Chen Tingan, Yang Ivana, Irby Rosalyn, Shain Kenneth H, Wang Hong Gang, Quackenbush John, Coppola Domenico, Cheng Jin Q, Yeatman Timothy J
Department of Interdisciplinary Oncology and Surgery, University of South Florida, Tampa, FL 33612, USA.
Cancer Res. 2003 Aug 1;63(15):4368-74.
The adenomatous polyposis coli (APC) gene, a member of the WNT pathway, has been shown to assign intestinal epithelial cells to a program of proliferation or differentiation through regulation of the beta-catenin/TCF-4 complex. Wild-type APC, in certain cellular contexts, appears to induce differentiation and apoptosis, although mutant forms of APC, known to produce polyps and ultimately cancers, may suppress these events. Here, we show that mutant forms of APC can induce repression of select terminal caspases as a potential means of attenuating responses to apoptotic stimuli. Using gene expression profiling to interrogate the intact intestines of Apc(+/min) mice harboring numerous polyps, we identified a reduction in the mRNA expression of both caspases 3 and 7. We additionally identified a reduction in protein levels of caspase-3, caspase-7, and caspase-9 in human colon cancer specimens known to harbor APC mutations. A reduction in caspase protein levels resulted in resistance to apoptotic-inducing agents and restoration of caspase levels reinstated apoptotic capacities. Consistent with Wnt pathway involvement, dominant negative TCF/LEF induced caspase protein expression. These data provide support for the hypothesis that one of the functions of APC is the regulation of caspase activity and other apoptotic proteins by controlling their expression levels in the cell.
腺瘤性结肠息肉病（APC）基因是WNT信号通路的成员之一，已被证明可通过调节β-连环蛋白/TCF-4复合物，使肠上皮细胞进入增殖或分化程序。在某些细胞环境中，野生型APC似乎可诱导分化和凋亡，然而，已知会产生息肉并最终发展为癌症的APC突变形式，可能会抑制这些事件。在此，我们表明，APC的突变形式可诱导特定终末半胱天冬酶的抑制，作为减弱对凋亡刺激反应的一种潜在方式。利用基因表达谱分析来研究携带众多息肉的Apc(+/min)小鼠的完整肠道，我们发现半胱天冬酶3和7的mRNA表达均降低。我们还在已知存在APC突变的人类结肠癌标本中，发现半胱天冬酶-3、半胱天冬酶-7和半胱天冬酶-9的蛋白水平降低。半胱天冬酶蛋白水平的降低导致对凋亡诱导剂产生抗性，而恢复半胱天冬酶水平则可恢复凋亡能力。与WNT信号通路的参与一致，显性负性TCF/LEF可诱导半胱天冬酶蛋白表达。这些数据支持了这样一种假说，即APC的功能之一是通过控制细胞中半胱天冬酶活性和其他凋亡蛋白的表达水平来进行调节。
