Regulatory effect between HMGA2 and the Wnt/β-catenin signaling pathway in the carcinogenesis of sporadic colorectal tubular adenoma.

Abstract

Due to the high incidence of colorectal cancer worldwide, the underlying molecular mechanisms have been extensively investigated. The Wnt/β-catenin signaling pathway plays a key role in the carcinogenesis of colorectal adenoma. In addition, the high mobility group AT-hook 2 (HMGA2) protein, which is involved in several biological processes, such as proliferation, differentiation, transformation and metastasis, is expressed at significantly high levels in colorectal cancer tissues compared with adjacent normal tissues. Currently, the role of HMGA2 in the carcinogenesis of sporadic colorectal tubular adenoma remains unclear. The downstream Wnt/β-catenin signaling molecule, T-cell factor/lymphoid enhancing factor (TCF/LEF), shares a similar domain with HMGA2, which enhances β-catenin transcriptional activity and TCF/LEF binding. Thus, the present study investigated the association between HMGA2 and the Wnt/β-catenin signaling pathway, and their role in the carcinogenesis of sporadic colorectal tubular adenoma via immunohistochemistry, siRNA, quantitative PCR and western blot analyses. The results demonstrated that the positive rate of HMGA2 expression gradually increased during tumor progression. Furthermore, HMGA2 expression was positively correlated with Wnt/β-catenin signaling protein expression [Wnt, β-catenin, cyclin-dependent kinase 4 (CDK4) and cyclin D1], suggesting its involvement in the carcinogenesis of sporadic colorectal tubular adenoma and its potential to synergistically interact with the Wnt/β-catenin signaling pathway. HMGA2 knockdown in the human colorectal cancer cell line, HCT 116 decreased β-catenin expression and its downstream targets, CDK4 and cyclin D1. Furthermore, silencing of Wnt or β-catenin decreased HMGA2 expression. Taken together, the results of the present study suggest the coordinated regulation of HMGA2 and the Wnt/β-catenin signaling pathway in the carcinogenesis of sporadic colorectal tubular adenoma.