Abstract
BackgroundARID1A has been described as a tumor suppressor gene, participating in chromatin re-modeling, epithelial-mesenchymal-transition and many other cellular and molecular processes. It has been cited as a contribute in tumorigenesis. The role of ARID1A in CRC is not yet defined.AimTo investigate the role of ARID1A methylation and CNV in its expression in CRC cell lines and to examine the relationship between ARID1A status with survival and clinicopathologic characteristics in patients with CRC.MethodsWe used RT-PCR to determine both CNV and expression of ARID1A from six CRC cell lines. We used MSP to evaluate methylation of ARID1A. IHC was used to assess ARID1A protein expression. We also evaluated MSI and EMAST status in 18 paired CRC and adjacent normal tissues. 5AzadC was used to assess effect of DNA demethylation on ARID1A expression. Statistical analysis was performed to establish correlations between ARID1A expression and other parameters.ResultsAmong the 18 CRC tumors studied, 7 (38.8%) and 5 tumors (27.7%) showed no or low ARID1A expression, respectively. We observed no significant difference in ARID1A expression for overall patient survival, and no difference between clinicopathological parameters including MSI and EMAST. However, lymphatic invasion was more pronounced in the low/no ARID1A expression group when compared to moderate and high expression group (33% VS. 16.6% respectively. ARID1A promoter methylation was observed in 4/6 (66%) cell lines and correlated with ARID1A mRNA expression level ranging from very low in SW48, to more pronounced in HCT116 and HT-29/219. Treatment with the methyltransferase inhibitor 5-Azacytidine (5-aza) resulted in a 25.4-fold and 6.1-fold increase in ARID1A mRNA expression in SW48 and SW742 cells, respectively, while there was no change in SW480 and LS180 cells. No ARID1A CNV was observed in the CRC cell lines.ConclusionARID1A expression is downregulated in CRC tissues which correlates with it being a tumor suppressor protein. This finding confirms ARID1A loss of expression in CRC development. Our in-vitro results suggest high methylation status associates with reduced ARID1A expression and contributes to CRC tumorigenesis. However, there was no significant association between ARID1A loss of expression and clinicopathological characteristics. Future in-vivo analysis is warranted to further establish ARID1A role in colorectal neoplastic transformation.
Highlights
Colorectal cancer (CRC) is rapidly increasing in prevalence among several regions of the world, such as Asia [1, 2]
We observed no significant difference in AT-rich interactive domain-containing protein 1A (ARID1A) expression for overall patient survival, and no difference between clinicopathological parameters including Microsatellite Instability (MSI) and Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)
ARID1A expression is downregulated in CRC tissues which correlates with it being a tumor suppressor protein
Summary
Colorectal cancer (CRC) is rapidly increasing in prevalence among several regions of the world, such as Asia [1, 2]. ARID1A is frequently deleted in multiple human tumors It is located on chromosome 1p36.11, a region that is commonly deleted in various cancer types and suspected to contain tumor suppressor genes [6,7,8,9,10]. ARID1A protein is typically deficient in oncogenic tissues, and is suspected to possess the tumor suppressor activity of the complex [16, 17]. ARID1A has been described as a tumor suppressor gene, participating in chromatin re-modeling, epithelial-mesenchymal-transition and many other cellular and molecular processes. It has been cited as a contribute in tumorigenesis. The role of ARID1A in CRC is not yet defined
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