Downregulated ARID1A by miR-185 Is Associated With Poor Prognosis and Adverse Outcomes in Colon Adenocarcinoma

Abstract

AT-rich interaction domain 1A (ARID1A) is a tumor suppressor gene that mutates in several cancer types, including breast cancer, ovarian cancer, and colorectal cancer (CRC). In colon adenocarcinoma (COAD), the low expression of ARID1A was reported but the molecular reason is unclear. We noticed that ARID1A low expression was associated with increased levels of miR-185 in the COAD. Therefore, this study aims to explore ncRNA-dependent mechanism that regulates ARID1A expression in COAD regarding miR-185. The expression of ARID1A was tested in COAD cell line under the effect of miR-185 mimics compared with inhibitor. The molecular features associated with loss of ARID1A and its association with tumor prognosis were analyzed using multi-platform data from The Cancer Genome Atlas (TCGA), and gene set enrichment analysis (GSEA) to identify potential signaling pathways associated with ARID1A alterations in colon cancer. Kaplan-Meier survival curve showed that a low level of ARID1A was closely related to low survival rate in patients with COAD. Results showed that inhibiting miR-185 expression in the COAD cell line significantly restored the expression of ARID1A. Further, the increased expression of ARID1A significantly improved the prolonged overall survival of COAD. We noticed that there is a possible relationship between ARID1A high expression and tumor microenvironment infiltrating immune cells. Furthermore, the increase of ARID1A in tumor cells enhanced the response of inflammatory chemokines. In conclusion, this study demonstrates that ARID1A is a direct target of miR-185 in COAD that regulates the immune modulations in the microenvironment of COAD.

ARID1A knockdown enhances carcinogenesis features and aggressiveness of Caco-2 colon cancer cells: An in vitro cellular mechanism study

“…As aforementioned, there are several previous studies demonstrating the association between ARID1A down-regulation and CRC in human tissues or animal models 16 - 22 . Herein, we thus focused our attention on the cellular mechanism study, whereas a validation to demonstrate the down-regulation of ARID1A expression in CRC tissues was not done.…”

“…In concordance, a more recent study has shown that 12/18 (approximately 67%) of CRC tissues had no or low ARID1A expression 17 . Additionally, several previous studies using human specimens or animal models have reported an association between ARID1A down-regulation and CRC tumorigenicity 18 - 22 . Moreover, the loss of ARID1A is associated with the poorly differentiated grade of CRC cells 16 .…”

Relevance of ARID1A Mutations in Endometrial Carcinomas

“…Intriguingly, in six cases ARID1A was lost at IHC, even if no alterations were detectable in the ARID1A sequence. In these samples it is possible that a loss of protein immunostaining is due to epigenetic mechanisms [34,35], including, but not limited to, ARID1A copy-number aberration [36], or the microRNAs effect [37]. In five cases a mutation in the ARID1A sequence did not correspond to a loss of protein expression.…”

Mechanism and strategies of immunotherapy resistance in colorectal cancer

“…AT-Rich Interactive Domain-containing protein 1A (ARID1A), as one of the components making up the largest SWI/SNF subunit together with AT-Rich Interactive Domain-containing protein 1B (ARID1B), is the most frequent target of SWI/SNF mutations. mutations in ARID1A impair enhancer-mediated gene regulation and prognosis in patients with colon cancer ( 124 , 125 ). Interestingly, SWI/SNF complex stability is also vital for tumor cell viability, which might be impaired by ARID1A mutation.…”