A two-step model for colon adenoma initiation and progression caused by APC loss.
A two-step model for colon adenoma initiation and progression caused by APC loss.
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DOI：
10.1016/j.cell.2009.02.037
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发表时间：
2009-05-15
期刊：
影响因子：
64.5
通讯作者：
Jones DA
中科院分区：
文献类型：
--
作者：
Phelps RA;Chidester S;Dehghanizadeh S;Phelps J;Sandoval IT;Rai K;Broadbent T;Sarkar S;Burt RW;Jones DA
肿瘤抑制因子腺瘤性息肉病大肠（APC）缺失后，异常的Wnt/β-catenin信号被认为启动了结肠腺瘤的形成。利用斑马鱼和人类细胞，我们发现APC的纯合缺失导致肠细胞分化失败，但这种情况发生在缺乏核β-连环蛋白和肠细胞增殖增加的情况下。因此，APC的丢失不足以引起β-catenin的核定位。APC突变诱导的肠道分化缺陷依赖于转录辅助抑制因子CtBP1，而增殖缺陷和β-catenin的核积累需要KRAS的额外激活。这些发现表明，APC丢失后，CtBP1作为第一步促进腺瘤的发生，而KRAS激活和β-catenin核定位促进腺瘤进展为癌是第二步。与该模型一致，人类FAP腺瘤在核β-catenin缺失的情况下显示CtBP1的强烈上调，而在癌中检测到核β-catenin。
Aberrant Wnt/β-catenin signaling following loss of the tumor suppressor adenomatous polyposis coli (APC) is thought to initiate colon adenoma formation. Using zebrafish and human cells, we show that homozygous loss of APC causes failed intestinal cell differentiation, but that this occurs in the absence of nuclear β-catenin and increased intestinal cell proliferation. Therefore, loss of APC is insufficient for causing β-catenin nuclear localization. APC mutation-induced intestinal differentiation defects instead depend on the transcriptional corepressor CtBP1 whereas proliferation defects, and nuclear accumulation of β-catenin, require the additional activation of KRAS. These findings suggest that, following APC loss, CtBP1 contributes to adenoma initiation as a first step, while KRAS activation and β-catenin nuclear localization promotes adenoma progression to carcinomas as a second step. Consistent with this model, human FAP adenomas showed robust upregulation of CtBP1 in the absence of detectable nuclear β-catenin, whereas nuclear β-catenin was detected in carcinomas.
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