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. 2012;7(7):e40364.
doi: 10.1371/journal.pone.0040364. Epub 2012 Jul 13.

Decreased Expression of the ARID1A Gene Is Associated With Poor Prognosis in Primary Gastric Cancer

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Free PMC article

Decreased Expression of the ARID1A Gene Is Associated With Poor Prognosis in Primary Gastric Cancer

Dan-dan Wang et al. PLoS One. .
Free PMC article

Abstract

Background: The 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 findings: To 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/significance: Our 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The mRNA expression of ARID1A in human primary gastric cancer surgical specimens was evaluated by real-time quantitative PCR.
The relative mRNA expression of ARID1A was significantly decreased in gastric cancer tissues compared with the matched adjacent nontumorous tissues (n = 66, P = 0.0029). Horizontal lines represent the mean.
Figure 2
Figure 2. Decreased protein expression of ARID1A in gastric cancer as assessed by Western blotting.
(A) Relative ARID1A protein expression levels in gastric cancer tissues and noncancerous tissues (ARID1A/GAPDH, n = 25, P = 0.0015). Horizontal lines represent the mean. (B) Representative result of ARID1A protein expression in 4 paired gastric tumorous and the matched adjacent nontumorous tissues (C, gastric cancer tissues; N, matched noncancerous gastric mucosa). (C) The ARID1A protein level was remarkably decreased in gastric cancer cell lines, SGC7901, AGS, especially in MGC803, compared with normal gastric cell line GES1.
Figure 3
Figure 3. ARID1A protein expression in gastric cancer surgical specimens shown by immunohistochemistry.
(A) Strong ARID1A staining was observed in noncancerous gastric mucosa. (B) ARID1A-negative gastric adenocarcinoma, Grade 3. (C) Weak ARID1A staining in gastric adenocarcinoma, Grade 2. (D) Strong ARID1A staining in gastric adenocarcinoma, Grade 1.
Figure 4
Figure 4. Kaplan-Meier survival curves of gastric cancer patients (n = 224) after gastrectomy.
The survival rate of patients in the ARID1A-negative group was significantly lower than that of patients in the ARID1A-positive group (log-rank test, P = 0.003).
Figure 5
Figure 5. The growth suppressor role of ARID1A in cell proliferation and colony formation assays of MGC803 and GES1 cell lines.
(A) Western blotting analysis of restoring ARID1A expression in MGC803 cells. (B) Western blotting analysis of silenced ARID1A expression in GES1 cells. (C) Cell proliferation assay showing the suppressive effect of restoring ARID1A expression on the in vitro proliferation of MGC803 cell line. (D) ARID1A inhibited colony formation of MGC803 cells. Images are shown on the left and on the right, quantitative analyses of plaque numbers are shown as mean ± SD. (E) Cell proliferation assay showing significantly enhanced proliferation rate of ARID1A-silenced GES1 cells compared with mock siRNA treatment GES1 cells. *, P<0.05 versus the mock-control; **, P<0.01 versus the mock-control.

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