Loss of ARID1A expression predicts poor survival prognosis in gastric cancer: a systematic meta-analysis from 14 studies

Yang, Lin; Wei, Sheng; Zhao, Rongxian; Wu, YingXing; Qian, Hong; Xiong, Huihua

doi:10.1038/srep28919

Cited by 37 publications

(38 citation statements)

References 48 publications

(72 reference statements)

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“…These findings are important clues supporting the hypothesis that miR-376c is oncogenic in gastric carcinogenesis. Our in silico analysis using databases substantiated the fact that there is a low abundance of the ARID4A transcript in GC tissue and cell lines [32]. The reporter activity showed that miR-376c directly bound to the 3’-UTR of ARID4A gene and repressed the expression of luciferase gene.…”

Section: Discussionsupporting

confidence: 62%

miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma

Hung

Chen

et al. 2017

PLoS ONE

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Gastric carcinoma is highly prevalent throughout the world. Understanding the pathogenesis of this disease will benefit diagnosis and resolution. Studies show that miRNAs are involved in the tumorigenesis of gastric carcinoma. An initial screening followed by subsequent validation identified that miR-376c is up-regulated in gastric carcinoma tissue and the plasma of patients with the disease. In addition, the urinary level of miR-376c is also significantly increased in gastric carcinoma patients. The plasma miR-376c level was validated as a biomarker for gastric carcinoma, including early stage tumors. The induction of miR-376c was found to enrich the proliferation, migration and anchorage-independent growth of carcinoma cells and, furthermore, the repression of the expression of endogenous miR-376c was able to reduce such oncogenic phenotypes. ARID4A gene is a direct target of miR-376c. Knockdown of endogenous ARID4A increased the oncogenicity of carcinoma cells, while ARID4A was found to be drastically down-regulated in tumor tissue. Thus, expression levels of miR-376c and ARID4A mRNA tended to be opposing in tumor tissue. Our results demonstrate that miR-376c functions by suppressing ARID4A expression, which in turn enhances the oncogenicity of gastric carcinoma cells. It seems likely that the level of miR-376c in plasma and urine could act as invaluable markers for the detection of gastric carcinoma.

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Section: Discussionsupporting

confidence: 62%

miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma

Hung

Chen

et al. 2017

PLoS ONE

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“…The tumour was macroscopically dissected and DNA extraction performed using the QIAmp formalin-fixed paraffin-embedded (FFPE) tissue kit (Qiagen, Germantown, MD, USA). The regions of different SMARCA4 expression in six cases with a heterogeneous pattern (GC2, 3,6,14,21,25) were identified and sequenced separately. The targeted massively parallel sequencing was performed on the Ion GeneStudio S5 prime system using the Ion 530 chip (Thermo Fisher Scientific, Waltham, MA, USA).…”

Section: T a R G E T E D M A S S I V E L Y P A R A L L E L S E Q U E mentioning

confidence: 99%

“…4,5 Similarly, low ARID1A expression displays a higher occurrence in EBV and MSI-associated GC and a positive correlation with advanced stage and poor prognosis. 6,7 Yamamichi et al demonstrated that decreased SMARCA2 expression occurred in 37 of 89 cases (42%) and more frequently in papillary or moderately to poorly differentiated adenocarcinoma. 8 Recently, SMARCA4 deficiency was shown to be a pivotal cause of several aggressive tumours, including small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), and undifferentiated sarcoma or carcinoma.…”

Section: Introductionmentioning

confidence: 99%

The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression

Huang

Yeh

et al. 2020

Histopathology

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Aims In this study, we examine the clinicopathological and molecular features of gastric cancer (GC) with SMARCA4 alterations. Methods and results We screened SMARCA4 alterations using immunohistochemistry on 1199 surgically resected GCs with information on Epstein–Barr virus (EBV), microsatellite instability (MSI) and other SWI/SNF subunits. SMARCA4, SMARCA2 and ARID1A mutations were investigated by targeted sequencing. The clinicopathological significance was determined by statistical analysis. Twenty‐seven cases (2%) with altered SMARCA4 expression were identified, exhibiting completely lost (six), reduced (nine) or heterogeneous (12) patterns. Frequent concomitant alterations of other SWI/SNF subunits were noted with an unusual discordant spatial heterogeneity. In comparison with SMARCA4‐retained GCs, SMARCA4‐lost GCs were observed more frequently in the non‐EBV/MSI subgroup (five of six) and reduced or heterogeneous SMARCA4 expression mainly occurred in EBV‐ or MSI‐associated cases (six of nine and six of 12, respectively; P < 0.001). Histologically, SMARCA4‐altered GC, irrespective of expression pattern, demonstrated divergent histomorphology, spanning tubular, poorly cohesive or mixed, neuroendocrine to solid and undifferentiated carcinoma, with a predilection to the latter two (P < 0.001). De‐differentiation‐like transition and rhabdoid features were noted in a minority of cases. For overall survival, altered SMARCA4 expression was an unfavourable prognostic factor in stage III, EBV‐associated GC and non‐EBV/MSI intestinal subtype (P ≤ 0.001). SMARCA4 or ARID1A mutations were detected mainly in SMARCA4‐lost or reduced GC, respectively. Conclusions SMARCA4‐altered GCs are rare and have intratumoral heterogeneity, histomorphological diversity, conditional prognostic significance and various genetic drivers. SMARCA4‐lost GC may represent a genuine SMARCA4‐deficient neoplasm, but most SMARCA4‐reduced/heterogeneous cases are secondary to ARID1A collapse or associated with different genotypes.

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“…7,9 Since ARID1A is considered a tumor suppressor, loss of ARID1A protein has been indicated as a poor prognostic factor in GCs. 10 Recent transcriptomic and clinical studies have revealed that GCs with MSI-H or Epstein-Barr virus (EBV) have higher PD-L1 expression. 8,11 In a recent clinical trial, these two subtypes of GCs have shown much better response rates to PD-1 inhibition.…”

Section: Introductionmentioning

confidence: 99%

Functional loss of ARID1A is tightly associated with high PD‐L1 expression in gastric cancer

Kim

Ahn

Bae

et al. 2019

Intl Journal of Cancer

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Notwithstanding remarkable treatment success with anti‐PD‐1 monoclonal antibody, oncogenic mechanism of PD‐L1 regulation in gastric cancer (GC) remains poorly understood. We hypothesized that ARID1A might be related to tumor PD‐L1 expression in GC. We found that tumor PD‐L1 positivity was associated with loss of ARID1A and showed trend toward better survival of patients with various molecular subtypes of GC (experimental set, n = 273). Considering heterogeneous ARID1A expression, we validated this using whole tissue sections (n = 159) and found that loss of ARID1A was correlated with microsatellite instability‐high (MSI‐H), Epstein–Barr virus (EBV), and PD‐L1 positivity. Furthermore, for patients with MSI‐H tumors, the degree of PD‐L1 expression was significantly higher in ARID1A‐deficient tumors. After ARID1A knockdown in GC cell lines, total and membranous PD‐L1 protein, and PD‐L1 mRNA levels were increased based on Western blot, flow cytometry, and qRT‐PCR, respectively. With IFN‐γ treatment, PD‐L1 expression was significantly increased both in ARID1A‐deficient cancer cells and controls, but the increase was not more pronounced in the former. Loss of ARID1A increased PD‐L1 via activating AKT signaling, while LY294002 (PI3K inhibitor) decreased PD‐L1 levels. Furthermore, we found that 3 MSI‐H tumors showing highest expression of PD‐L1 had simultaneous KRAS mutation and loss of ARID1A, suggesting a possible synergistic role boosting PD‐L1. Our results strongly indicate that loss of ARID1A is tightly associated with high PD‐L1 expression in GC. These results would increase our understanding of the oncogenic mechanism of PD‐L1 regulation in GC, and also help to find the optimal candidates for immunotherapy.

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Loss of ARID1A expression predicts poor survival prognosis in gastric cancer: a systematic meta-analysis from 14 studies

Cited by 37 publications

References 48 publications

miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma

miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma

The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression

Functional loss of ARID1A is tightly associated with high PD‐L1 expression in gastric cancer

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