Cargando…

Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation

Long glucocorticoid-induced leucine zipper (L-GILZ) has recently been implicated in cancer cell proliferation. Here, we investigated its role in human thyroid cancer cells. L-GILZ protein was highly expressed in well-differentiated cancer cells from thyroid cancer patients and differentiated thyroid...

Descripción completa

Detalles Bibliográficos
Autores principales: Ayroldi, Emira, Petrillo, Maria Grazia, Marchetti, Maria Cristina, Cannarile, Lorenza, Ronchetti, Simona, Ricci, Erika, Cari, Luigi, Avenia, Nicola, Moretti, Sonia, Puxeddu, Efisio, Riccardi, Carlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833869/
https://www.ncbi.nlm.nih.gov/pubmed/29467389
http://dx.doi.org/10.1038/s41419-018-0346-y
_version_ 1783303556251516928
author Ayroldi, Emira
Petrillo, Maria Grazia
Marchetti, Maria Cristina
Cannarile, Lorenza
Ronchetti, Simona
Ricci, Erika
Cari, Luigi
Avenia, Nicola
Moretti, Sonia
Puxeddu, Efisio
Riccardi, Carlo
author_facet Ayroldi, Emira
Petrillo, Maria Grazia
Marchetti, Maria Cristina
Cannarile, Lorenza
Ronchetti, Simona
Ricci, Erika
Cari, Luigi
Avenia, Nicola
Moretti, Sonia
Puxeddu, Efisio
Riccardi, Carlo
author_sort Ayroldi, Emira
collection PubMed
description Long glucocorticoid-induced leucine zipper (L-GILZ) has recently been implicated in cancer cell proliferation. Here, we investigated its role in human thyroid cancer cells. L-GILZ protein was highly expressed in well-differentiated cancer cells from thyroid cancer patients and differentiated thyroid cancer cell lines, but poorly expressed in anaplastic tumors. A fusion protein containing L-GILZ, when overexpressed in an L-GILZ-deficient 8505C cell line derived from undifferentiated human thyroid cancer tissue, inhibited cellular proliferation in vitro. In addition, when this protein was injected into nude mice, in which cells from line 8505C had been transplanted, xenograft growth was reduced. Since the mitogen-activated protein kinase (MAPK) pathway is frequently hyperactivated in thyroid cancer cells as a result of the BRAF(V600E) or Ras mutation, we sought to further investigate the role of L-GILZ in the MAPK pathway. To this end, we analyzed L-GILZ expression and function in cells treated with MAPK inhibitors. We used 8505C cells, which have the BRAF(V600E) mutation, or the CAL-62 cell line, which harbors a Ras mutation. The cells were treated with the BRAF-specific drug vemurafenib (PLX4032) or the MEK1/2 inhibitor, U0126, respectively. Treatment with these agents inhibited MAPK activation, reduced cell proliferation, and upregulated L-GILZ expression. L-GILZ silencing reversed the antiproliferative activity of the MAPK inhibitors, consistent with an antiproliferative role. Treatment with MAPK inhibitors led to the phosphorylation of the cAMP/response element-binding protein (CREB), and active CREB bound to the L-GILZ promoter, contributing to its transcription. We suggest that the CREB signaling pathway, frequently deregulated in thyroid tumors, is involved in L-GILZ upregulation and that L-GILZ regulates thyroid cancer cell proliferation, which may have potential in cancer treatment.
format Online
Article
Text
id pubmed-5833869
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-58338692018-03-06 Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation Ayroldi, Emira Petrillo, Maria Grazia Marchetti, Maria Cristina Cannarile, Lorenza Ronchetti, Simona Ricci, Erika Cari, Luigi Avenia, Nicola Moretti, Sonia Puxeddu, Efisio Riccardi, Carlo Cell Death Dis Article Long glucocorticoid-induced leucine zipper (L-GILZ) has recently been implicated in cancer cell proliferation. Here, we investigated its role in human thyroid cancer cells. L-GILZ protein was highly expressed in well-differentiated cancer cells from thyroid cancer patients and differentiated thyroid cancer cell lines, but poorly expressed in anaplastic tumors. A fusion protein containing L-GILZ, when overexpressed in an L-GILZ-deficient 8505C cell line derived from undifferentiated human thyroid cancer tissue, inhibited cellular proliferation in vitro. In addition, when this protein was injected into nude mice, in which cells from line 8505C had been transplanted, xenograft growth was reduced. Since the mitogen-activated protein kinase (MAPK) pathway is frequently hyperactivated in thyroid cancer cells as a result of the BRAF(V600E) or Ras mutation, we sought to further investigate the role of L-GILZ in the MAPK pathway. To this end, we analyzed L-GILZ expression and function in cells treated with MAPK inhibitors. We used 8505C cells, which have the BRAF(V600E) mutation, or the CAL-62 cell line, which harbors a Ras mutation. The cells were treated with the BRAF-specific drug vemurafenib (PLX4032) or the MEK1/2 inhibitor, U0126, respectively. Treatment with these agents inhibited MAPK activation, reduced cell proliferation, and upregulated L-GILZ expression. L-GILZ silencing reversed the antiproliferative activity of the MAPK inhibitors, consistent with an antiproliferative role. Treatment with MAPK inhibitors led to the phosphorylation of the cAMP/response element-binding protein (CREB), and active CREB bound to the L-GILZ promoter, contributing to its transcription. We suggest that the CREB signaling pathway, frequently deregulated in thyroid tumors, is involved in L-GILZ upregulation and that L-GILZ regulates thyroid cancer cell proliferation, which may have potential in cancer treatment. Nature Publishing Group UK 2018-02-21 /pmc/articles/PMC5833869/ /pubmed/29467389 http://dx.doi.org/10.1038/s41419-018-0346-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ayroldi, Emira
Petrillo, Maria Grazia
Marchetti, Maria Cristina
Cannarile, Lorenza
Ronchetti, Simona
Ricci, Erika
Cari, Luigi
Avenia, Nicola
Moretti, Sonia
Puxeddu, Efisio
Riccardi, Carlo
Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
title Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
title_full Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
title_fullStr Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
title_full_unstemmed Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
title_short Long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
title_sort long glucocorticoid-induced leucine zipper regulates human thyroid cancer cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833869/
https://www.ncbi.nlm.nih.gov/pubmed/29467389
http://dx.doi.org/10.1038/s41419-018-0346-y
work_keys_str_mv AT ayroldiemira longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT petrillomariagrazia longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT marchettimariacristina longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT cannarilelorenza longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT ronchettisimona longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT riccierika longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT cariluigi longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT avenianicola longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT morettisonia longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT puxedduefisio longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation
AT riccardicarlo longglucocorticoidinducedleucinezipperregulateshumanthyroidcancercellproliferation