Decreased expression of ARID1A associates with poor prognosis and promotes metastases of hepatocellular carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is a common malignancy worldwide, which is especially prevalent in Asia. Elucidating the molecular basis of HCC is crucial to develop targeted diagnostic tools and novel therapies. Recent studies have identified AT-rich interactive domain-containing protein 1A (ARID1A) as a broad-spectrum tumor suppressor. We evaluated the clinical implications of decreased ARID1A expression in HCC, and investigated the mechanisms of ARID1A-mediated tumor suppression.MethodsQuantitative PCR, western blotting, immunohistochemical analysis of ARID1A mRNA and protein expression was conducted in 64 paired HCC and adjacent non-tumorous tissues. ARID1A function was evaluated in vitro in MHCC-97H and Huh7 HCC cell lines, and in vivo in a xenografted HCC tumor model.ResultsARID1A mRNA and protein expression were significantly decreased in HCC tissues, and decreased expression was significantly associated with overall metastasis, including local lymph node and distant metastasis, and poor prognosis. ARID1A knockdown promoted HCC cell migration and invasion in vitro, whereas overexpression of ARID1A inhibited migration and invasion. E-cadherin levels were closely correlated with ARID1A expression, suggesting a role in migration and invasion. In addition, ARID1A and E-cadherin (CDH1) expression were found to be regulated in a coordinated fashion in HCC samples. Furthermore, ARID1A knockdown significantly increased HCC tumor growth and lung metastasis in vivo.ConclusionsARID1A served as an important tumor suppressor. Decreased expression of ARID1A was associated with tumor progression, metastasis, and reduced overall survival in mice and humans. ARID1A could represent a promising candidate therapeutic target for HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0164-3) contains supplementary material, which is available to authorized users.

Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer

“…The fact that Arid1a heterozygosity promoted metastasis is consistent with previous studies that showed partial ARID1A loss in human gastric and liver cancer samples was associated with metastasis and that incomplete ARID1A knockdown in cancer cell lines promoted migration and invasion (He et al, 2015; Huang et al, 2012; Yan et al, 2014). While we provided in vivo evidence that this also occurred in genetically engineered mouse models and offered mechanisms by which this occurs, it is likely that the downregulation of many metastasis or growth suppressing genes collectively contribute to the phenotypic effects of ARID1A loss in tumors, and our study identified only a subset of such genes.…”

Chromatin remodeling geneARID2targets cyclin D1 and cyclin E1 to suppress hepatoma cell progression

“…Previous studies have demonstrated that decreased expression of ARID1A, which encodes another protein of the ARID family, enhances gastric cancer cell or HCC cell migration via transcriptional silencing of E-cadherin [25, 26]. Moreover, the BRG-1 subunit of the SWI/SNF complex has been reported to regulate CD44 expression and play a critical role in regulating cellular adhesion and metastasis [27, 28].…”

HBx protein‐mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma

“…Previous studies have reported that downregulation of ARID1A, which encodes another ARID protein of the SWI/SNF family, promotes gastric cancer cells or HCC cell migration by repression of epithelial marker E‐cadherin . Thus, we further explored the effects of ARID2 on E‐cadherin expression and cell migration in stable HBx‐expressing cell lines.…”

“…Previous studies have reported that downregulation of ARID1A, which encodes another ARID protein of the SWI/SNF family, promotes gastric cancer cells or HCC cell migration by repression of epithelial marker E-cadherin. (27,28) Thus, we further explored the effects of ARID2 on E-cadherin expression and cell migration in stable HBx-expressing cell lines. Transwell assays demonstrated that ARID2 significantly inhibited cell migration and enhanced the expression of the epithelial marker E-cadherin in SK-HBx and Huh7-HBx cell lines (Fig.…”