Janssen Klaus-Peter, Alberici Paola, Fsihi Hafida, Gaspar Claudia, Breukel Cor, Franken Patrick, Rosty Christophe, Abal Miguel, El Marjou Fatima, Smits Ron, Louvard Daniel, Fodde Riccardo, Robine Sylvie
UMR144/Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Gastroenterology. 2006 Oct;131(4):1096-109. doi: 10.1053/j.gastro.2006.08.011. Epub 2006 Aug 16.
BACKGROUND & AIMS: Synchronous activation of the Wnt signaling pathway, mostly because of loss of function of the APC tumor suppressor, and of the oncogenic KRAS-signaling pathway is very frequent in colorectal cancer and is associated with poor prognosis.
We have generated a compound transgenic mouse model, KRAS(V12G)/Apc(+/1638N), to recapitulate the human disease and compared it with single transgenic littermates.
Compound mutant mice are characterized by a 10-fold increase in tumor multiplicity and by accelerated tumor progression, resulting in strongly enhanced morbidity and mortality. Tumors from compound mutant mice proliferate faster and show decreased levels of apoptosis. Several lines of evidence indicate that the observed increase in tumor multiplicity and malignant transformation is caused by the synergistic activation of Wnt signaling in cells with oncogenic KRAS and loss-of-function Apc mutations. Activated KRAS is known to induce tyrosine phosphorylation of beta-catenin, leading to its release from E-cadherin at the adherens junction. This results in an increased beta-catenin pool in the cytoplasma, its subsequent translocation to the nucleus, and the transcriptional activation of Wnt downstream target genes. Accordingly, intestinal tumors from KRAS(V12G)/Apc(+/1638N) mice show a significant increase in cells with nuclear accumulation of beta-catenin when compared with Apc(+/1638N) animals. Moreover, Apc/KRAS-mutant embryonic stem cells show a significantly enhanced beta-catenin/T-cell factor-mediated transcriptional activation, accompanied by increased beta-catenin nuclear localization.
This KRAS-induced increase in Wnt/beta-catenin signaling may enhance the plasticity and self-renewal capacity of the tumor, thus resulting in the drastically augmented tumor multiplicity and malignant behavior in compound mutant animals.
Wnt信号通路的同步激活，主要是由于APC肿瘤抑制基因功能丧失，以及致癌性KRAS信号通路在结直肠癌中非常常见，且与预后不良相关。
我们构建了一种复合转基因小鼠模型KRAS(V12G)/Apc(+/1638N)，以重现人类疾病，并将其与单转基因同窝小鼠进行比较。
复合突变小鼠的肿瘤发生率增加了10倍，肿瘤进展加速，导致发病率和死亡率显著提高。复合突变小鼠的肿瘤增殖更快，凋亡水平降低。多项证据表明，观察到的肿瘤发生率增加和恶性转化是由致癌性KRAS和功能丧失性Apc突变细胞中Wnt信号的协同激活引起的。已知激活的KRAS会诱导β-连环蛋白的酪氨酸磷酸化，导致其从黏附连接处的E-钙黏蛋白中释放出来。这导致细胞质中β-连环蛋白池增加，随后转移到细胞核，并激活Wnt下游靶基因的转录。因此，与Apc(+/1638N)小鼠相比，KRAS(V12G)/Apc(+/1638N)小鼠的肠道肿瘤中β-连环蛋白核积累的细胞显著增加。此外，Apc/KRAS突变的胚胎干细胞显示出β-连环蛋白/T细胞因子介导的转录激活显著增强，同时β-连环蛋白核定位增加。
KRAS诱导的Wnt/β-连环蛋白信号增加可能增强肿瘤的可塑性和自我更新能力，从而导致复合突变动物的肿瘤发生率急剧增加和恶性行为。
