CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression.
Hepatol Commun
; 7(7)2023 Jul 01.
Article
in En
| MEDLINE
| ID: mdl-37347224
ABSTRACT
BACKGROUND:
We established a novel diethylnitrosamine (DEN) -induced mouse model that reflected the progression of cholangiocarcinoma (CCA) from atypical cystic hyperplasia.METHODS:
BALB/c mice were administered DEN by oral gavage. Cells isolated from livers were analyzed for expression of CSNK2A1, MAX and MAX-interacting proteins. Human CCA cell lines (MzChA-1, HuCCT1), normal human cholangiocyte (H69), human hepatic stellate cells (LX-2), macrophages (RAW 264.7), and primary hepatic cells were used for cellular and molecular biology assays.RESULTS:
Expression of MAX, CSNK2A1, C-MYC, ß-catenin, HMGB1, and IL-6 was upregulated in hepatic cells from CCA liver tissue. The half-life of MAX is higher in CCA cells, and this favors their proliferation. Overexpression of MAX increased growth, migration, and invasion of MzChA-1, whereas silencing of MAX had the opposite effect. MAX positively regulated IL-6 and HMGB1 through paracrine signaling in HepG2, LX2, and RAW cells and autocrine signaling in MzChA-1 cells. CSNK2A1-mediated MAX phosphorylation shifts MAX-MAX homodimer to C-MYC-MAX and ß-catenin-MAX heterodimers and increases the HMGB1 and IL-6 promoter activities. Increase of MAX phosphorylation promotes cell proliferation, migration, invasion, and cholangiocarcinogenesis. The casein kinase 2 inhibitor CX-4945 induces cell cycle arrest and inhibits cell proliferation, migration, invasion, and carcinogenesis in MzChA-1 cells through the downregulation of CSNK2A1, MAX, and MAX-interaction proteins.CONCLUSION:
C-MYC-MAX and ß-catenin-MAX binding to E-box site or ß-catenin-MAX bound to TCFs/LEF1 enhanced HMGB1 or IL-6 promoter activities, respectively. IL-6 and HMGB1 secreted by hepatocytes, HSCs, and KCs exert paracrine effects on cholangiocytes to promote cell growth, migration, and invasion and lead to the progression of cholangiocarcinogenesis. CX-4945 provides perspectives on therapeutic strategies to attenuate progression from atypical cystic hyperplasia to cholangiocarcinogenesis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Bile Duct Neoplasms
/
Cholangiocarcinoma
/
HMGB1 Protein
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Hepatol Commun
Year:
2023
Document type:
Article
Affiliation country:
United States