Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

Guyer, Richard A.; Macara, Ian G.

doi:10.1074/jbc.m114.621011

Cited by 33 publications

(26 citation statements)

References 57 publications

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“…Therefore, Par3 may exert its oncogenic potential through the STAT3 pathway in a subset of ovarian cancer cells that are similar to JHOC5 cells. Although at present, we have not been able to investigate the mechanism by which Par3 regulates the IL-6/STAT3 pathway, previous studies have shown that the Par3 complex has a strong relationship with the STAT3-IL-6 axis in mammalian cells [32]. Here, we provide the first indication that Par3 is associated with ovarian cancer progression through the IL-6/STAT3 pathway.…”

Section: Discussionmentioning

confidence: 61%

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Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

et al. 2016

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BackgroundPrevious studies have shown that the cell polarity protein partitioning defective 3 (Par3) plays an essential role in the formation of tight junctions and definition of apical-basal polarity. Aberrant function of this protein has been reported to be involved in epithelial–mesenchymal transition (EMT) and cancer invasion. The aim of this study was to examine the functional mechanism of Par3 in ovarian cancer.MethodsFirst, we investigated the association between Par3 expression level and survival of 50 ovarian cancer patients. Next, we conducted an in vitro analysis of ovarian cancer cell lines, focusing on the cell line JHOC5, to investigate Par3 function. To investigate the function of Par3 in invasion, the IL-6/STAT3 pathway was analyzed upon Par3 knockdown with siRNA. The effect of siRNA treatment was assessed by qPCR, ELISA, and western blotting. Invasiveness and cell proliferation following treatment with siRNA against Par3 were investigated using Matrigel chamber, wound healing, and cell proliferation assays.ResultsExpression array data for ovarian cancer patient samples revealed low Par3 expression was significantly associated with good prognosis. Univariate analysis of clinicopathological factors revealed significant association between high Par3 levels and peritoneal dissemination at the time of diagnosis. Knockdown of Par3 in JHOC5 cells suppressed cell invasiveness, migration, and cell proliferation with deregulation of IL-6/STAT3 activity.ConclusionTaken together, these results suggest that Par3 expression is likely involved in ovarian cancer progression, especially in peritoneal metastasis. The underlying mechanism may be that Par3 modulates IL-6 /STAT3 signaling. Here, we propose that the expression of Par3 in ovarian cancer may control disease outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2929-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 61%

“…The detailed mechanism of how Par3 is involved in tumorigenesis and invasion may depend on tumor type and is still to be elucidated. The Rac1/JNK proliferation pathway and the IL-6/STAT3 pathway may be key for understanding the functions of Par3 in promoting cancer growth [22, 25, 31, 32]. …”

Section: Introductionmentioning

confidence: 99%

Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

et al. 2016

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“…Our novel data demonstrate strong inverted correlations among the BAY 11‐7082‐induced levels of the analysed tumour suppressors” miR‐34a, miR‐375 and miR451a, and NF‐κB‐related genes, such as RELA(p65), STAT3, TNF‐α, IL‐6 and IL‐1β, that previous studies documented as crucial mediators of inflammatory and neoplastic events in head and neck cancer35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 (Figure 7). In line with our recent study,33 our current data suggest that NF‐κB inhibition may reverse acidic bile‐induced molecular events in normal human hypopharyngeal cells that are known to link inflammation to cancer, thereby in a sense shielding HHPC from the effects of bile‐induced oncogenic molecular events.…”

Section: Discussionmentioning

confidence: 69%

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

Doukas¹,

Vageli²,

Sasaki³

2018

J Cellular Molecular Medi

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We previously demonstrated that acidic bile activates NF‐κB, deregulating the expression of oncogenic miRNA markers, in pre‐malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer‐related miRNA markers that can be reversed by BAY 11‐7082, a pharmacologic NF‐κB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 μmol/L), at pH 4.0 and 7.0, with/without BAY 11‐7082 (20 μmol/L). We centred our study on the transcriptional activation of oncogenic miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375, miR‐451a and NF‐κB‐related genes, previously linked to acidic bile‐induced pre‐neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11‐7082 significantly reverses the acidic bile‐induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11‐7082 strongly inhibits the acidic bile‐induced up‐regulation of miR‐192 and down‐regulation of miR‐451a and significantly decreases the miR‐21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile‐induced events are directly or indirectly dependent on NF‐κB signalling.

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“…Of note, others have reported that Par3 inhibits NFκB activation in polarized epithelial cells by restricting aPKC activation. Thus Par3 may intersect with NFκB signaling in multiple ways (Mashukova et al , 2011; Forteza et al , 2013; Guyer and Macara, 2015). It may be important to examine the interplay between aPKC and Par3 in future studies.…”

Section: Resultsmentioning

confidence: 99%

Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity

Ruch

Bryant

Mostov

et al. 2017

MBoC

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Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

Cited by 33 publications

References 57 publications

Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

Expression of Par3 polarity protein correlates with poor prognosis in ovarian cancer

NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

Par3 integrates Tiam1 and phosphatidylinositol 3-kinase signaling to change apical membrane identity

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