NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.

TitleNF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.
Publication TypeJournal Article
Year of Publication2020
AuthorsSaengboonmee, C, Phoomak, C, Supabphol, S, Covington, KR, Hampton, O, Wongkham, C, Gibbs, RA, Umezawa, K, Seubwai, W, Gingras, M-C, Wongkham, S
JournalLife Sci
Volume262
Pagination118548
Date Published2020 Dec 01
ISSN1879-0631
KeywordsBile Duct Neoplasms, Cell Line, Tumor, Cell Movement, Cholangiocarcinoma, Gene Expression Regulation, Neoplastic, Glucose, Humans, Interleukin-1beta, Neoplasm Invasiveness, NF-kappa B, STAT3 Transcription Factor
Abstract

AIMS: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness.

MAIN METHODS: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence.

KEY FINDINGS: Data indicated that high glucose increased the expression of interleukin-1β (IL-1β), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705.

SIGNIFICANCE: These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia.

DOI10.1016/j.lfs.2020.118548
Alternate JournalLife Sci
PubMed ID33038372
PubMed Central IDPMC7686287
Grant ListU54 HG003273 / HG / NHGRI NIH HHS / United States

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