The role of AT rich interactive domain 3A in the tumorigenesis of colorectal carcinomas

Abstract

AT rich interactive domain 3A (ARID3A) is a member of the ARID family of DNA-binding proteins. Previous reports have shown that ARID3A controls the cell growth through p53-dependent manner. Recently, it has been reported that expression of ARID3A protein was 14.29-fold increased in colon cancer tissue, compared to matched normal colonic mucosa. To date, biological function of ARID3A in human disease, especially in colorectal cancer (CRC), remains largely unknown. Therefore, my research was focused on studying the role of ARID3A in the tumorigenesis and the physiological implication of CRC.The expression of ARID3A was investigated by immunohistochemistry. ARID3A expression was detected in a subset of colorectal adenomas and carcinomas, and the location of ARID3A was mainly in the nucleus. To investigate the prognostic impact of ARID3A in CRC, tissue specimens from 690 patients with CRC were examined. Of the 690 cases, 195 tumors were strong-positive for ARID3A, 187 tumors were weak-positive and 308 tumors were negative. The expression of ARID3A in CRC was significantly correlated with age, degree of differentiation, depth of invasion, lymph node metastasis, distant metastasis, TNM stage, status of microsatellite instability, and CEA levels. The overall survival of CRC patients with ARID3A-strong expression was significantly longer than that of patients with ARID3A-negative or weak expression. On multivariate analysis, the strong expression of ARID3A was proven to be an independent predictor for better prognosis in CRC. Recent studies support a model in which ARID3A acts as a suppressor of lineage plasticity. I found that upregulation of ARID3A expression correlated with the reduction of transcriptional levels of several pluripotency-associated markers (OCT4, SOX2 and KLF4) and colorectal cancer stem cell (CSC) markers (CD133, CD44, CD166, CD24, and ALDH1) in CRC cell lines. Among these markers, I demonstrated the inverse relationship between ARID3A and CD133 expression in protein levels.In conclusion, my study strongly suggests that ARID3A might play an important role in colorectal carcinogenesis and can be used as a biomarker to predict the prognosis of CRC. Additionally, upregulation of ARID3A in CRC cell lines reduces expression levels of CD133, one of most important cancer stem cell markers in CRC. Further studies are necessary to delineate the mechanistic basis of these features.