AT-rich Interactive Domain 1A Protein Research Articles

Loss of ARID1A expression is associated with systemic inflammation markers and has important prognostic significance in gastric cancer.

The tumor suppressor gene AT-rich interactive domain 1A (ARID1A) and systemic inflammatory response (SIR) have been reported to be related to the sensitivity to immunotherapy. This study intended to explore the relationship between ARID1A expression and SIR, and to further elucidate the prognostic value of ARID1A expression in gastric cancer (GC). The mRNA and protein expression of ARID1A were detected in 272 formalin-fixed paraffin-embedded (FFPE) tumor tissues. The data of nine systemic inflammation markers were collected 1 week before gastrectomy. Univariate and multivariate COX analysis were used to screen out independent predictors of GC. Negative expression of ARID1A protein was related to GC with deficient mismatch repair (dMMR) (p = 0.033), positive programmed cell death-ligand 1 (PD-L1) (p = 0.005) and lower albumin level (p = 0.0064). Low expression of ARID1A mRNA was common in GC with abnormal E-cadherin (p = 0.020) and a higher platelet/lymphocyte ratio (PLR) (p = 0.0391). Multivariate COX analysis showed that the expression of ARID1A protein (p = 0.023), age (p = 0.004), T stage (p = 0.009) and N stage (p = 0.009) were independent predictors of GC. The nomogram established by independent predictors can accurately evaluate the survival risk of patients with GC. The loss of ARID1A protein expression was associated with the dMMR subtype and high expression of PD-L1 in GC. Negative ARID1A protein and low expression of mRNA were associated with aberrant systemic inflammatory markers. The expression of ARID1A protein had important prognostic significance in GC.

152P ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation

AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene, which is frequently mutated in Epstein-Barr virus-positive gastric cancer (EBV (+) GC). While most ARID1Amutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the hypothesis that DNA promotor hypermethylation is a significant epigenetic modification in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1Awas evaluated in EBV-infected cells and GC patients using a publicly available microarray database and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1Awere identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, expression of the predicted miRNAs was evaluated by qRT-PCR and correlated with ARID1A expression, as assessed by IHC staining. ARID1Awas not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1AmRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART-X and miR-BART-Y, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART-X and miR-BART-Y were correlated with decreased ARID1A levels in GC tumors. The present findings revealed a pivotal role for epigenetic modifications that EBV-encoded miRNAs contribute to gastric carcinogenesis via ARID1A suppression.

AT-rich interactive domain 1A protein expression in normal and pathological pregnancies complicated by preeclampsia.

AT-rich interactive domain 1A (ARID1A, as known as BAF250a) is a subunit of human switch/sucrose nonfermentable chromatin remodeling complex with tumour suppressor function. Mutations of Arid1a have been reported in many human cancers and low expression of this protein has been correlated to a poor prognosis outcome in patients affected by some types of cancer. Although there are many studies regarding ARID1A functions in cancer, little is known about its role in regulating cell differentiation and normal tissues homeostasis. Here, we investigate ARID1A expression in normal placental tissues of first and third trimester of gestation and in pathological placental tissues of pregnancy complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) to evaluate a possible role of this protein in trophoblast differentiation. We found that ARID1A was specifically expressed in villous and extravillous cytotrophoblastic cells in normal placentas whereas syncytiotrophoblast was negative. Interestingly, ARID1A was expressed in both cytotrophoblastic cells and syncytiotrophoblast in placentas affected by PE and PE-IUGR. Moreover, ARID1A was also present in syncitial knots of pathological placentas. The present results indicate that ARID1A is a good marker of poor trophoblast differentiation in these pathologies, because the significant high positive staining in syncytiotrophoblast nuclei may suggest a poor differentiation of this trophoblast layer due to the cytotrophoblast cells fusion with the syncytiotrophoblast overlaying before arresting their cell cycle.

ARID1A knockdown triggers epithelial-mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma.

Down-regulation/mutation of AT-rich interactive domain 1A (ARID1A), a novel tumor suppressor gene, has been reported in various cancers. Nevertheless, its role in renal cell carcinoma (RCC) remained unclear and underinvestigated. We thus evaluated carcinogenesis effects of ARID1A knockdown in nonmalignant Madin-Darby canine kidney (MDCK) renal cells using small interfering RNA (siRNA) against ARID1A (siARID1A). The siARID1A-transfected cells had decreased cell death, increased cell proliferation, and cell cycle shift (from G0/G1 to G2/M) compared with those transfected with controlled siRNA (siControl). Additionally, the siARID1A-transfected cells exhibited epithelial-mesenchymal transition (EMT) shown by greater spindle index, increased mesenchymal markers (fibronectin/vimentin), and decreased epithelial markers (E-cadherin/zonula occludens-1). Moreover, the siARID1A-transfected cells had increases in migratory activity, nuclear size, self-aggregated multicellular spheroid size, invasion capability, chemoresistance (to docetaxel), Snail family transcriptional repressor 1 expression, and TGF-β1 secretion. All of these siARID1A-knockdown effects on the carcinogenic features were reproducible in malignant RCC (786-O) cells, which exhibited a higher degree of carcinogenic phenotypes compared with the nonmalignant MDCK cells. Finally, immunohistochemistry showed obvious decrease in ARID1A protein expression in human RCC tissues (n = 23) compared with adjacent normal renal tissues (n = 23). These data indicate that ARID1A down-regulation triggers EMT and carcinogenesis features of renal cells in vitro, and its role in RCC could be proven in human tissues.-Somsuan, K., Peerapen, P., Boonmark, W., Plumworasawat, S., Samol, R., Sakulsak, N., Thongboonkerd, V. ARID1A knockdown triggers epithelial-mesenchymal transition and carcinogenesis features of renal cells: role in renal cell carcinoma.

Loss of ARID1A Expression Correlates With Tumor Differentiation and Tumor Progression Stage in Pancreatic Ductal Adenocarcinoma.

Mutations in the AT-rich interactive domain 1A gene, which encodes a subunit of the Switch/Sucrose nonfermentable chromatin remodeling complex, can result in loss of protein expression and are associated with different cancers. Here, we used immunohistochemistry to investigate the significance of AT-rich interactive domain 1A loss in 73 pancreatic ductal adenocarcinoma cases with paired paracancerous normal pancreatic tissues. The relationship between levels of the AT-rich interactive domain 1A protein product, BAF250a, and clinicopathological parameters in the 73 pancreatic cancer specimens was also analyzed. We found that the expression of AT-rich interactive domain 1A in normal pancreatic tissue was higher than that in tumor tissue. Loss of AT-rich interactive domain 1A expression in pancreatic tumors was associated with tumor differentiation (P = .002) and tumor stage (P = .048). Meanwhile, BAF250a protein levels were not related to lymph node metastasis, distant metastasis, sex, or age and were not associated with survival. Transfection of the pancreatic cancer cell lines AsPC-1 and PANC-1 with small-interfering RNA specific for AT-rich interactive domain 1A resulted in elevated messenger RNA and protein expression levels of B-cell lymphoma-2 (Bcl-2), CyclinD1, and Kirsten rat sarcoma viral oncogene (KRAS). The AT-rich interactive domain 1A expression level in the cells was increased following microRNA-31 (miR-31) inhibitor transfection. Our data provide additional evidence that AT-rich interactive domain 1A might function as a tumor suppressor gene in pancreatic carcinogenesis.

Loss of ARID1A Expression is Related to Gastric Cancer Progression, Epstein-Barr Virus Infection, and Mismatch Repair Deficiency.

The AT-rich interactive domain 1A (ARID1A) gene encodes a member of the switch/sucrose nonfermentable (SWI-SNF) chromatin remodeling complex, and is considered to work as a tumor suppressor in concert with p53. We investigated the clinical significance of ARID1A protein expression in gastric cancer (GC), and examined its association with Epstein-Barr virus-associated (EBV) GC, mismatch repair (MMR) deficiency, and p53 alteration. We performed immunohistochemistry for ARID1A in 417 GC specimens using tissue microarray. EBV infection was examined using EBV-encoded small RNA in situ hybridization. Evaluation of MMR protein deficiency and p53 alteration was performed using immunohistochemistry, and microsatellite instability status was also assessed. Loss of ARID1A expression was observed in 21.1% of GC (88/417), but was not observed in gastric adenoma tissues or non-neoplastic gastric mucosa tissues. Loss of ARID1A showed positive correlations with advanced pTNM stage and tumor invasion (P=0.029 and 0.001, respectively). Overall survival was significantly influenced by the loss of ARID1A expression in wild-type p53 group (P=0.016, log-rank test). Moreover, ARID1A loss was significantly associated with EBV positivity, loss of MMR protein expression, and microsatellite instability high status (P=0.028, <0.001, and 0.011, respectively). All of the results from our cohort were verified using data from the Cancer Genome Atlas. In conclusion, loss of ARID1A is more common in advanced GC and is related to EBV positivity and MMR deficiency.

Differences in the ARID-1 alpha expressions in squamous and adenosquamous carcinomas of uterine cervix.

AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene involved in chromatin remodeling which encodes ARID1A (BAF250a) protein. Recent studies have shown the loss of ARID1A expression in several types of tumors. This retrospective study was designed to evaluate the differences in tissue expressions of ARID1A in a spectrum of cervical neoplasms. Cervical intraepithelial neoplasms, invasive squamous or adenosquamous carcinomas were identified in 100 patients recently diagnosed as cervical neoplasms based on pathology databases. In this series, there were 29 low- and 29 high-grade cervical intraepithelial neoplasms, 27 squamous cell carcinomas, and 15 adenosquamous carcinomas. Mean age of the patients was 47.8±13years (20-80years). It was determined that the expression of ARID1A was statistically significantly down-regulated in adenosquamous carcinomas when compared with non-invasive or invasive squamous cell carcinomas (p=0.015). Lower levels of the ARID1A expression were detected in cases with adenosquamous carcinomas (60%), low- or high-grade squamous intraepithelial lesion (SIL) (31%), and squamous cell carcinomas (18.5%). Our findings have demonstrated the presence of a correlation between ARID1A expression and adenomatous differentiation of uterine squamous cell carcinomas. Therefore, ARID1A gene may suggestively have a role in the pathogenesis of cervical adenosquamous carcinomas.

Decreased expression of ARID1A contributes to infiltrative growth of esophageal squamous cell carcinoma.

The clinical outcome for esophageal squamous cell carcinoma (ESCC) patients is often poor because of the invasive nature of this tumor type. AT-rich interactive domain 1A (ARID1A) functions as a tumor suppressor, and its gene mutation has been reported in various human malignancies. ARID1A is a non-catalytic subunit of the SWItch/Sucrose Non Fermentable (SWI/SNF) chromatin-remodeling complex that regulates gene transcription. Decreased expression of ARID1A protein has been reported to decrease the expression of E-cadherin, an adhesion protein. However, the correlation between ARID1A and E-cadherin expression status in ESCC remains largely unknown. To address this issue, we examined the expression of ARID1A and E-cadherin in tumor specimens excised from 83 ESCC patients using immunohistochemical analysis. The intensity of the ARID1A immunoreactivity was significantly lower in tumors with a growth pattern characterized by ill-defined borders than that in tumors with an expansive growth pattern having a well-demarcated border or tumors with an intermediate growth pattern. Thus, decreased ARID1A immunoreactivity correlated with infiltrative growth of ESCC. In contrast, E-cadherin status did not correlate with the infiltrative growth pattern of ESCC. Moreover, ARID1A expression status did not significantly correlate with any of other clinicopathological factors, E-cadherin expression levels, or the clinical outcome of the patients. On the other hand, the patients with tumors expressing low levels of E-cadherin exhibited significantly lower survival rates than those with high expression. In conclusion, reduced ARID1A expression in tumor tissues contributes to infiltrative growth of ESCC, irrespective of E-cadherin expression levels.

Subcellular localization of AT-rich interactive domain1A protein expression is associated with survival in epithelial ovarian and peritoneal carcinoma

Subcellular localization of AT-rich interactive domain1A protein expression is associated with survival in epithelial ovarian and peritoneal carcinoma

Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer.

To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer. We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7(th) edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed. ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51). ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.

ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas

ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene in various, predominantly gynecological cancers. We wanted to investigate the distribution of ARID1A in endometrial hyperplasia, carcinomas and metastatic lesions to elucidate the timing of expression loss of its protein ARID1A in the course of endometrial cancer carcinogenesis. In addition, we wanted to assess the relationship between the loss of ARID1A and clinicopathological variables in endometrial cancer in general and the endometrioid subtype in particular. We analyzed a prospectively collected series of 535 primary endometrial cancers, 77 metastatic lesions, as well as 38 retrospectively collected endometrial hyperplasias with evaluable immunohistochemical staining for ARID1A. Fresh frozen tissue was available for mRNA microarray analysis in 122 primary tumors in parallel. Loss of ARID1A protein expression was noted in none of the hyperplasias without atypia, 16% of hyperplasias with atypia, 19% of primary endometrioid tumors and 28% of metastatic lesions. Loss of ARID1A in primary tumor was significantly associated with endometrioid grade 1 or 2 and clear-cell histology, diploid tumor cells, younger patient age and deeper myometrial infiltration, but not survival. ARID1A RNA expression was significantly correlated with ARID1A protein loss. Thus, loss of ARID1A appears to be an early event in the carcinogenesis of endometrioid uterine carcinomas and the association with deep myometrial infiltration may suggest an importance for invasiveness.

Functional Analysis of In-frame Indel ARID1A Mutations Reveals New Regulatory Mechanisms of Its Tumor Suppressor Functions

AT-rich interactive domain 1A (ARID1A) has emerged as a new tumor suppressor in which frequent somatic mutations have been identified in several types of human cancers. Although most ARID1A somatic mutations are frame-shift or nonsense mutations that contribute to mRNA decay and loss of protein expression, 5% of ARID1A mutations are in-frame insertions or deletions (indels) that involve only a small stretch of peptides. Naturally occurring in-frame indel mutations provide unique and useful models to explore the biology and regulatory role of ARID1A. In this study, we analyzed indel mutations identified in gynecological cancers to determine how these mutations affect the tumor suppressor function of ARID1A. Our results demonstrate that all in-frame mutants analyzed lost their ability to inhibit cellular proliferation or activate transcription of CDKN1A, which encodes p21, a downstream effector of ARID1A. We also showed that ARID1A is a nucleocytoplasmic protein whose stability depends on its subcellular localization. Nuclear ARID1A is less stable than cytoplasmic ARID1A because ARID1A is rapidly degraded by the ubiquitin-proteasome system in the nucleus. In-frame deletions affecting the consensus nuclear export signal reduce steady-state protein levels of ARID1A. This defect in nuclear exportation leads to nuclear retention and subsequent degradation. Our findings delineate a mechanism underlying the regulation of ARID1A subcellular distribution and protein stability and suggest that targeting the nuclear ubiquitin-proteasome system can increase the amount of the ARID1A protein in the nucleus and restore its tumor suppressor functions.

Clinicopathologic analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer

Loss of the AT-rich interactive domain 1A (a putative tumor suppressor) protein BAF250a has recently been described as a frequent event in endometrial carcinoma. In this study, we determined the significance of the loss of AT-rich interactive domain 1A immunoreactivity for several clinicopathologic features of uterine endometrioid carcinoma. AT-rich interactive domain 1A expression was assessed by immunohistochemistry using 111 paraffin-embedded tissue specimens and clinical data collected by a retrospective medical record review. The correlations between loss of AT-rich interactive domain 1A protein and clinicopathologic and prognostic features were examined. In addition, the expression of PTEN, p53, Her2, and MLH1 was assessed by immunohistochemistry and compared with AT-rich interactive domain 1A expression. AT-rich interactive domain 1A immunoreactivity was undetectable in 27 (24%) of 111 analyzed endometrioid endometrial carcinomas. There was no significant difference between negative and positive cases of AT-rich interactive domain 1A in terms of any clinicopathologic features examined (International Federation of Gynecology and Obstetrics stage, grade, depth of myometrial invasion, lymph node metastasis, lymphovascular space invasion, body mass index, postmenopausal status, patient age at diagnosis, and estrogen and progesterone receptor status). The comparison between the expression of AT-rich interactive domain 1A and the expression of PTEN, p53, Her2, and MLH1 also revealed no significant association. There was no significant correlation between AT-rich interactive domain 1A expression and progression-free/overall survival of patients. This study provides the first examination of the clinicopathologic relationship between AT-rich interactive domain 1A protein expression and endometrial carcinoma. No significant differences between positive and negative cases of AT-rich interactive domain 1A were observed with respect to any clinicopathologic features or patient survival.