Abstract
BTG (B-cell translocation gene) could inhibit cell proliferation, metastasis, and angiogenesis and regulate cell cycle progression and differentiation in a variety of cancer cell types. To clarify the role of BTG1 in invasion and metastasis, its expression was compared with the clinicopathological parameters of colorectal cancer by bioinformatics and immunohistochemical analyses. We also overexpressed BTG1 in HCT-15 cells and examined its effects on adhesion, migration, and metastasis with their related molecules screened. BTG1 mRNA expression was negatively correlated with its promoter methylation in colorectal cancer (P < 0.05). Among them, cg08832851 and cg05819371 hypermethylation and mRNA expression of BTG1 were positively related with poor prognosis of the colorectal cancer patients (P < 0.05). BTG1 expression was found to positively correlate with depth of invasion, venous invasion, lymph node metastasis, distant metastasis, and TNM staging of colorectal cancer (P < 0.05) but negatively with serum levels of CEA and CA19-9 (P < 0.05). According to the TCGA database, BTG1 mRNA expression was lower in well-, moderately, and poorly differentiated than mucinous adenocarcinomas and positively correlated with ras or BRAF mutation (P < 0.05). Kaplan–Meier analysis showed the negative correlation between BTG1 mRNA expression and overall survival rate of all cancer patients (P < 0.05). BTG1 overexpression weakened adhesion and strengthened migration and invasion of HCT-15 cells (P < 0.05). There was E-cadherin hypoexpression, N-cadherin and MMP-9 hyperexpression, Zeb1 and Vimentin mRNA overexpression, a high expression of CEA mRNA and protein, and a strong secretion of CEA in BTG1 transfectants, compared with the control or mock. It was suggested that BTG1 expression might promote invasion and metastasis by decreasing adhesion, and inducing epithelial–mesenchymal transition.
Highlights
Colorectal cancer is one of the most common cancers in the world, accounting for nearly 10% of new cases of all cancers
BTG1 hypermethylation at cg05819371 and cg08832851 was significantly related with poor prognosis of the colorectal cancer patients (Figure 1B, P < 0.05)
There was no difference in BTG1 mRNA expression between colorectal cancer and normal tissues using Oncomine database (P > 0.05, data not shown)
Summary
Colorectal cancer is one of the most common cancers in the world, accounting for nearly 10% of new cases of all cancers. Its invasion and metastasis greatly determine clinical outcome, survival time, and quality of the patients [1]. It is important to find out the molecular mechanisms and related targets for the invasion and metastasis of colorectal cancers. BTG1 overexpression is observed in the G0/G1 phases of the cell cycle and its down-regulation once cell progression through G1. It might inhibit cell proliferation and cell cycle progression [2]. BTG1 overexpression might promote tube formation and cell migration of endothelial cells during angiogenesis [5]. BTG1 could interact with nuclear receptor TRa, myogenic factor MyoD, carbon catabolite repressor protein-associative factor 1, and arginine methyltransferase 1 [6,7,8]
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