Abstract
Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, its expression is deregulated in preeclamptic placentas. We have reported that BCL6 is required for the proliferation, survival, fusion, and syncytialization of trophoblasts. In the present work, we show that the inhibition of BCL6, either by its gene silencing or by using specific small molecule inhibitors, impairs the migration and invasion of trophoblastic cells, by reducing cell adhesion and compromising the dynamics of the actin cytoskeleton. Moreover, the suppression of BCL6 weakens the signals of the phosphorylated focal adhesion kinase, Akt/protein kinase B, and extracellular regulated kinase 1/2, accompanied by more stationary, but less migratory, cells. Interestingly, transcriptomic analyses reveal that a small interfering RNA-induced reduction of BCL6 decreases the levels of numerous genes, such as p21 activated kinase 1, myosin light chain kinase, and gamma actin related to cell adhesion, actin dynamics, and cell migration. These data suggest BCL6 as a crucial player in the migration and invasion of trophoblasts in the early stages of placental development through the regulation of various genes associated with the migratory machinery.
Highlights
The oncogene B-cell lymphoma 6 (BCL6), which is a crucial regulator of B-lymphocyte development, is a transcriptional modulator and often deregulated in lymphomas [1,2]
To examine whether BCL6 is expressed in early extravillous trophoblasts (EVTs), placental tissue sections from first trimester placentas were immunohistochemically stained for BCL6
In support of this assumption, our transcriptome analysis reveals that multiple important genes responsible for cell adhesion formation and its turnover, such as thrombospondin 2 and 3, which are mediators of cell adhesion and extracellular matrix remodeling [52]; matrix metalloproteinase-2 (MMP2), which is a crucial player in the breakdown of the ECM [53]; and caveolin 1 (CAV1), which is a promoter of cell adhesion [54], are downregulated in HTR cells depleted of BCL6, suggesting that these genes are regulated by BCL6, either directly or indirectly
Summary
The oncogene B-cell lymphoma 6 (BCL6), which is a crucial regulator of B-lymphocyte development, is a transcriptional modulator and often deregulated in lymphomas [1,2]. Along with B-cell activation and differentiation, BCL6 plays roles in the DNA damage response, cell cycle regulation, and apoptosis induction of lymphocytes [3,4], as well as in the invasion and migration of breast cancer cells [5]. In ovarian and breast tissues, deregulated BCL6 blocks the differentiation of epithelial cells, supporting malignant progression [2,6,7]. BCL6 promotes proliferation [14] and affects the fusion of villous trophoblastic cells (vCTBs) [15]. BCL6 is highly expressed in EVT cell line
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