Abstract
BackgroundThe ARID1A gene encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. ARID1A has been showed to function as a tumor suppressor in various cancer types. In the current study, we investigated the expression and prognosis value of ARID1A in primary gastric cancer. Meanwhile, the biological role of ARID1A was further investigated using cell model in vitro.Methodology/Principal FindingsTo investigate the role of ARID1A gene in primary gastric cancer pathogenesis, real-time quantitative PCR and western blotting were used to examine the ARID1A expression in paired cancerous and noncancerous tissues. Results revealed decreased ARID1A mRNA (P = 0.0029) and protein (P = 0.0015) expression in most tumor-bearing tissues compared with the matched adjacent non-tumor tissues, and in gastric cancer cell lines. To further investigate the clinicopathological and prognostic roles of ARID1A expression, we performed immunohistochemical analyses of the 224 paraffin-embedded gastric cancer tissue blocks. Data revealed that the loss of ARID1A expression was significantly correlated with T stage (P = 0.001) and grade (P = 0.006). Consistent with these results, we found that loss of ARID1A expression was significantly correlated with poor survival in gastric cancer patients (P = 0.003). Cox regression analyses showed that ARID1A expression was an independent predictor of overall survival (P = 0.029). Furthermore, the functions of ARID1A in the proliferation and colony formation of gastric cell lines were analyzed by transfecting cells with full-length ARID1A expression vector or siRNA targeting ARID1A. Restoring ARID1A expression in gastric cancer cells significantly inhibited cell proliferation and colony formation. Silencing ARID1A expression in gastric epithelial cell line significantly enhanced cell growth rate.Conclusions/SignificanceOur data suggest that ARID1A may play an important role in gastric cancer and may serve as a valuable prognostic marker and potential target for gene therapy in the treatment of gastric cancer.
Highlights
Gastric cancer is the fourth most common malignancy worldwide and the second most common cause of cancer-related deaths each year (10.4% of cancer deaths) [1]
The results showed an ARID1A band at the expected size of 242 kDa and the amount of ARID1A protein present was further measured by densitometry
The clinical outcome of gastric cancer is determined by a series of tumor characteristics, such as locoregional tumor growth and invasion, differentiation grade, angiogenesis, distant metastasis and cell cycle progression, which are regulated by a variety of related genes, including oncogenes and tumor suppressor genes
Summary
Gastric cancer is the fourth most common malignancy worldwide and the second most common cause of cancer-related deaths each year (10.4% of cancer deaths) [1]. Treatment of gastric cancer includes a combination of surgery, chemotherapy, or radiation therapy. It has long been known that gastric cancer results from a combination of environmental factors and the accumulation of generalized and specific genetic alterations. Many of the genetic or epigenetic alterations associated with gastric cancer, including loss of heterozygosity, microsatellite and chromosomal instability and hypermethylation, have been reported [3]. Understanding these alterations and the molecular mechanisms involved in gastric carcinogenesis will be critical for the improvement of diagnosis, therapy and prognosis prediction of this disease. We investigated the expression and prognosis value of ARID1A in primary gastric cancer. The biological role of ARID1A was further investigated using cell model in vitro
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