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

Charupong Saengboonmee; Chatchai Phoomak; Suangson Supabphol; Kyle R Covington; Oliver Hampton; Chaisiri Wongkham; Richard A Gibbs; Kazuo Umezawa; Wunchana Seubwai; Marie-Claude Gingras; Sopit Wongkham

doi:10.1016/j.lfs.2020.118548

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

Life Sci. 2020 Dec 1:262:118548. doi: 10.1016/j.lfs.2020.118548. Epub 2020 Oct 7.

Affiliations

¹ Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: [email protected].
² Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.
³ The Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
⁴ Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁵ Department of Molecular Target Medicine, Aichi Medical University, Nagakute 480-1195, Japan.
⁶ Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Forensic Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
⁷ Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: [email protected].

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.

Keywords: Biliary tract cancer; Cholangiocarcinoma; Diabetes mellitus; High glucose; Interleukin-1β; Nuclear factor-κB; STAT3; Transcriptomics.

MeSH terms

Bile Duct Neoplasms / pathology*
Cell Line, Tumor
Cell Movement / physiology
Cholangiocarcinoma / pathology*
Gene Expression Regulation, Neoplastic
Glucose / metabolism
Humans
Interleukin-1beta / genetics
NF-kappa B / metabolism*
Neoplasm Invasiveness
STAT3 Transcription Factor / metabolism*

Substances

Interleukin-1beta
NF-kappa B
STAT3 Transcription Factor
STAT3 protein, human
Glucose

Grants and funding

U54 HG003273/HG/NHGRI NIH HHS/United States