TY - JOUR
T1 - Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation
AU - Yamashita, Alex Shimura
AU - Geraldo, Murilo Vieira
AU - Fuziwara, Cesar Seigi
AU - Kulcsar, Marco Aurélio Vamondes
AU - Friguglietti, Celso Ubirajara Moretto
AU - da Costa, Ricardo Borges
AU - Baia, Gilson Soares
AU - Kimura, Edna Teruko
N1 - Funding Information:
Address all correspondence to: Edna T. Kimura, MD, PhD, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Av. Professor Lineu Prestes, 1524, Room 414, 05508000 Sao Paulo, SP, Brazil. E-mail: etkimura@usp.br 1This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work. 2This article refers to supplementary materials, which are designated by Table W1 and Figures W1 and W2 and are available online at www.transonc.com. Received 29 November 2012; Revised 4 January 2013; Accepted 8 January 2013 Copyright © 2013 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124/13 DOI 10.1593/tlo.12442
PY - 2013/4
Y1 - 2013/4
N2 - Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogenactivated protein kinase (MAPK) signaling, are present in about 70%of papillary thyroid carcinomas (PTCs). However, the effect of MAPK activation on other signaling pathways involved in oncogenic transformation, such as Notch, remains unclear. In this study, we tested the hypothesis that the MAPK pathway regulates Notch signaling and that Notch signaling plays a role in PTC cell proliferation. Conditional induction of MAPK signaling oncogenes RET/PTC3 or BRAFT1799A in normal rat thyroid cell line mediated activation of Notch signaling, upregulating Notch1 receptor and Hes1, the downstream effector of Notch pathway. Conversely, pharmacological inhibition of MAPK reduced Notch signaling in PTC cell. Thyroid tumor samples from transgenic mice expressing BRAFT1799A and primary human PTC samples showed high levels of Notch1 expression. Down-regulation of Notch signaling by γ-secretase inhibitor (GSI) or NOTCH1 RNA interference reduces PTC cell proliferation. Moreover, the combination of GSI with a MAPK inhibitor enhanced the growth suppression in PTC cells. This study revealed that RET/PTC and BRAFT1799A activate Notch signaling and promote tumor growth in thyroid follicular cell. Taken together, these data suggest that Notch signaling may be explored as an adjuvant therapy for thyroid papillary cancer.
AB - Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogenactivated protein kinase (MAPK) signaling, are present in about 70%of papillary thyroid carcinomas (PTCs). However, the effect of MAPK activation on other signaling pathways involved in oncogenic transformation, such as Notch, remains unclear. In this study, we tested the hypothesis that the MAPK pathway regulates Notch signaling and that Notch signaling plays a role in PTC cell proliferation. Conditional induction of MAPK signaling oncogenes RET/PTC3 or BRAFT1799A in normal rat thyroid cell line mediated activation of Notch signaling, upregulating Notch1 receptor and Hes1, the downstream effector of Notch pathway. Conversely, pharmacological inhibition of MAPK reduced Notch signaling in PTC cell. Thyroid tumor samples from transgenic mice expressing BRAFT1799A and primary human PTC samples showed high levels of Notch1 expression. Down-regulation of Notch signaling by γ-secretase inhibitor (GSI) or NOTCH1 RNA interference reduces PTC cell proliferation. Moreover, the combination of GSI with a MAPK inhibitor enhanced the growth suppression in PTC cells. This study revealed that RET/PTC and BRAFT1799A activate Notch signaling and promote tumor growth in thyroid follicular cell. Taken together, these data suggest that Notch signaling may be explored as an adjuvant therapy for thyroid papillary cancer.
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U2 - 10.1593/tlo.12442
DO - 10.1593/tlo.12442
M3 - Article
AN - SCOPUS:84875767339
SN - 1944-7124
VL - 6
SP - 197
EP - 205
JO - Translational Oncology
JF - Translational Oncology
IS - 2
ER -