FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer
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Qipeng Fan1, Qingchun Cai1, Yan Xu1
1Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Yan Xu, e-mail: [email protected]
Keywords: EOC (epithelial ovarian cancer), FOXM1, HGSC (high grade serous ovarian cancer), LPA (lysophosphatidic acid), YAP (yes-associated protein)
Received: April 14, 2015 Accepted: June 01, 2015 Published: June 13, 2015
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. Gi-PI3K-AKT and G12/13-Rho-YAP signaling pathways were both involved in the LPA receptor (LPA1–3) 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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