Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFb Axis
Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFb Axis
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DOI：
10.1158/0008-5472.can-21-0003
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发表时间：
2022-04-15
期刊：
影响因子：
11.2
通讯作者：
Liang, Xiaohong
中科院分区：
文献类型：
--
作者：
Cheng, Yang;Bai, Fuxiang;Liang, Xiaohong
巨噬细胞通过精细调节其激活状态在维持组织稳态中发挥关键和独特的功能。在肿瘤微环境中，巨噬细胞被重塑以驱动肿瘤进展。在这里，我们报告，肿瘤坏死因子诱导蛋白8样1（TIPE 1）是高表达的巨噬细胞和TIPE 1的耗竭阻碍了巨噬细胞的替代激活。TIPE 1通过直接与磷脂酰肌醇4，5-二磷酸（PIP 2）和磷脂酰肌醇3，4，5-三磷酸（PIP 3）结合并调节其代谢，增强巨噬细胞中PI 3 K/Akt通路的激活。因此，PI 3 K/Akt通路的抑制显著减弱了TIPE 1对巨噬细胞交替激活的影响。人肝癌和黑色素瘤组织中的肿瘤相关巨噬细胞（TAM）显示TIPE 1表达显著上调，与患者生存率呈负相关。在体外和体内，巨噬细胞中TIPE 1的敲低延缓了肝癌和黑色素瘤的生长和转移。此外，巨噬细胞中TGFI 3信号传导的阻断或耗尽消除了TIPE 1对肿瘤细胞生长和迁移的作用。总之，这些结果强调了磷酸肌醇相关的信号通路参与了重新编程TAM以优化癌症进展的微环境。
Macrophages perform key and distinct functions in maintaining tissue homeostasis by finely tuning their activation state. Within the tumor microenvironment, macrophages are reshaped to drive tumor progression. Here we report that tumor necrosis factor a-induced protein 8-like 1 (TIPE1) is highly expressed in macrophages and that depletion of TIPE1 impedes alternative activation of macrophages. TIPE1 enhanced activation of the PI3K/Akt pathway in macrophages by directly binding with and regulating the metabolism of phosphatidylinositol4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5trisphosphate (PIP3). Accordingly, inhibition of the PI3K/Akt pathway significantly attenuated the effect of TIPE1 on macrophage alternative activation. Tumor-associated macrophages (TAM) in human liver cancer and melanoma tissues showed significantly upregulated TIPE1 expression that negatively correlated with patient survival. In vitro and in vivo, TIPE1 knockdown in macrophages retarded the growth and metastasis of liver cancer and melanoma. Furthermore, blockade or depletion of TGFI3 signaling in macrophages abrogated the effects of TIPE1 on tumor cell growth and migration. Together, these results highlight that the phosphoinositide-related signaling pathway is involved in reprogramming TAMs to optimize the microenvironment for cancer progression.