Cargando…
Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways
Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented i...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875272/ https://www.ncbi.nlm.nih.gov/pubmed/35207462 http://dx.doi.org/10.3390/life12020174 |
_version_ | 1784657878667231232 |
---|---|
author | Khiaowichit, Juthamas Talabnin, Chutima Dechsukhum, Chavaboon Silsirivanit, Atit Talabnin, Krajang |
author_facet | Khiaowichit, Juthamas Talabnin, Chutima Dechsukhum, Chavaboon Silsirivanit, Atit Talabnin, Krajang |
author_sort | Khiaowichit, Juthamas |
collection | PubMed |
description | Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway. |
format | Online Article Text |
id | pubmed-8875272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88752722022-02-26 Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways Khiaowichit, Juthamas Talabnin, Chutima Dechsukhum, Chavaboon Silsirivanit, Atit Talabnin, Krajang Life (Basel) Article Alteration of mucin-type O-glycosylation is implicated in tumor progression and metastasis of cholangiocarcinoma (CCA). Core 1 β1-3 Galactosyltransferase (C1GALT1) is a primary enzyme that regulates the elongation of core 1-derived mucin-type O-glycans. Dysregulation of C1GALT1 has been documented in multiple cancers and is associated with aberrant core 1 O-glycosylation and cancer aggressiveness; however, the expression of C1GALT1 and its role in CCA progression remains unknown. Our study demonstrated that C1GALT1 was downregulated in CCA tissues at both the mRNA and protein levels. The biological function of C1GALT1 using siRNA demonstrated that suppression of C1GALT1 in the CCA cell lines (KKU-055 and KKU-100) increased CCA progression, evidenced by: (i) Induction of CCA cell proliferation and 5-fluorouracil resistance in a dose-dependent manner; (ii) up-regulation of growth-related genes, ABC transporter genes, and anti-apoptotic proteins; and (iii) an increase in the activation/phosphorylation of AKT and ERK in silencing C1GALT1 cells. We demonstrated that silencing C1GALT1 in CCA cell lines was associated with immature core 1 O-glycosylation, demonstrated by high expression of VVL-binding glycans and down-regulation of other main O-linked glycosyltransferases β1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) in C1GALT1 knockdown. Our findings demonstrate that down-regulation of C1GALT1 in CCA increases the expression of immature core 1 O-glycan, enhancing CCA progression, including growth and 5-fluorouracil resistance via the activation of the AKT/ERK signaling pathway. MDPI 2022-01-25 /pmc/articles/PMC8875272/ /pubmed/35207462 http://dx.doi.org/10.3390/life12020174 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Khiaowichit, Juthamas Talabnin, Chutima Dechsukhum, Chavaboon Silsirivanit, Atit Talabnin, Krajang Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
title | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
title_full | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
title_fullStr | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
title_full_unstemmed | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
title_short | Down-Regulation of C1GALT1 Enhances the Progression of Cholangiocarcinoma through Activation of AKT/ERK Signaling Pathways |
title_sort | down-regulation of c1galt1 enhances the progression of cholangiocarcinoma through activation of akt/erk signaling pathways |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8875272/ https://www.ncbi.nlm.nih.gov/pubmed/35207462 http://dx.doi.org/10.3390/life12020174 |
work_keys_str_mv | AT khiaowichitjuthamas downregulationofc1galt1enhancestheprogressionofcholangiocarcinomathroughactivationofakterksignalingpathways AT talabninchutima downregulationofc1galt1enhancestheprogressionofcholangiocarcinomathroughactivationofakterksignalingpathways AT dechsukhumchavaboon downregulationofc1galt1enhancestheprogressionofcholangiocarcinomathroughactivationofakterksignalingpathways AT silsirivanitatit downregulationofc1galt1enhancestheprogressionofcholangiocarcinomathroughactivationofakterksignalingpathways AT talabninkrajang downregulationofc1galt1enhancestheprogressionofcholangiocarcinomathroughactivationofakterksignalingpathways |