Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Biochem Biophys Res Commun. 2011 Mar 4;406(1):1-6. doi: 10.1016/j.bbrc.2010.12.070. Epub 2010 Dec 22.
In a majority of cases, colorectal cancer is initiated by aberrant activation of the WNT signaling pathway. Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin causes constitutively active β-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to cancer precursor lesions, called dysplastic aberrant crypt foci. Deregulated apoptosis is a hallmark of adenomatous colon tissue. However, the contribution of WNT signaling to this process is not fully understood. We addressed this role by analyzing the rate of epithelial apoptosis in aberrant crypts and adenomas of the Apc(Min/+) mouse model. In comparison with normal crypts and adenomas, aberrant crypts displayed a dramatically increased rate of apoptotic cell death. Expression profiling of apoptosis-related genes along the crypt-villus axis and in Apc mutant adenomas revealed increased expression of two pro-apoptotic Bcl-2 family members in intestinal adenomas, Bok and Bax. Analysis of the colon of familial adenomatous polyposis (FAP) patients along the crypt-to-surface axis, and of dysplastic crypts, corroborated this expression pattern. Disruption of β-catenin/TCF-4-mediated signaling in the colorectal cancer cell line Ls174T significantly decreased BOK and BAX expression, confirming WNT-dependent regulation in intestinal epithelial cells. Our results suggest a feedback mechanism by which uncontrolled epithelial cell proliferation in the stem cell compartment can be counterbalanced by an increased propensity to undergo cell death.
在大多数情况下，结直肠癌是由 WNT 信号通路的异常激活引发的。编码 WNT 信号成分腺瘤性结肠息肉病或 β-连环蛋白的基因突变导致持续激活的 β-连环蛋白/TCF 介导的转录，驱动肠隐窝向癌前病变转化，称为发育不良的异常隐窝焦点。凋亡失调是腺瘤性结肠组织的标志。然而，WNT 信号对这一过程的贡献尚不完全清楚。我们通过分析 Apc(Min/+)小鼠模型中异常隐窝和腺瘤中的上皮细胞凋亡率来研究这一作用。与正常隐窝和腺瘤相比，异常隐窝显示出明显增加的凋亡细胞死亡速率。对沿隐窝-绒毛轴和 Apc 突变腺瘤的凋亡相关基因表达谱进行分析，揭示了两种促凋亡 Bcl-2 家族成员在肠腺瘤中 Bok 和 Bax 的表达增加。对家族性腺瘤性息肉病 (FAP) 患者结肠沿隐窝-表面轴的分析，以及对发育不良隐窝的分析，证实了这种表达模式。在结直肠癌细胞系 Ls174T 中破坏 β-连环蛋白/TCF-4 介导的信号显著降低了 Bok 和 Bax 的表达，证实了 WNT 在肠上皮细胞中的依赖性调节。我们的结果表明，一种反馈机制可以平衡干细胞区不受控制的上皮细胞增殖，增加细胞死亡的倾向。
