STAT3 cooperates with the non-canonical NF-κB signaling to regulate pro-labor genes in the human placenta

TY - JOUR

T1 - STAT3 cooperates with the non-canonical NF-κB signaling to regulate pro-labor genes in the human placenta

AU - Yu, L. J.

AU - Parobchak, N.

AU - Roche, N.

AU - Rosen, T.

N1 - Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Abstract Introduction Our recent studies have shown that constitutively activated non-canonical RelB/NF-κB2 (p52) in the human placenta positively regulates the pro-labor genes CRH and COX-2. STAT3 regulates NF-κB2 (p100) processing to active p52, and in turn, nuclear activation of RelB/p52, by directly binding to p100/p52 in a variety of cancer cells. In the current study, we tested the hypothesis that STAT3 is involved in regulation of pro-labor genes by associating with RelB/p52 heterodimers in the human placenta. Methods We used a variety of techniques including immunohistochemical staining, gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, RT-qPCR, and immunofluorescence assays in primary culture of cytotrophoblast and placental tissues. Results We found that knockdown of STAT3 led to down-regulation of both CRH and COX-2 in a dose-dependent manner. By using chromatin immunoprecipitation, we further showed that interaction of RelB with the CRH or COX-2 gene promoters decreased when STAT3 was depleted. Immunofluorescence demonstrated co-localization of STAT3 with RelB or p100/p52 in both the cytoplasm and nucleus of term cytotrophoblasts. Discussion Collectively, these results suggest that STAT3 constitutes part of the RelB/p52-containing activator complex that positively regulates pro-labor genes in the human placenta.

AB - Abstract Introduction Our recent studies have shown that constitutively activated non-canonical RelB/NF-κB2 (p52) in the human placenta positively regulates the pro-labor genes CRH and COX-2. STAT3 regulates NF-κB2 (p100) processing to active p52, and in turn, nuclear activation of RelB/p52, by directly binding to p100/p52 in a variety of cancer cells. In the current study, we tested the hypothesis that STAT3 is involved in regulation of pro-labor genes by associating with RelB/p52 heterodimers in the human placenta. Methods We used a variety of techniques including immunohistochemical staining, gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, RT-qPCR, and immunofluorescence assays in primary culture of cytotrophoblast and placental tissues. Results We found that knockdown of STAT3 led to down-regulation of both CRH and COX-2 in a dose-dependent manner. By using chromatin immunoprecipitation, we further showed that interaction of RelB with the CRH or COX-2 gene promoters decreased when STAT3 was depleted. Immunofluorescence demonstrated co-localization of STAT3 with RelB or p100/p52 in both the cytoplasm and nucleus of term cytotrophoblasts. Discussion Collectively, these results suggest that STAT3 constitutes part of the RelB/p52-containing activator complex that positively regulates pro-labor genes in the human placenta.

KW - Non-canonical NF-kB

KW - Pro-labor genes

KW - STAT3

UR - https://www.scopus.com/pages/publications/84927000453

UR - https://www.scopus.com/pages/publications/84927000453#tab=citedBy

U2 - 10.1016/j.placenta.2015.02.013

DO - 10.1016/j.placenta.2015.02.013

M3 - Article

C2 - 25771405

SN - 0143-4004

VL - 36

SP - 581

EP - 586

JO - Placenta

JF - Placenta

IS - 5

M1 - 3168

ER -