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The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells.

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.

SUBMITTER: Ritter A

PROVIDER: S-EPMC7664908 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells.

Ritter Andreas A Safdar Babek Khan BK Jasmer Britta B Kreis Nina-Naomi NN Friemel Alexandra A Roth Susanne S Solbach Christine C Louwen Frank F Yuan Juping J

International journal of molecular sciences 20201109 21

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 s ...[more]

PMID: 33182312

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Project description:IntroductionT-cell lymphoma invasion and metastasis-inducing protein (Tiam1) is a Ras-related C3 botulinum toxin substrate (Rac)-specific guanine nucleotide exchange factor that was isolated based on its ability to induce a metastatic phenotype. In polarized migrating keratinocytes, Tiam1 is found at the leading edge where it cooperates with the Protease-activated receptor 1 (Par1) complex to establish front-rear polarity. Although a positive correlation has been observed between Tiam1 expression and tumor grade in a variety of human malignancies, including breast, its role in breast cancer cells has not yet been examined.MethodsTiam1 expression and Rac activity were examined in a panel of human breast cancer cell lines which exhibit different degrees of cell motility. The contribution of Tiam1 to cell motility was directly examined using transwell motility, and wound healing assays.ResultsAlthough we observe a striking, positive correlation between Tiam1 expression and cell motility in the panel of breast cancer cell lines, we do not observe a correlation between Tiam1 expression and overall levels of Rac activity. Consistent with this, small interfering ribonucleic acid (siRNA)-mediated suppression of Tiam1 expression limits the motility of cell lines in which Tiam1 expression is high (MDA-MB-231 and MDA-MB-453), but does not substantially alter the overall levels of activated Rac. Tiam1 overexpression is also not sufficient to increase the motility of more poorly motile cells (T-47D) or increase Rac activity. Immunofluorescence and cellular fractionations indicate that Tiam1 is found predominantly in the Golgi of breast cancer cells, and in the latter case Tiam1 was shown to co-fractionate with a limited pool of Rac1. Consistent with this Golgi localization, Tiam1 supports cell motility and Golgi reorientation in response to serum in a wound healing assay using MDA-MB-231and MDA-MB-435S cells.ConclusionsTiam1 expression correlates with cell motility in human breast cancer cells, and is required to support the motile phenotype. Localization of endogenous Tiam1 to the Golgi, and its demonstrated role in Golgi reorientation, suggest that it may support motility through a mechanism that is discrete from its known function in leading edge dynamics.

Dataset Information

The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells.

Publications

The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells.

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