFP level (p < 0.0353), advanced tumor stages (p < 0.0358), and vascular invasion (p < 0.0211) (Table 1)
IHC staining of an independent sample set (n = 82) represented on tissue microarrays confirmed the over-expression of ATAD2 protein in 58.5% (48/82) of HCC patients
Summary
Hepatocellualr carcinoma (HCC), the primary malignancy of the adult liver, is a global health problem with unmet medical needs. Current global cancer statistics rank it as the second leading cause of cancer related death, with a high mortality-to-incidence ratio of 0.95 (2012 Globocan (WHO IARC). HCC patients are often detected when the disease is in its advanced stages, when there are limited therapeutic options. Together with inherent drug resistance and high recurrence rates, HCC patients often have poor prognosis with short overall survival time following diagnosis. There is still an imperative need to identify clinically and biologically relevant molecular targets of HCC that can be exploited for therapeutic purposes
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