Targeting STAT3 prevents bile reflux-induced oncogenic molecular events linked to hypopharyngeal carcinogenesis.
Nifuroxazide
SI3-201
STA-21
STAT3
STAT3 inhibition
bile reflux
gastro-oesophageal reflux
head and neck cancer
hypopharyngeal cancer
laryngopharyngeal reflux
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
04
10
2021
received:
29
06
2021
accepted:
06
10
2021
pubmed:
2
12
2021
medline:
1
4
2022
entrez:
1
12
2021
Statut:
ppublish
Résumé
The signal transducer and activator of transcription 3 (STAT3) oncogene is a transcription factor with a central role in head and neck cancer. Hypopharyngeal cells (HCs) exposed to acidic bile present aberrant activation of STAT3, possibly contributing to its oncogenic effect. We hypothesized that STAT3 contributes substantially to the bile reflux-induced molecular oncogenic profile, which can be suppressed by STAT3 silencing or pharmacological inhibition. To explore our hypothesis, we targeted the STAT3 pathway, by knocking down STAT3 (STAT3 siRNA), and inhibiting STAT3 phosphorylation (Nifuroxazide) or dimerization (SI3-201; STA-21), in acidic bile (pH 4.0)-exposed human HCs. Immunofluorescence, luciferase assay, Western blot, enzyme-linked immunosorbent assay and qPCR analyses revealed that STAT3 knockdown or pharmacologic inhibition significantly suppressed acidic bile-induced STAT3 activation and its transcriptional activity, Bcl-2 overexpression, transcriptional activation of IL6, TNF-α, BCL2, EGFR, STAT3, RELA(p65), REL and WNT5A, and cell survival. Our novel findings document the important role of STAT3 in bile reflux-related molecular oncogenic events, which can be dramatically prevented by STAT3 silencing. STA-21, SI3-201 or Nifuroxazide effectively inhibited STAT3 and cancer-related inflammatory phenotype, encouraging their single or combined application in preventive or therapeutic strategies of bile reflux-related hypopharyngeal carcinogenesis.
Identifiants
pubmed: 34850540
doi: 10.1111/jcmm.17011
pmc: PMC8742186
doi:
Substances chimiques
NF-kappa B
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
75-87Informations de copyright
© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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