Cargando…

CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Bing, Zhang, Jing, Wang, Jiaohong, Fan, Wei, Barbier-Torres, Lucía, Yang, Xi, Justo, Monica Anne R., Liu, Ting, Chen, Yongheng, Steggerda, Justin, Ramani, Komal, Lu, Shelly C., Yang, Heping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10289747/
https://www.ncbi.nlm.nih.gov/pubmed/37347224
http://dx.doi.org/10.1097/HC9.0000000000000144
_version_ 1785062347118739456
author Yang, Bing
Zhang, Jing
Wang, Jiaohong
Fan, Wei
Barbier-Torres, Lucía
Yang, Xi
Justo, Monica Anne R.
Liu, Ting
Chen, Yongheng
Steggerda, Justin
Ramani, Komal
Lu, Shelly C.
Yang, Heping
author_facet Yang, Bing
Zhang, Jing
Wang, Jiaohong
Fan, Wei
Barbier-Torres, Lucía
Yang, Xi
Justo, Monica Anne R.
Liu, Ting
Chen, Yongheng
Steggerda, Justin
Ramani, Komal
Lu, Shelly C.
Yang, Heping
author_sort Yang, Bing
collection PubMed
description 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, β-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 β-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 β-catenin-MAX binding to E-box site or β-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.
format Online
Article
Text
id pubmed-10289747
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Lippincott Williams & Wilkins
record_format MEDLINE/PubMed
spelling pubmed-102897472023-06-24 CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression Yang, Bing Zhang, Jing Wang, Jiaohong Fan, Wei Barbier-Torres, Lucía Yang, Xi Justo, Monica Anne R. Liu, Ting Chen, Yongheng Steggerda, Justin Ramani, Komal Lu, Shelly C. Yang, Heping Hepatol Commun Original Article 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, β-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 β-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 β-catenin-MAX binding to E-box site or β-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. Lippincott Williams & Wilkins 2023-06-22 /pmc/articles/PMC10289747/ /pubmed/37347224 http://dx.doi.org/10.1097/HC9.0000000000000144 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (https://creativecommons.org/licenses/by/4.0/) (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Original Article
Yang, Bing
Zhang, Jing
Wang, Jiaohong
Fan, Wei
Barbier-Torres, Lucía
Yang, Xi
Justo, Monica Anne R.
Liu, Ting
Chen, Yongheng
Steggerda, Justin
Ramani, Komal
Lu, Shelly C.
Yang, Heping
CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression
title CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression
title_full CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression
title_fullStr CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression
title_full_unstemmed CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression
title_short CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression
title_sort csnk2a1-mediated max phosphorylation upregulates hmgb1 and il-6 expression in cholangiocarcinoma progression
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10289747/
https://www.ncbi.nlm.nih.gov/pubmed/37347224
http://dx.doi.org/10.1097/HC9.0000000000000144
work_keys_str_mv AT yangbing csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT zhangjing csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT wangjiaohong csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT fanwei csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT barbiertorreslucia csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT yangxi csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT justomonicaanner csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT liuting csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT chenyongheng csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT steggerdajustin csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT ramanikomal csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT lushellyc csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression
AT yangheping csnk2a1mediatedmaxphosphorylationupregulateshmgb1andil6expressionincholangiocarcinomaprogression