Abstract
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.
Highlights
Placental trophoblasts and cancer cells exhibit shared characteristics
placenta enriched 1 (PLAC1) is co-expressed with fibroblast growth factor 7 (FGF7) and Fibroblast growth factor receptor 2 (FGFR2) in placenta and human cancer cells and is localized in the extracellular matrix (ECM)
We demonstrate firsthand the potential role of PLAC1 in the tumorigenesis of breast cancer cells and choriocarcinoma cells via formation of a trimeric complex between PLAC1, FGF7, and FGFR2IIIb, which binds to Heparin sulfate glycosaminoglycan (HSGAG) in the ECM, and leads to cell proliferation via the activation of AKT
Summary
Placental trophoblasts and cancer cells exhibit shared characteristics. Both cell types are motile, migratory, and exhibit immune tolerance mechanisms to evade as well as modify the host’s immune response [1].Proteins typically associated with human embryonic or fetal development are reactivated in cancer cells [2, 3], and may confer tumor cells with invasive potential.One placental protein that is highly expressed in a wide range of human tumors is placenta enriched 1 (PLAC1) [4]. Placental trophoblasts and cancer cells exhibit shared characteristics. Both cell types are motile, migratory, and exhibit immune tolerance mechanisms to evade as well as modify the host’s immune response [1]. Proteins typically associated with human embryonic or fetal development are reactivated in cancer cells [2, 3], and may confer tumor cells with invasive potential. One placental protein that is highly expressed in a wide range of human tumors is placenta enriched 1 (PLAC1) [4]. PLAC1 is frequently activated and highly expressed in various tumor types, especially in breast cancer [6,7,8,9] and prostate cancer [10]. The expression of PLAC1 in cancer cells induces cellular and humoral immune responses via activation of cytotoxic T cells and antibody responses to antigen-presenting cells that carry PLAC1-derived peptides, which leads to the elimination of PLAC1-positive cancer cells [11]
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