Expression of nuclear beta-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas

Abstract

Most colorectal cancers have loss-of-function mutations in the adenomatosis polyposis coli (APC) tumor suppressor gene. This leads to the accumulation of nuclear beta-catenin, which, together with the DNA-binding protein TCF-4, functions as a transcriptional activator. The recently defined target genes c-myc, cyclin D1, and matrilysin are responsible for tumor proliferation or malignant progression and explain the oncogenic potential of nuclear beta-catenin. To investigate its role in early colon carcinogenesis, we analyzed the expression of beta-catenin, its target gene c-myc, and the proliferative activity in 88 colorectal adenomas of varying size and grade of dysplasia. The results revealed i) the most significant correlation of nuclear beta-catenin and c-myc expression was not with the grade of dysplasia but with the size of the colon adenoma; ii) perfect correlation of nuclear beta-catenin and c-myc expression; iii) no significant correlation of adenoma size with the proliferative activity; and iv) no significant correlation of proliferative activity and the nuclear expression of beta-catenin and c-myc. These results imply that APC mutations have additional beta-catenin-independent functions; APC mutations alone are not sufficient for nuclear overexpression of beta-catenin; and nuclear beta-catenin has additional important functions for exceeding a threshold tumor size.

Figure 1.

Correlation between adenoma size and nuclear β-catenin (A), c-myc (B), and mib-1 (C) expression. Boxplot charts (50% of values are within the box; horizontal bar, median; vertical bar, range of values). Included are the P values of the correlations between the indicated staining scores. A P value <0.05 was considered significant. n.s., not significant.

Figure 2.

Correlation of β-catenin expression with the expression of c-myc but not with proliferative activity. Immunohistochemical staining for mib-1, β-catenin, and c-myc (red staining). Serial section of the same area of two colorectal adenomas with low (a−c) and high (d−f) proliferative activity. Strongly correlated expression of nuclear β-catenin (b) and c-myc (c) in the low-proliferating adenoma and no expression of both nuclear β-catenin (e) and c-myc (f) in the tumor cells of the high-proliferating adenoma. Original magnification, ×400.