Interplay between VHL/HIF1α and Wnt/β-catenin pathways during colorectal tumorigenesis
Interplay between VHL/HIF1α and Wnt/β-catenin pathways during colorectal tumorigenesis
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DOI：
10.1038/sj.onc.1209330
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发表时间：
2006-05-18
期刊：
影响因子：
8
通讯作者：
Voest, E. E.
中科院分区：
文献类型：
--
作者：
Giles, R. H.;Lolkema, M. P.;Voest, E. E.
Wnt 信号通路的激活启动结直肠上皮细胞的转化，尽管向转移性癌症的转变需要血管生成。我们研究了 von Hippel-Lindau (VHL) 肿瘤抑制因子在人和小鼠肠道中的表达。在这里，我们表明 VHL 表达受 TCF4 调节，并且仅限于肠隐窝底部的增殖区室。因此，Tcf4(-/-)围产期小鼠的增殖性肠袋中完全不存在VHL。我们在正常肠上皮以及结直肠癌 (CRC) 的所有阶段中观察到缺氧诱导因子 (HIF) 1 α 与 VHL 的互补染色。据我们所知，这是第一份证明常氧健康成人组织中存在核 HIF1 α 的报告。尽管我们观察到散发性和家族性腺瘤性息肉病患者的极早期 CRC 病变中 VHL 水平上调（可能是由于 Wnt 信号传导激活），但在 CRC 进展的后期阶段观察到 VHL 表达明显减少，这与 HIF1 α 的稳定一致。由于 CRC 进展后期 VHL 的缺失导致 HIF 稳定，因此这些数据提供的证据表明，VHL 下调的选择为 CRC 进展提供了促血管生成冲动。
Activation of the Wnt signaling pathway initiates the transformation of colorectal epithelial cells, although the transition to metastatic cancer requires angiogenesis. We have investigated the expression of the von Hippel-Lindau (VHL) tumor suppressor in the intestines from humans and mice. Here, we show that VHL expression is regulated by TCF4 and is restricted to the proliferative compartment at the bottom of intestinal crypts. Accordingly, VHL is completely absent from the proliferative intestinal pockets of Tcf4(-/-) perinatal mice. We observed complementary staining of the hypoxia-inducible factor (HIF) 1 alpha to VHL in normal intestinal epithelium as well as in all stages of colorectal cancer (CRC). To the best of our knowledge, this is the first report demonstrating the presence of nuclear HIF1 alpha in normoxic healthy adult tissue. Although we observed upregulated levels of VHL in very early CRC lesions from sporadic and familial adenomatous polyposis patients-presumably due to activated Wnt signaling - a clear reduction of VHL expression is observed in later stages of CRC progression, coinciding with stabilization of HIF1 alpha. As loss of VHL in later stages of CRC progression results in stabilization of HIF, these data provide evidence that selection for VHL downregulation provides a proangiogenic impulse for CRC progression.