Abstract
Metastatic carcinoma cells exploit the same molecular machinery that allows human placental cytotrophoblasts to develop an invasive phenotype. As altered expression levels of ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin repeats) subtypes have been associated with cancer progression, we have examined the function and regulation of members of this gene family in epithelial cell invasion using cultures of highly invasive extravillous cytotrophoblasts and the poorly invasive JEG-3 cytotrophoblast cell line as model systems. Of the multiple ADAMTS subtypes identified in first trimester human placenta and these two trophoblastic cell types, only ADAMTS-12 was preferentially expressed by extravillous cytotrophoblasts. Transforming growth factor-β1 and interleukin-1β, two cytokines that promote and restrain cytotrophoblast invasion in vitro, were also found to differentially regulate trophoblastic ADAMTS-12 mRNA levels. Loss- or gain-of-function studies confirmed that ADAMTS-12, independent of its proteolytic activity, plays a specific, non-redundant role in trophoblast invasion. Furthermore, we demonstrated that ADAMTS-12 regulated cell-extracellular matrix adhesion and invasion through a mechanism involving the αvβ3 integrin heterodimer. This study identifies a novel biological role for ADAMTS-12, and highlights the importance and complexity of its non-proteolytic domain(s) pertaining to its function.
Highlights
Human placental development and function are dependent upon mononucleate cytotrophoblasts entering one of two distinct and mutually exclusive differentiation pathways [1,2]
ADAMTS-1, -2, -7, and -9 mRNA levels were significantly lower in Extravillous cytotrophoblast (EVT), whereas there was no significant difference between the levels of the ADAMTS-4 and -6 mRNA transcripts present in these two trophoblastic cell types
The overall biological significance of this expression pattern of ADAMTS proteins in the human placenta remains to be elucidated, our studies demonstrate that ADAMTS-12 plays a non-redundant role in human trophoblastic cell invasion in vitro
Summary
Human placental development and function are dependent upon mononucleate cytotrophoblasts entering one of two distinct and mutually exclusive differentiation pathways [1,2]. Cytotrophoblasts entering the extravillous pathway develop a highly invasive phenotype, which in turn allows these cells to invade deeply into the underlying maternal tissues and vasculature, thereby ensuring a continuous supply of blood to the developing fetus. The onset of trophoblastic cell differentiation along the extravillous pathway is dependent upon the proteolytic degradation and/or activation of distinct extracellular matrix (ECM) components, and regulated changes in cell-cell and cell-ECM interactions [5,6]. There is increasing evidence to suggest that the regulated expression of members of the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin repeats) gene family may represent a significant molecular mechanism for mediation of the terminal differentiation of human cytotrophoblasts and the development of an invasive phenotype
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