Li Dan, Cao Yanan, Wang Juan, Yang Haiyan, Liu Weina, Cui Jinfeng, Wu Wenxin
Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China.
Oncol Lett. 2021 Dec;22(6):849. doi: 10.3892/ol.2021.13110. Epub 2021 Oct 25.
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.
由于全球范围内结直肠癌的发病率较高，其潜在的分子机制已得到广泛研究。Wnt/β-连环蛋白信号通路在结直肠腺瘤的致癌过程中起关键作用。此外，高迁移率族AT-钩2（HMGA2）蛋白参与多种生物学过程，如增殖、分化、转化和转移，与相邻正常组织相比，其在结直肠癌组织中的表达水平显著升高。目前，HMGA2在散发性结直肠管状腺瘤致癌过程中的作用尚不清楚。下游的Wnt/β-连环蛋白信号分子T细胞因子/淋巴增强因子（TCF/LEF）与HMGA2具有相似结构域，可增强β-连环蛋白的转录活性及与TCF/LEF的结合。因此，本研究通过免疫组织化学、小干扰RNA（siRNA）、定量聚合酶链反应（PCR）和蛋白质免疫印迹分析，研究HMGA2与Wnt/β-连环蛋白信号通路之间的关联及其在散发性结直肠管状腺瘤致癌过程中的作用。结果表明，HMGA2表达的阳性率在肿瘤进展过程中逐渐升高。此外，HMGA2表达与Wnt/β-连环蛋白信号蛋白表达[Wnt、β-连环蛋白、细胞周期蛋白依赖性激酶4（CDK4）和细胞周期蛋白D1]呈正相关，提示其参与散发性结直肠管状腺瘤的致癌过程，并有可能与Wnt/β-连环蛋白信号通路协同相互作用。在人结直肠癌细胞系HCT 116中敲低HMGA2可降低β-连环蛋白及其下游靶点CDK4和细胞周期蛋白D1的表达。此外，沉默Wnt或β-连环蛋白可降低HMGA2的表达。综上所述，本研究结果提示HMGA2与Wnt/β-连环蛋白信号通路在散发性结直肠管状腺瘤致癌过程中存在协同调控作用。
