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Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas
BACKGROUND: Papillary thyroid carcinoma (PTCs), the most frequent thyroid cancer, is usually not life threatening, but may recur or progress to aggressive forms resistant to conventional therapies. A more detailed understanding of the signaling pathways activated in PTCs may help to identify novel t...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943897/ https://www.ncbi.nlm.nih.gov/pubmed/20877637 http://dx.doi.org/10.1371/journal.pone.0012701 |
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author | Degl'Innocenti, Debora Alberti, Chiara Castellano, Giancarlo Greco, Angela Miranda, Claudia Pierotti, Marco A. Seregni, Ettore Borrello, Maria Grazia Canevari, Silvana Tomassetti, Antonella |
author_facet | Degl'Innocenti, Debora Alberti, Chiara Castellano, Giancarlo Greco, Angela Miranda, Claudia Pierotti, Marco A. Seregni, Ettore Borrello, Maria Grazia Canevari, Silvana Tomassetti, Antonella |
author_sort | Degl'Innocenti, Debora |
collection | PubMed |
description | BACKGROUND: Papillary thyroid carcinoma (PTCs), the most frequent thyroid cancer, is usually not life threatening, but may recur or progress to aggressive forms resistant to conventional therapies. A more detailed understanding of the signaling pathways activated in PTCs may help to identify novel therapeutic approaches against these tumors. The aim of this study is to identify signaling pathways activated in PTCs. METHODOLOGY/PRINCIPAL FINDINGS: We examined coordinated gene expression patterns of ligand/receptor (L/R) pairs using the L/R database DRLP-rev1 and five publicly available thyroid cancer datasets of gene expression on a total of 41 paired PTC/normal thyroid tissues. We identified 26 (up) and 13 (down) L/R pairs coordinately and differentially expressed. The relevance of these L/R pairs was confirmed by performing the same analysis on REarranged during Transfection (RET)/PTC1-infected thyrocytes with respect to normal thyrocytes. TGFA/EGFR emerged as one of the most tightly regulated L/R pair. Furthermore, PTC clinical samples analyzed by real-time RT-PCR expressed EGFR transcript levels similar to those of 5 normal thyroid tissues from patients with pathologies other than thyroid cancer, whereas significantly elevated levels of TGFA transcripts were only present in PTCs. Biochemical analysis of PTC cell lines demonstrated the presence of EGFR on the cell membrane and TGFA in conditioned media. Moreover, conditioned medium of the PTC cell line NIM-1 activated EGFR expressed on HeLa cells, culminating in both ERK and AKT phosphorylation. In NIM-1 cells harboring BRAF mutation, TGFA stimulated proliferation, contributing to PI3K/AKT activation independent of MEK/ERK signaling. CONCLUSIONS/SIGNIFICANCE: We compiled a reliable list of L/R pairs associated with PTC and validated the biological role of one of the emerged L/R pair, the TGFA/EGFR, in this cancer, in vitro. These data provide a better understanding of the factors involved in the biology of PTCs and would be useful in developing combination therapeutic approaches against these cancers. |
format | Text |
id | pubmed-2943897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29438972010-09-28 Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas Degl'Innocenti, Debora Alberti, Chiara Castellano, Giancarlo Greco, Angela Miranda, Claudia Pierotti, Marco A. Seregni, Ettore Borrello, Maria Grazia Canevari, Silvana Tomassetti, Antonella PLoS One Research Article BACKGROUND: Papillary thyroid carcinoma (PTCs), the most frequent thyroid cancer, is usually not life threatening, but may recur or progress to aggressive forms resistant to conventional therapies. A more detailed understanding of the signaling pathways activated in PTCs may help to identify novel therapeutic approaches against these tumors. The aim of this study is to identify signaling pathways activated in PTCs. METHODOLOGY/PRINCIPAL FINDINGS: We examined coordinated gene expression patterns of ligand/receptor (L/R) pairs using the L/R database DRLP-rev1 and five publicly available thyroid cancer datasets of gene expression on a total of 41 paired PTC/normal thyroid tissues. We identified 26 (up) and 13 (down) L/R pairs coordinately and differentially expressed. The relevance of these L/R pairs was confirmed by performing the same analysis on REarranged during Transfection (RET)/PTC1-infected thyrocytes with respect to normal thyrocytes. TGFA/EGFR emerged as one of the most tightly regulated L/R pair. Furthermore, PTC clinical samples analyzed by real-time RT-PCR expressed EGFR transcript levels similar to those of 5 normal thyroid tissues from patients with pathologies other than thyroid cancer, whereas significantly elevated levels of TGFA transcripts were only present in PTCs. Biochemical analysis of PTC cell lines demonstrated the presence of EGFR on the cell membrane and TGFA in conditioned media. Moreover, conditioned medium of the PTC cell line NIM-1 activated EGFR expressed on HeLa cells, culminating in both ERK and AKT phosphorylation. In NIM-1 cells harboring BRAF mutation, TGFA stimulated proliferation, contributing to PI3K/AKT activation independent of MEK/ERK signaling. CONCLUSIONS/SIGNIFICANCE: We compiled a reliable list of L/R pairs associated with PTC and validated the biological role of one of the emerged L/R pair, the TGFA/EGFR, in this cancer, in vitro. These data provide a better understanding of the factors involved in the biology of PTCs and would be useful in developing combination therapeutic approaches against these cancers. Public Library of Science 2010-09-22 /pmc/articles/PMC2943897/ /pubmed/20877637 http://dx.doi.org/10.1371/journal.pone.0012701 Text en Degl'Innocenti et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Degl'Innocenti, Debora Alberti, Chiara Castellano, Giancarlo Greco, Angela Miranda, Claudia Pierotti, Marco A. Seregni, Ettore Borrello, Maria Grazia Canevari, Silvana Tomassetti, Antonella Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas |
title | Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas |
title_full | Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas |
title_fullStr | Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas |
title_full_unstemmed | Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas |
title_short | Integrated Ligand-Receptor Bioinformatic and In Vitro Functional Analysis Identifies Active TGFA/EGFR Signaling Loop in Papillary Thyroid Carcinomas |
title_sort | integrated ligand-receptor bioinformatic and in vitro functional analysis identifies active tgfa/egfr signaling loop in papillary thyroid carcinomas |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943897/ https://www.ncbi.nlm.nih.gov/pubmed/20877637 http://dx.doi.org/10.1371/journal.pone.0012701 |
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