Zhang Hui, Liu Chengli, Kong Yalin, Huang Hui, Wang Cheng, Zhang Hongyi
Department of Hepatobiliary Surgery, Air Force General Hospital of PLA, 30 Fucheng Road, Beijing, 100142, China.
Tumour Biol. 2015 Mar;36(3):1613-8. doi: 10.1007/s13277-014-2757-4. Epub 2014 Oct 31.
Transforming growth factor β (TGFβ) receptor signaling plays a paradoxical effect in the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC), in which its tumor-inhibitory role at early stages turns into a tumor-promoting role at later stages. The underlying mechanism remains far from clear. Here we provide strong evidence that the activation of TGFβ receptor signaling in PDAC cells increased SMAD3 phosphorylation and nuclear translocation to inhibit cell growth. Meanwhile, it also activated SMAD7 to induce nuclear translocation and retention of β-catenin, which not only attenuated the inhibition of cell growth by nuclear SMAD3 but also activated vascular endothelial growth factor A (VEGF-A) to promote vascularization. Our data thus support a model involving crosstalk of the TGFβ and Wnt signaling pathways, for regulating the complicated effect of TGFβ signaling on the tumorigenesis of PDAC.
转化生长因子β（TGFβ）受体信号传导在胰腺导管腺癌（PDAC）的肿瘤发生过程中发挥着矛盾的作用，其中其在早期阶段的肿瘤抑制作用在后期转变为肿瘤促进作用。其潜在机制仍远未明确。在此，我们提供了有力证据表明，PDAC细胞中TGFβ受体信号传导的激活增加了SMAD3的磷酸化和核转位，从而抑制细胞生长。同时，它还激活SMAD7以诱导β-连环蛋白的核转位和滞留，这不仅减弱了核SMAD3对细胞生长的抑制作用，还激活血管内皮生长因子A（VEGF-A）以促进血管生成。因此，我们的数据支持一种涉及TGFβ和Wnt信号通路相互作用的模型，用于调节TGFβ信号传导对PDAC肿瘤发生的复杂作用。
