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Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

ABSTRACT: The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression, thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.

SUBMITTER: Panupinthu N

PROVIDER: S-EPMC4115609 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

Panupinthu N N Yu S S Zhang D D Zhang F F Gagea M M Lu Y Y Grandis J R JR Dunn S E SE Lee H Y HY Mills G B GB

Oncogene 20130715 22

The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth fa ...[more]

PMID: 23851501

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Project description:Background: A compelling number of studies, conducted in both children and adults, have reported an association between sleep disturbances/circadian sleep alterations and autism spectrum disorder (ASD); however, the data are sparse and the nature of this link is still unclear. The present review aimed to systematically collect the literature data relevant on sleep disturbances and circadian sleep dysrhythmicity related to ASD across all ages and to provide an integrative theoretical framework of their association. Methods: A systematic review of the MEDLINE, PubMed, and Cochrane databases was conducted from November 2018 to February 2019. The search strategies used were MeSH headings and keywords for "sleep-wake circadian rhythms" OR "circadian sleep disorders" OR "sleep-wake pattern" OR "sleep disorders" OR "melatonin" AND "autism spectrum disorder" OR "autism". Results: One hundred and three studies were identified, 15 regarded circadian sleep dysrhythmicity, 74 regarded sleep disturbances, and 17 regarded melatonin alterations in children and adults with ASD. Our findings suggested that autistic subjects frequently present sleep disturbances in particular short sleep duration, low sleep quality/efficiency, and circadian sleep desynchronization such as delayed phases and/or eveningness. Sleep disturbances and circadian sleep alterations have been related to the severity of autistic symptoms. Genetic studies have shown polymorphisms in circadian CLOCK genes and in genes involved in melatonin pathways in subjects with ASD. Conclusions: Sleep disturbances and circadian sleep alterations are frequent in subjects with autistic symptoms. These subjects have shown polymorphisms in clock genes expression and in genes involved in melatonin production. The impairment of circadian sleep regulation may increase the individual's vulnerability to develop symptoms of ASD by altering the sleep regulation in toto, which plays a key role in normal brain development. Even though controversies and "research gaps" are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing feedback loop. By targeting sleep disturbances and circadian sleep dysrhythmicity, we may improve treatment strategies for both children and adults with ASD.

Dataset Information

Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

Publications

Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer.

Similar Datasets

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