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FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer

Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human e...

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Autores principales: Fan, Qipeng, Cai, Qingchun, Xu, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695018/
https://www.ncbi.nlm.nih.gov/pubmed/26299613
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author Fan, Qipeng
Cai, Qingchun
Xu, Yan
author_facet Fan, Qipeng
Cai, Qingchun
Xu, Yan
author_sort Fan, Qipeng
collection PubMed
description Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human epithelial ovarian cancers (EOC). We conducted in vitro mechanistic studies using pharmacological inhibitors, genetic forms of the signaling molecules, and RNAi-mediated gene knock-down to uncover the molecular mechanisms of how these two molecules interact in EOC cells. Additionally, in vivo mouse studies were performed to confirm the functional involvement of FOXM1 in EOC tumor formation and progression. We show for the first time that LPA up-regulates expression of active FOXM1 splice variants in a time- and dose-dependent manner in the human EOC cell lines OVCA433, CAOV3, and OVCAR5. G(i)-PI3K-AKT and G(12/13)-Rho-YAP signaling pathways were both involved in the LPA receptor (LPA(1–3)) mediated up-regulation of FOXM1 at the transcriptional level. In addition, down-regulation of FOXM1 in CAOV3 xenografts significantly reduced tumor and ascites formation, metastasis, and expression of FOXM1 target genes involved in cell proliferation, migration, or invasion. Collectively, our data link the oncolipid LPA, the oncogene YAP, and the central regulator of cell proliferation/mutagenesis FOXM1 in EOC cells. Moreover, these results provide further support for the importance of these pathways as potential therapeutic targets in EOC.
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spelling pubmed-46950182016-01-20 FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer Fan, Qipeng Cai, Qingchun Xu, Yan Oncotarget Research Paper Lysophosphatidic acid (LPA), a prototypical ligand for G protein coupled receptors, and Forkhead box protein M1 (FOXM1), a transcription factor that regulates expression of a wide array of genes involved in cancer initiation and progression, are two important oncogenic signaling molecules in human epithelial ovarian cancers (EOC). We conducted in vitro mechanistic studies using pharmacological inhibitors, genetic forms of the signaling molecules, and RNAi-mediated gene knock-down to uncover the molecular mechanisms of how these two molecules interact in EOC cells. Additionally, in vivo mouse studies were performed to confirm the functional involvement of FOXM1 in EOC tumor formation and progression. We show for the first time that LPA up-regulates expression of active FOXM1 splice variants in a time- and dose-dependent manner in the human EOC cell lines OVCA433, CAOV3, and OVCAR5. G(i)-PI3K-AKT and G(12/13)-Rho-YAP signaling pathways were both involved in the LPA receptor (LPA(1–3)) mediated up-regulation of FOXM1 at the transcriptional level. In addition, down-regulation of FOXM1 in CAOV3 xenografts significantly reduced tumor and ascites formation, metastasis, and expression of FOXM1 target genes involved in cell proliferation, migration, or invasion. Collectively, our data link the oncolipid LPA, the oncogene YAP, and the central regulator of cell proliferation/mutagenesis FOXM1 in EOC cells. Moreover, these results provide further support for the importance of these pathways as potential therapeutic targets in EOC. Impact Journals LLC 2015-06-13 /pmc/articles/PMC4695018/ /pubmed/26299613 Text en Copyright: © 2015 Fan et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Fan, Qipeng
Cai, Qingchun
Xu, Yan
FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
title FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
title_full FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
title_fullStr FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
title_full_unstemmed FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
title_short FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
title_sort foxm1 is a downstream target of lpa and yap oncogenic signaling pathways in high grade serous ovarian cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695018/
https://www.ncbi.nlm.nih.gov/pubmed/26299613
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