Loss of the predicted cell adhesion molecule MPZL3 promotes EMT and chemoresistance in ovarian cancer
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ABSTRACT:
PROVIDER: PRJNA1258277 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33415084_1.fastq.gz | Fastqsanger.gz | |||
| SRR33415084_2.fastq.gz | Fastqsanger.gz | |||
| SRR33415085_1.fastq.gz | Fastqsanger.gz | |||
| SRR33415085_2.fastq.gz | Fastqsanger.gz | |||
| SRR33415086_1.fastq.gz | Fastqsanger.gz |
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Project description:Myelin protein zero-like 3 (MPZL3) is an Immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, where the MPZL3 gene resides, is frequently observed in cancer. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, where both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. While high and low MPZL3 expressing populations are similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely display decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knock-down leads to an increase in EMT gene expression in OVCAR4 and OVCA433 cell lines, a transcript signature that is associated with poor patient outcomes. MPZL3 promotes homotypic cancer cell adhesion in some cell lines, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. Conversely, MPZL3 loss abrogates cell cycle progression and proliferation. This was associated with increased resistance to cisplatin and olaparib and reduced DNA damage and apoptosis in response to these agents in OVCAR4 cells. Enhanced cisplatin resistance was further validated in vivo. These data demonstrate for the first time that loss of the predicted adhesion molecule MPZL3 results in EMT and decreased proliferation in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients.
2025-05-06 | GSE296256 | GEO
Project description:Loss of the predicted cell adhesion molecule MPZL3 promotes EMT in OVCAR4 cells
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Project description:Myelin protein zero-like 3 (MPZL3) is an Immunoglobulin-containing transmembrane protein with predicted cell adhesion molecule function. Loss of 11q23, where the MPZL3 gene resides, is frequently observed in cancer. Yet the role and consequences of altered MPZL3 expression have not been explored in tumor development and progression. We addressed this in ovarian cancer, where both MPZL3 amplification and deletions are observed in respective subsets of high-grade serous specimens. While high and low MPZL3 expressing populations are similarly observed in primary ovarian tumors from an independent patient cohort, metastatic omental tumors largely display decreased MPZL3 expression, suggesting that MPZL3 loss is associated with metastatic progression. MPZL3 knock-down leads to an increase in EMT gene expression in OVCAR4 and OVCA433 cell lines, a transcript signature that is associated with poor patient outcomes. MPZL3 promotes homotypic cancer cell adhesion in some cell lines, and decreasing MPZL3 expression enhances invasion and clearance of mesothelial cell monolayers. Conversely, MPZL3 loss abrogates cell cycle progression and proliferation. This was associated with increased resistance to cisplatin and olaparib and reduced DNA damage and apoptosis in response to these agents in OVCAR4 cells. Enhanced cisplatin resistance was further validated in vivo. These data demonstrate for the first time that loss of the predicted adhesion molecule MPZL3 results in EMT and decreased proliferation in ovarian cancer. Our study suggests that decreased MPZL3 expression is a phenotype of ovarian cancer tumor progression and metastasis and may contribute to treatment failure in advanced-stage patients.
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Project description:Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the central nervous system. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 T helper (Th)17 cells can directly interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we conducted single cell RNA sequencing of human primary oligodendrocytes cultured alone, in contact or separated by an insert with primary Th17 polarized T cells and identified several cell adhesion molecules that may modulate T cell contact mediated damage of oligodendrocytes. Furthermore, we used flow cytometry and immunofluorescence studies on central nervous system tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule and activated leukocyte cell adhesion molecule in multiple sclerosis, EAE and controls although their regulation differ between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of melanoma cell adhesion molecule but not activated leukocyte cell adhesion molecule at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live-imaging, immunofluorescence, and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking activated leukocyte cell adhesion molecule but not melanoma cell adhesion molecule limited prolonged interactions between oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferred significant protection of oligodendrocytic processes.
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2014-04-09 | E-GEOD-55604 | biostudies-arrayexpress
Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound.
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