CTCFL regulates the PI3K-Akt pathway and it is a target for personalized ovarian cancer therapy
Por:
Salgado-Albarrán M., Späth J., González-Barrios R., Baumbach J., Soto-Reyes E.
Publicada:
1 ene 2022
Resumen:
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy due to the lack of reliable biomarkers, effective treatment, and chemoresistance. Improving the diagnosis and the development of targeted therapies is still needed. The molecular pathomechanisms driving HGSC progression are not fully understood though crucial for effective diagnosis and identification of novel targeted therapy options. The oncogene CTCFL (BORIS), the paralog of CTCF, is a transcriptional factor highly expressed in ovarian cancer (but in rarely any other tissue in females) with cancer-specific characteristics and therapeutic potential. In this work, we seek to understand the regulatory functions of CTCFL to unravel new target genes with clinical relevance. We used in vitro models to evaluate the transcriptional changes due to the presence of CTCFL, followed by a selection of gene candidates using de novo network enrichment analysis. The resulting mechanistic candidates were further assessed regarding their prognostic potential and druggability. We show that CTCFL-driven genes are involved in cytoplasmic membrane functions; in particular, the PI3K-Akt initiators EGFR1 and VEGFA, as well as ITGB3 and ITGB6 are potential drug targets. Finally, we identified the CTCFL targets ACTBL2, MALT1 and PCDH7 as mechanistic biomarkers to predict survival in HGSC. Finally, we elucidated the value of CTCFL in combination with its targets as a prognostic marker profile for HGSC progression and as putative drug targets. © 2022, The Author(s).
Filiaciones:
Salgado-Albarrán M.:
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa (UAM-C), Mexico City, Mexico
Chair of Experimental Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany
Späth J.:
Chair of Computational Systems Biology, University of Hamburg, Hamburg, Germany
González-Barrios R.:
Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, Mexico City, Mexico
Baumbach J.:
Chair of Computational Systems Biology, University of Hamburg, Hamburg, Germany
Computational BioMedicine Lab, Institute of Mathematics and Computer Science, University of Southern Denmark, Odense, Denmark
Soto-Reyes E.:
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa (UAM-C), Mexico City, Mexico
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