Cargando…

A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression

Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CR...

Descripción completa

Detalles Bibliográficos
Autores principales: Saha, Arka, Cheriyamundath, Sanith, Kumar, Anmol, Gavert, Nancy, Brabletz, Thomas, Ben-Ze’ev, Avri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745639/
https://www.ncbi.nlm.nih.gov/pubmed/35008869
http://dx.doi.org/10.3390/ijms23010445
_version_ 1784630393416187904
author Saha, Arka
Cheriyamundath, Sanith
Kumar, Anmol
Gavert, Nancy
Brabletz, Thomas
Ben-Ze’ev, Avri
author_facet Saha, Arka
Cheriyamundath, Sanith
Kumar, Anmol
Gavert, Nancy
Brabletz, Thomas
Ben-Ze’ev, Avri
author_sort Saha, Arka
collection PubMed
description Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis, and liver metastasis, and L1 is exclusively localized at invasive areas of human CRC tissue. Several genes are induced after L1 transfection into CRC cells by a mechanism involving the L1-ezrin-NF-κB pathway. We conducted a secretomic analysis of the proteins in the culture medium of L1-overexpressing CRC cells. We detected a highly increased level of biglycan, a small leucine-rich ECM component, and a signaling molecule. We found that induction of biglycan is required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis, and liver metastasis. The suppression of endogenous biglycan levels or a point mutation in the L1 ectodomain that regulates cell–cell adhesion mediated by L1 blocked the enhanced tumorigenic properties conferred by L1. The mechanism of biglycan induction by L1 involves the L1-NF-κB pathway. Blocking NF-κB signaling in L1 expressing cells suppressed the induction of biglycan and the tumorigenic properties conferred by L1. Biglycan expression was undetectable in the normal colonic mucosa, but expressed at highly increased levels in the tumor tissue, especially in the stroma. The therapeutic strategies to target biglycan expression might provide a useful approach for CRC treatment in L1-overexpressing tumors.
format Online
Article
Text
id pubmed-8745639
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-87456392022-01-11 A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression Saha, Arka Cheriyamundath, Sanith Kumar, Anmol Gavert, Nancy Brabletz, Thomas Ben-Ze’ev, Avri Int J Mol Sci Article Aberrant activation of Wnt/β-catenin signaling and downstream β-catenin-TCF target genes is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin-like cell adhesion receptor L1CAM (L1) as a target of β-catenin-TCF transactivation in CRC cells. Overexpression of L1 in CRC cells confers enhanced proliferation, motility, tumorigenesis, and liver metastasis, and L1 is exclusively localized at invasive areas of human CRC tissue. Several genes are induced after L1 transfection into CRC cells by a mechanism involving the L1-ezrin-NF-κB pathway. We conducted a secretomic analysis of the proteins in the culture medium of L1-overexpressing CRC cells. We detected a highly increased level of biglycan, a small leucine-rich ECM component, and a signaling molecule. We found that induction of biglycan is required for the cellular processes conferred by L1, including enhanced proliferation, motility, tumorigenesis, and liver metastasis. The suppression of endogenous biglycan levels or a point mutation in the L1 ectodomain that regulates cell–cell adhesion mediated by L1 blocked the enhanced tumorigenic properties conferred by L1. The mechanism of biglycan induction by L1 involves the L1-NF-κB pathway. Blocking NF-κB signaling in L1 expressing cells suppressed the induction of biglycan and the tumorigenic properties conferred by L1. Biglycan expression was undetectable in the normal colonic mucosa, but expressed at highly increased levels in the tumor tissue, especially in the stroma. The therapeutic strategies to target biglycan expression might provide a useful approach for CRC treatment in L1-overexpressing tumors. MDPI 2021-12-31 /pmc/articles/PMC8745639/ /pubmed/35008869 http://dx.doi.org/10.3390/ijms23010445 Text en © 2021 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
Saha, Arka
Cheriyamundath, Sanith
Kumar, Anmol
Gavert, Nancy
Brabletz, Thomas
Ben-Ze’ev, Avri
A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression
title A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression
title_full A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression
title_fullStr A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression
title_full_unstemmed A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression
title_short A Necessary Role for Increased Biglycan Expression during L1-Mediated Colon Cancer Progression
title_sort necessary role for increased biglycan expression during l1-mediated colon cancer progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745639/
https://www.ncbi.nlm.nih.gov/pubmed/35008869
http://dx.doi.org/10.3390/ijms23010445
work_keys_str_mv AT sahaarka anecessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT cheriyamundathsanith anecessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT kumaranmol anecessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT gavertnancy anecessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT brabletzthomas anecessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT benzeevavri anecessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT sahaarka necessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT cheriyamundathsanith necessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT kumaranmol necessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT gavertnancy necessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT brabletzthomas necessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression
AT benzeevavri necessaryroleforincreasedbiglycanexpressionduringl1mediatedcoloncancerprogression