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

Fei He,Zhenyu Yin,Yaping Xu,Sheng Zhang,Wenxiu Zhao,Xiaomin Wang,Jianfeng Xu,Jie Li

doi:10.1186/s13046-015-0164-3

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.

Highlights

Hepatocellular carcinoma (HCC) is a common malignancy worldwide, which is especially prevalent in Asia
Reduced expression of AT-rich interactive domain-containing protein 1A (ARID1A) in HCC patients was associated with poor prognosis and an increased risk of metastasis As revealed by quantitative real-time reverse transcription polymerase chain reaction (qPCR), ARID1A mRNA levels were significantly downregulated in HCC tissues compared with nontumorous tissues (n = 64, Student’s t-test, p
In the same 64 paired HCC samples, immunohistochemical analysis revealed that ARID1A protein expression was decreased in 41 out of 64 (64.1 %) tumor tissues when compared with adjacent nontumorous counterparts

Summary

Introduction

Hepatocellular 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. Elucidating the molecular basis of HCC is crucial to develop targeted diagnostic tools and therapies [2]. Cancer genome sequencing has identified frequent mutations in epigenetic regulators, chromatin remodeling. AT-rich interactive domain-containing protein 1A (ARID1A) is a key member of the SWI/SNF chromatin-remodeling complex. Known as BAF250a, SMARCF1, or p270, ARID1A belongs to a family of proteins that contain a highly conserved, ~100 amino acid DNA binding domain termed ARID (AT-rich interacting domain) [5].

Methods

Results

Conclusion