AT-rich Interactive Domain-containing Protein 1A Expression Research Articles

Abstract B002: ARID1A loss activates MAPK signaling via DUSP4 downregulation: a mechanistic insight in endometrial carcinoma

Abstract The intricate interplay between chromatin remodelers, transcriptional regulation, and downstream cellular processes is gradually unraveling. AT-rich interactive domain-containing protein 1A (ARID1A), a tumor suppressor and chromatin remodeler, is frequently mutated in endometrium-related malignancies including ovarian or uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). How ARID1A mutation alters downstream signaling is yet to be established. Based on the TCGA proteomics datasets, MAPK and ARID1A are negatively correlated in endometrial cancer. Yet, the underlying molecular mechanism of this association remains unclear. Using ARID1A-proficient and ARID1A-deficient isogenic human endometrial epithelial cells, we explored transcriptomic changes and discovered notable downregulation of a MAPK phosphatase, dual-specificity phosphatase 4 (DUSP4), in ARID1A-deficient cells. This expression pattern was further validated in additional pairs of isogenic cell lines, ES-2, MCF10a, and HCT116. Chromatin immunoprecipitation sequencing (ChIP-seq) was utilized to assess active and repressive transcription histone marks on global and 5’ transcriptional regulatory regions of DUSP4. ChIP-seq demonstrated decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 enhancer and promoter regions of ARID1A-deficient cells, suggesting ARID1A's role in modulating chromatin accessibility and gene expression. Furthermore, a positive correlation between ARID1A and DUSP4 expression was established using a Pax8-driven conditional knockout mouse cohort and in human endometroid carcinoma tissues. Moreover, an inverse expression correlation between ARID1A and the phosphatase substrates of DUSP4, including p-p38, p-JNK, and p-ERK in the MAPK signaling pathway, was observed in this genetically engineered murine model and in the TCGA datasets of human uterine carcinomas. Interestingly, ectopic DUSP4 expression decreased cell proliferation, and MAPK pathway targeting, specifically via ERK inhibitor Ulixertinib, significantly mitigated tumor growth in vivo. In conclusion, our findings suggest ARID1A modulates DUSP4 expression by remodeling the chromatin landscape which leads to an inhibitory effect on the MAPK pathway and suppresses tumor progression. ARID1A-DUSP4-MAPK axis offers a promising avenue for developing targeted therapies against ovarian or uterine CCC and EMCA. Citation Format: Jayaprakash Mandal, Zheng-Cheng Yu, Ie-Ming Shih, Tian-Li Wang. ARID1A loss activates MAPK signaling via DUSP4 downregulation: a mechanistic insight in endometrial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B002.

Biomarkers for checkpoint inhibitor therapy in mucinous epithelial ovarian cancer

ObjectiveThe prognosis of patients with advanced stage mucinous epithelial ovarian cancer remains poor due to a modest response to platinum-based chemotherapy and the absence of therapeutic alternatives. As targeted approaches...

ARID1A Downregulation Predicts High PD-L1 Expression and Worse Clinical Outcome in Patients With Gallbladder Cancer.

BackgroundRecent studies have confirmed that AT-rich interactive domain-containing protein 1A (ARID1A) plays a critical role in tumorigenesis, but its role in gallbladder cancer (GBC) remains unclear.MethodsIn total, 224 patients from Zhongshan Hospital were recruited for this retrospective study. The clinicopathological and baseline characteristics of the patients were collected. Bioinformatics analysis was performed to reveal variations in genes and signaling pathways, and ARID1A and PD-L1 expression and the number of PD1+ tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemical staining.ResultsARID1A expression was negatively correlated with overall survival in patients with GBC, and multivariate analysis identified ARID1A as an independent prognostic factor for overall survival. A heatmap and gene set enrichment analysis suggested that cytotoxic T lymphocyte signatures and immune-related signaling pathways were downregulated in ARID1A low tumors. Subsequent immunohistochemical staining confirmed that ARID1A expression was negatively correlated with PD-L1 expression and PD1+ TILs in the tumor microenvironment. The Kaplan–Meier analysis suggested that high ARID1A expression combined with low PD-L1 expression or low PD1+ TIL counts is associated with the best prognosis in patients with GBC.ConclusionARID1A inactivation can lead to a worse prognosis in patients with GBC, potentially by mediating immune evasion through the PD1/PD-L1 pathway.

Combinatorial biomarkers to predict responses to immune checkpoint therapy in metastatic urothelial cancer.

488 Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of immune checkpoint therapy in mUCC, we lack predictive biomarkers to guide patient selection. Therefore, there is a critical need to develop clinically useful biomarkers to refine patient selection. The single biomarker studies either focused on tumor mutations or immune response biomarkers, which may limit predictive power due to lack of integration between cancer cell biology and immune cell responses. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Methods: We performed retrospective multi-platform immuno-genomic analyses of pre-treatment tumor tissues in a discovery cohort (n = 31). Next, we tested the clinical relevance of ARID1A mutation and pre-treatment CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). Additionally, we performed reverse translational studies using murine model of bladder cancer to demonstrate direct association of the biomarkers in anti-PD-(L)-1 mediated anti-tumor immunity. Results: We identified genomic mutation of AT-rich interactive domain-containing protein 1A ( ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the pre-treatment tumor tissues as two predictors of clinical responses. We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). Further, reverse translational studies revealed that CXCL13−/− tumor-bearing mice were resistant to immune checkpoint therapy whereas ARID1A knockdown enhanced sensitivity to immune checkpoint therapy in a murine model of bladder cancer. We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to immune checkpoint therapy in CheckMate275 and IMvigor210. Combination of the 2 biomarkers in baseline tumor tissues showed improved OS compared to either single biomarker. Conclusions: Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A mutation may improve patient selection in mUCC for immune checkpoint therapy.

Remodeling of the ARID1A tumor suppressor.

In recent years, AT-rich interactive domain-containing protein 1A (ARID1A) has been widely accepted as a bona fide tumor suppressor due to its essential role in preventing tumorigenesis and tumor progression in both mouse and human contexts. ARID1A shows high mutation frequencies in both cancers and preneoplastic lesions. The loss of ARID1A expression in cancer cells leads to increases in cell proliferation, invasion and migration and reductions in cell apoptosis and chemosensitivity. The tumor-suppressive role of ARID1A is mainly attributed to its regulation of gene transcription, which can be induced either directly by chromatin remodeling or indirectly by affecting histone modifications. ARID1A also acts independently of its cardinal transcription-regulating mechanisms, which include interfering with protein-protein interactions. Interestingly, nonmutational mechanisms, such as regulation by DNA hypermethylation, microRNAs, and ubiquitinases/deubiquitinases, have provided another perspective on ARID1A inactivation in cancer. Since the critical tumor-suppressive role of ARID1A has been revealed, several studies have attempted to identify synthetic lethal targets with ARID1A mutation/inactivation as an alternative strategy for cancer treatment.

ARID1A upregulation predicts better survival in patients with urothelial bladder carcinoma.

ObjectiveAT-rich interactive domain-containing protein 1A (ARID1A) is frequently mutated or deficient in various types of tumors. However, the role of ARID1A in bladder cancer remains unclear. We aimed to evaluate ARID1A expression and its biological role and correlation with prognosis in patients with urothelial bladder carcinoma (BUC).MethodsARID1A expression levels in BUC and normal tissues were assessed by immunohistochemistry and correlated with clinicopathological characteristics and patient outcomes. Downregulation of ARID1A was mimicked by transfection with small interfering RNA in T24 bladder cancer cells, and the effects on cell proliferation and migration were evaluated.ResultsARID1A expression was significantly reduced in BUC tissues and was significantly associated with T stage and AJCC stage. Upregulation of ARID1A predicted a better prognosis in BUC patients. ARID1A expression and lymph node status were identified as independent prognostic factors for overall survival. Silencing of ARID1A promoted the proliferation of BUC cells.ConclusionsARID1A may represent a novel diagnostic and prognostic biomarker in patients with BUC.

Loss of ARID1A promotes proliferation, migration and invasion via the Akt signaling pathway in NPC.

Background: AT-rich interactive domain-containing protein 1A (ARID1A) is a member of the switch/sucrose nonfermentable chromatin remodeling complex, which has been observed to be mutated in various tumors. The loss of ARID1A is reported to be frequently associated with PI3K/Akt pathway activation.Objective: The roles of ARID1A in nasopharyngeal carcinoma (NPC) have not been reported until now. The aim of this research was to explore the clinical significance and potential mechanism of ARID1A in NPC development and progression.Methods: ARID1A expression levels were investigated in human NPC tissues and cell lines. The effects of ARID1A knockdown on nasopharyngeal cancer cell proliferation, migration and invasion were evaluated in vitro using CCK8, wound healing, transwell and flow cytometry assays. The expression of relevant proteins was evaluated by Western blot assays.Results: In this study, ARID1A was significantly downregulated in NPC tissues and cells. Furthermore, low ARID1A expression was significantly associated with aggressive clinicopathological characteristics and poor survival in NPC patients. Depletion of endogenous ARID1A by siRNA promoted proliferation, migration and invasion in CNE1 and HNE1 cells. Additionally, ARID1A knockdown increased the phosphorylation of Akt in NPC cells. High levels of p-Akt were also observed in NPC biopsies and correlated with ARID1A downregulation. These results imply that the loss of ARID1A could activate Akt signaling. In addition, MK-2206 (a highly selective inhibitor of Akt) partially suppressed NPC cell proliferation, migration and invasion, which were induced by ARID1A knockdown.Conclusion: Our findings indicate that ARID1A plays an essential role in modulating the Akt pathway, functions as a tumor suppressor in NPC and may be a potential target for NPC treatment.

Hypoxia-Inducible Factor 1α and AT-Rich Interactive Domain-Containing Protein 1A Expression in Pituitary Adenomas: Association with Pathological, Clinical, and Radiological Features

Hypoxia-inducible factor (HIF) plays a major role in tumorigenesis and cancer progression. In hypoxic conditions, HIF is upregulated and has been shown to activate multiple genes required for cells to adapt to hypoxia. AT-rich interactive domain-containing protein 1A (ARID1A), a SWI/SNF (switch/sucrose nonfermentable) chromatin remodeling gene has context-dependent tumor-suppressive and oncogenic roles in cancer. We assessed the correlations between the expression and mutations of HIF1A and ARID1A in histopathologically confirmed pituitary adenomas. We performed a retrospective analysis of 71 patients who had undergone surgery for pituitary adenoma. Patient demographic, radiological, and histopathological features were correlated with HIF1A and ARID1A expression. Most cases were HIF1A positive (62%). No significant correlation was found between HIF1A expression and age, gender, tumor size, bone erosion, hemorrhage, or Ki-67 index. An inverse correlation was demonstrated between HIF1A and cavernous sinus invasion (P= 0.035). ARID1A loss was found in 28.2% of pituitary adenomas. No significant correlation was found between ARID1A and any of the assessed variables. In our patient cohort, we found that most pituitary adenomas expressed HIF1A. To the best of our knowledge, we are the first to assess the presence of ARID1A loss in pituitary adenomas, which occurred in 28.2% of cases. No individual demographic, imaging, or histopathological feature was predictive of ARID1A. Likewise, with the exception of an increased incidence of cavernous sinus invasion, no correlation was found with HIF1A. Given the prognostic value of these markers in other malignancies, their frequency in pituitary adenomas warrants further exploration of their potential role in pituitary adenoma treatment and outcome.

Loss of ARID1A, a component of the SWI/SNF chromatin remodeling complex, at the invasion front is related to poor outcomes in oral squamous cell carcinoma

This study aimed to investigate the relationship between loss of AT-rich interactive domain-containing protein 1A (ARID1A) expression and the prognosis of patients with oral squamous cell carcinoma (OSCC). Seventy-five OSCC tissue specimens were immunohistochemically stained with a specific antibody to ARID1A. The immunoreactivity of ARID1A was then correlated with clinicopathological factors, including the prognosis of the patients. Non-tumorous oral squamous cells exhibited nuclear ARID1A staining, whereas the invasive OSCC cells showed different degrees of loss of ARID1A immunoreactivity. Little-to-no ARID1A immunoreactivity was found at the cancer invasion front in 20 of the 75 OSCC tissue specimens, with significant association with unfavorable patient outcomes. Notably, downregulation of ARID1A immunoreactivity was also related to lymphovascular involvement and poor outcome in patients with T1 and T2 OSCC without lymph node metastasis. The results suggest that loss of ARID1A expression at the cancer invasion front might be related to tumor progression in many OSCCs.

Inhibition of PI3K/AKT Signaling Pathway Radiosensitizes Pancreatic Cancer Cells with ARID1A Deficiency in Vitro.

Pancreatic cancer is among the most aggressive human cancers, and is resistant to regular chemotherapy and radiotherapy. The AT-rich interactive domain containing protein 1A (ARID1A) gene, a crucial chromatin remodeling gene, mutates frequently in a broad spectrum of cancers, including pancreatic cancer. Recent evidence suggests that ARID1A acts as tumor suppressor and plays an important role in DNA damage repair (DDR). However, the effect of ARID1A on the radiosensitivity of pancreatic cancer remains unclear. Herein, we investigated the involvement of ARID1A depletion in the radioresistance of pancreatic cancer cells, and explored the underlying mechanisms. The results reveal that knockdown of ARID1A enhances the radioresistance of pancreatic cancer cells through suppressing apoptosis, impairing G2-M checkpoint arrest, strengthening DDR, and accompanying activation of PI3K/AKT signaling pathway. Moreover, upon inhibition of PI3K/AKT pathway by PI3K-inhibitor LY294002 or AKT-inhibitor mk2206, the radiosensitivity of ARID1A-deficient pancreatic cancer cells is improved in vitro via increased apoptosis and weakened DDR. Taken together, these data suggest that loss of ARID1A expression enhances radioresistance of pancreatic cancer through activation of PI3K/AKT pathway, which maybe a promising target for radiosensitization of ARID1A-deficient pancreatic cancer.

Low Arid1a Expression Correlates with Poor Prognosis and Promotes Cell Proliferation and Metastasis in Osteosarcoma.

AT-rich interactive domain-containing protein 1A (ARID1A) has been shown to function as a tumour suppressor in various malignancies. However, the biological role of ARID1A in osteosarcoma is not clear. The present study aimed to investigate the expression pattern, prognostic value and the biological role of ARID1A in human osteosarcoma. ARID1A expression in 53 osteosarcoma surgical specimens was examined by quantitative real-time polymerase chain reaction, and its clinical significance was analysed. The role of ARID1A in cell proliferation, apoptosis, and metastasis were examined. ARID1A mRNA expression were significantly down-regulated in osteosarcoma tumours from that in matched adjacent non-tumour tissues. ARID1A expression was significantly inversely correlated with tumour stage and distant metastasis, as well as poor overall survival in patients with osteosarcoma. Furthermore, ARID1A mRNA was down-regulated in four human osteosarcoma cell lines MG-63, U2OS, HOS and Saos-2. Restoring of ARID1A expression in MG-63 and U2OS cells significantly inhibited cell proliferation and metastasis in vitro. Collectively, our data demonstrate that ARID1A may serve as a tumour suppressor in osteosarcoma progression, and represent a valuable prognostic marker and potential therapeutic target for osteosarcoma.

Abstract NTOC-093: SYNTHETIC LETHAL APPROACHES TO TARGET ARID1A DEFICIENT OVARIAN CANCERS

Abstract Epithelial ovarian cancer (EOC) remains the most lethal gynaecological malignancy in the Western world. Ovarian clear cell carcinoma (OCCC), a distinct histological subtype, has a notably poor prognosis in the advanced setting compared to patients with high-grade serous ovarian cancer (HGSOC). Understanding why these patients have a poor outcome may be due to the underlying genetic drivers and their response to treatment. Dysregulation of the SWI/SNF complex is one of the most commonly occurring defects in solid cancers. Mutations in ARID1A (AT-rich interactive domain-containing protein 1A), a gene that encodes for BAF250A, forming part of the SWI/SNF chromatin remodeling complex, rarely occur in HGSOC but are common in ovarian clear cell carcinomas. The vast majority of these are loss of function frameshift or nonsense mutations, resulting in loss of protein function. In addition, loss of ARID1A expression in tumour specimens has been associated with a shorter progression free survival and chemoresistance in ovarian clear cell carcinoma (OCCC). Despite the understanding that ARID1A defects are associated with tumourigenesis, targeted therapy approaches that exploit this deficiency have not as yet been developed. Our aims were to identify ways of targeting ARID1A deficient tumours by performing a large-scale functional genomics screen to identify actionable synthetic lethal effects. Using a high-throughput combination drug screen with a plate library of 80 compounds and a phase 1 compound, in isogenic ARID1A null and wild type HCT116 cells, we have identified candidate therapeutic approaches to targeting ARID1A mutant tumours that could be assessed in proof of concept clinical trials. We have undertaken subsequent high throughput drug screens in isogenic ARID1A null and wild type MCF10A cells that in we have identified a series of novel synthetic lethal effects. Assessment of this combinatorial approach in in vivo models of ARID1A mutant cancers is now underway. In conclusion, we have identified clinically actionable combinatorial approaches that may provide additional therapeutic benefit for ARID1A deficient patients. Citation Format: Saira Khalique, Chris T. Williamson, Helen Pemberton, Patty T. Wai, Malini Menon, Rachel Brough, Andri Leonidou, Barrie Peck, Susana Banerjee, Rachael C. Natrajan and Christopher J. Lord,. SYNTHETIC LETHAL APPROACHES TO TARGET ARID1A DEFICIENT OVARIAN CANCERS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-093.

ARID1A gene knockdown promotes neuroblastoma migration and invasion

Neuroblastoma is the most common extracranial solid tumor in childhood which often acquires drug resistance and becomes aggressive phenotypes. The high-risk patients suffer from high mortality due to the limitation of the treatment strategies. ARID1A (AT-rich interactive domain-containing protein 1A), a subunit of SWI/SNF complexes, is considered as a tumor suppressor in many cancers. The aim of the present study was to investigate the effect of ARID1A on migration and invasion in neuroblastoma cells. The shRNA targeting ARID1A was designed and delivered into SK-N-SH cells to knock down ARID1A expression. Knockdown of ARID1A by shRNA significantly increased the viability and invasion ability, and caused G1 arrest inhibition and DNA synthesis increase in SK-N-SH cells. Moreover, Knockdown of ARID1A increased the activity and expression of matrix metalloproteinase (MMP)-2 and -9 in SK-N-SH cells. Furthermore, ARID1A knockdown caused diminished expression of E-cadherin, enhanced expression of N-cadherin and β-catenin nuclear translocation in SK-N-SH cells. These results suggest that loss of ARID1A may associate with the promotion of invasion and metastasis of neuroblastoma. Our findings indicate ARID1A is a tumor suppressor in neuroblastoma.

Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer.

Recent studies unraveled that AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the mammary SWI/SNF chromatin remodeling complex, acts as a tumor suppressor in various cancers. In this study, we first evaluated ARID1A expression by immunohistochemistry in invasive breast cancer tissue specimens and assessed the correlation with the prognosis of patients with breast cancer. Non-tumorous mammary duct epithelial cells exhibited strong nuclear ARID1A staining, whereas different degrees of loss in ARID1A immunoreactivity were observed in many invasive breast cancer cells. We scored ARID1A immunoreactivity based on the sum of the percentage score in invasive cancer cells (on a scale of 0 to 5) and the intensity score (on a scale of 0 to 3), for a possible total score of 0 to 8. Interestingly, partial loss of ARID1A expression, score 2 to 3, was significantly correlated with poor disease free survival of the patients. Subsequently, we performed siRNA-mediated ARID1A knockdown in cultured breast cancer cells followed by comprehensive gene profiling and quantitative RT-PCR. Interestingly, many genes were downregulated by partial loss of ARID1A, whereas RAB11FIP1 gene expression was significantly upregulated by partial loss of ARID1A expression in breast cancer cells. In contrast, a more than 50% reduction in ARID1A mRNA decreased RAB11FIP1gene expression. Immunoblotting also demonstrated that partial downregulation of ARID1A mRNA at approximately 20% reduction significantly increased the expression of RAB11FIP1 protein in MCF-7 cells, whereas, over 50% reduction of ARID1A mRNA resulted in reduction of RAB11FIP1 protein in cultured breast cancer cells. Recent studies reveal that RAB11FIP1 overexpression leads to breast cancer progression. Altogether, the present findings indicated that partial loss of ARID1A expression is linked to unfavorable outcome for patients with breast cancer, possibly due to increased RAB11FIP1 expression.

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

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.

Loss of ARID1A expression is associated with poor prognosis in small intestinal carcinoma.

To investigate AT-rich interactive domain-containing protein 1A (ARID1A) and p53 expression in small intestinal carcinoma (SIC) and to determine its prognostic significance. Immunohistochemical staining for ARID1A and p53 was performed in 178 SICs using a tissue microarray (TMA). Loss of or low ARID1A expression was observed in 36 (20.2%) and 60 (33.7%) of cases, respectively. Aberrant p53 expression was observed in 99 (55.6%) cases. Loss of or low ARID1A expression was found to be associated with signet ring cell carcinoma and undifferentiated carcinoma, a high-grade tumour, and a higher T stage. No relationship was found between aberrant p53 expression and clinicopathological factors or overall survival. Patients with loss of ARID1A expression, irrespective of p53 expressional status, showed significantly poorer overall survival than those expressing ARID1A. Multiple regression analysis revealed that grade and pT stage were associated significantly with ARID1A loss, and multivariate analysis showed that patients with high ARID1A expression had a lower risk of death than those with loss of ARID1A expression. Low or loss of ARID1A expression is correlated significantly with a high-grade tumour, higher T stage, and poorer overall survival. These findings suggest that ARID1A expression could be used as a prognostic marker in SIC.

Reduced expression of the chromatin remodeling gene ARID1A enhances gastric cancer cell migration and invasion via downregulation of E-cadherin transcription

The chromatin remodeling gene AT-rich interactive domain-containing protein 1A (ARID1A) encodes the protein BAF250a, a subunit of human SWI/SNF-related complexes. Recent studies have identified ARID1A as a tumor suppressor. Here, we show that ARID1A expression is reduced in gastric cancer (GC) tissues, which are significantly associated with local lymph node metastasis, tumor infiltration and poor patient prognosis. ARID1A silencing enforces the migration and invasion of GC cells, whereas ectopic expression of ARID1A inhibits migration. The adhesive protein E-cadherin is remarkably downregulated in response to ARID1A silencing, but it is upregulated by ARID1A overexpression. E-cadherin overexpression significantly inhibits GC cell migration and invasion, whereas CDH1 (coded E-cadherin) silencing promotes migration. Restored expression of CDH1 in ARID1A-silenced cell lines restores the inhibition of cell migration. Luciferase reporter assays and chromatin immunoprecipitation indicate that the ARID1A-associated SWI/SNF complex binds to the CDH1 promoter and modulates CDH1 transcription. ARID1A knockdown induces evident morphological changes of GC cells with increased expression of mesenchymal markers, indicating an epithelial-mesenchymal transition. ARID1A silencing does not alter the level of β-catenin but induces a subcellular redistribution of β-catenin from the plasma membrane to the cytoplasm and nucleus. Immunohistochemical studies demonstrate that reduced expression of E-cadherin is associated with local lymph node metastasis, tumor infiltration and poor clinical prognosis. ARID1A and E-cadherin expression show a strong correlation in 75.4% of the analyzed GC tissues. They are synergistically downregulated in 23.5% of analyzed GC tissues. In conclusion, ARID1A targets E-cadherin during the modulation of GC cell migration and invasion.