Roldán Diana Barea, Grimmler Matthias, Hartmann Christoph, Hubich-Rau Stefanie, Beißert Tim, Paret Claudia, Cagna Giuseppe, Rohde Christoph, Wöll Stefan, Koslowski Michael, Türeci Özlem, Sahin Ugur
TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
These authors contributed equally to this work.
Oncotarget. 2020 May 19;11(20):1862-1875. doi: 10.18632/oncotarget.27582.
PLAC1 (placenta enriched 1) is a mammalian trophoblast-specific protein. Aberrant expression of PLAC1 is observed in various human cancers, where it is involved in the motility, migration, and invasion of tumor cells, which are associated with the phosphoinositide 3-kinase (PI3K)/AKT pathway. We previously demonstrated that AKT activation mediates the downstream effects of PLAC1; however, the molecular mechanisms of PLAC1-induced AKT-mediated tumor-related processes are unclear. We studied human choriocarcinoma and breast cancer cell lines to explore the localization and receptor-ligand interactions, as well as the downstream effects of PLAC1. We show secretion and adherence of PLAC1 to the extracellular matrix, where it forms a trimeric complex with fibroblast growth factor 7 (FGF7) and its receptor, FGF receptor 2 IIIb (FGFR2IIIb). We further show that PLAC1 signaling via FGFR2IIIb activates AKT phosphorylation in cancer cell lines. As the FGF pathway is of major interest in anticancer therapeutic strategies, these data further promote PLAC1 as a promising anticancer drug target.
PLAC1（胎盘富集蛋白1）是一种哺乳动物滋养层特异性蛋白。在多种人类癌症中均观察到PLAC1的异常表达，它参与肿瘤细胞的运动、迁移和侵袭，这些过程与磷酸肌醇3激酶（PI3K）/AKT信号通路相关。我们之前证明AKT激活介导了PLAC1的下游效应；然而，PLAC1诱导的AKT介导的肿瘤相关过程的分子机制尚不清楚。我们研究了人绒毛膜癌细胞系和乳腺癌细胞系，以探索PLAC1的定位、受体-配体相互作用及其下游效应。我们发现PLAC1分泌并黏附于细胞外基质，在那里它与成纤维细胞生长因子7（FGF7）及其受体成纤维细胞生长因子受体2 IIIb（FGFR2IIIb）形成三聚体复合物。我们进一步表明，通过FGFR2IIIb的PLAC1信号传导可激活癌细胞系中的AKT磷酸化。由于FGF信号通路在抗癌治疗策略中备受关注，这些数据进一步提升了PLAC1作为一个有前景的抗癌药物靶点的地位。
