Department of Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Gastroenterology. 2010 Sep;139(3):869-81, 881.e1-9. doi: 10.1053/j.gastro.2010.05.037. Epub 2010 May 24.
BACKGROUND & AIMS: Mechanisms responsible for crypt architectural distortion in chronic ulcerative colitis (CUC) are not well understood. Data indicate that serine/threonine protein kinase Akt (Akt) signaling cooperates with Wingless (Wnt) to activate beta-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-beta-catenin(552)). We investigated whether phosphoinositide 3-kinase (PI3K) is required for Akt-mediated activation of beta-catenin during intestinal inflammation.
The class IA subunit of PI3K was conditionally deleted from intestinal epithelial cells in mice named I-pik3r1KO. Acute inflammation was induced in mice and intestines were analyzed by biochemical and histologic methods. The effects of chemically blocking PI3K in colitic interleukin-10(-/-) mice were examined. Biopsy samples from patients were examined.
Compared with wild-type, I-pik3r1KO mice had reduced T-cell-mediated Akt and beta-catenin signaling in intestinal stem and progenitor cells and limited crypt epithelial proliferation. Biochemical analyses indicated that PI3K-Akt signaling increased nuclear total beta-catenin and P-beta-catenin(552) levels and reduced N-terminal beta-catenin phosphorylation, which is associated with degradation. PI3K inhibition in interleukin-10(-/-) mice impaired colitis-induced epithelial Akt and beta-catenin activation, reduced progenitor cell expansion, and prevented dysplasia. Human samples had increased numbers of progenitor cells with P-beta-catenin(552) throughout expanded crypts and increased messenger RNA expression of beta-catenin target genes in CUC, colitis-associated cancer, tubular adenomas, and sporadic colorectal cancer, compared with control samples.
PI3K-Akt signaling cooperates with Wnt to increase beta-catenin signaling during inflammation. PI3K-induced and Akt-mediated beta-catenin signaling are required for progenitor cell activation during the progression from CUC to CAC; these factors might be used as biomarkers of dysplastic transformation in the colon.
慢性溃疡性结肠炎（CUC）中导致隐窝结构扭曲的机制尚不清楚。有数据表明丝氨酸/苏氨酸蛋白激酶 Akt（Akt）信号通过在 Ser552 位磷酸化（P-β-catenin(552)）与 Wingless（Wnt）协同作用于肠干细胞和祖细胞，激活β-连环蛋白。我们研究了在肠道炎症过程中，PI3K 是否需要 Akt 介导的β-连环蛋白激活。
我们在一种名为 I-pik3r1KO 的小鼠中条件性敲除了肠上皮细胞中的 PI3K 类 IA 亚基。通过生化和组织学方法分析小鼠的急性炎症，并用化学方法阻断 PI3K 在溃疡性结肠炎白介素-10（-/-）小鼠中的作用，并检测患者活检样本。
与野生型相比，I-pik3r1KO 小鼠的肠干细胞和祖细胞中 T 细胞介导的 Akt 和β-连环蛋白信号减弱，隐窝上皮增殖受限。生化分析表明，PI3K-Akt 信号增加了核内总β-连环蛋白和 P-β-catenin(552)水平，并减少了 N 端β-连环蛋白磷酸化，这与降解有关。在白介素-10（-/-）小鼠中抑制 PI3K 会损害结肠炎诱导的上皮 Akt 和β-连环蛋白激活，减少祖细胞的扩增，并防止发育不良。与对照样本相比，人类 CUC、结肠炎相关癌症、管状腺瘤和散发性结直肠癌样本中，整个扩张隐窝中具有 P-β-catenin(552)的祖细胞数量增加，β-连环蛋白靶基因的信使 RNA 表达增加。
PI3K-Akt 信号与 Wnt 合作，在炎症过程中增加β-连环蛋白信号。PI3K 诱导的 Akt 介导的β-连环蛋白信号在从 CUC 到 CAC 的进展过程中，是祖细胞激活所必需的；这些因素可作为结直肠发育不良转化的生物标志物。
