Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China.
Oncogene. 2021 Nov;40(46):6456-6468. doi: 10.1038/s41388-021-02035-6. Epub 2021 Oct 4.
Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and subsequent proliferation after colonization. However, it has long been recognized that cancer cell migration and proliferation can be uncoupled; but the mechanism underlying this paradox is not well understood. Here we report that TNFAIP8 (tumor necrosis factor-α-induced protein 8), a "professional" transfer protein of phosphoinositide second messengers, promotes cancer cell migration or metastasis but inhibits its proliferation or cancer growth. TNFAIP8-deficient mice developed larger tumors, but TNFAIP8-deficient tumor cells completely lost their ability to migrate toward chemoattractants and were defective in colonizing lung tissues as compared to wild-type counterparts. Mechanistically, TNFAIP8 served as a cellular "pilot" of tumor cell migration by locally amplifying PI3K-AKT and Rac signals on the cell membrane facing chemoattractant; at the same time, TNFAIP8 also acted as a global inhibitor of tumor cell growth and proliferation by regulating Hippo signaling pathway. These findings help explain the migration-proliferation paradox of cancer cells that characterizes many cancers.
癌症转移导致了近 90%的癌症死亡。转移性癌症的进展需要癌细胞迁移到转移部位，以及随后在定植后的增殖。然而，长期以来人们一直认识到，癌细胞的迁移和增殖可以解耦；但这种悖论的机制尚不清楚。在这里，我们报告 TNFAIP8（肿瘤坏死因子-α诱导蛋白 8），一种磷酸肌醇第二信使的“专业”转位蛋白，促进癌细胞迁移或转移，但抑制其增殖或癌症生长。TNFAIP8 缺陷型小鼠发展出更大的肿瘤，但与野生型相比，TNFAIP8 缺陷型肿瘤细胞完全丧失了向趋化因子迁移的能力，并且在肺组织定植中存在缺陷。在机制上，TNFAIP8 通过在面向趋化因子的细胞膜上局部放大 PI3K-AKT 和 Rac 信号，充当肿瘤细胞迁移的细胞“领航员”；同时，TNFAIP8 还通过调节 Hippo 信号通路，作为肿瘤细胞生长和增殖的全局抑制剂发挥作用。这些发现有助于解释许多癌症的特征性的癌细胞迁移-增殖悖论。
