Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation

Alex Shimura Yamashita, Murilo Vieira Geraldo, Cesar Seigi Fuziwara, Marco Aurélio Vamondes Kulcsar, Celso Ubirajara Moretto Friguglietti, Ricardo Borges da Costa, Gilson Soares Baia, Edna Teruko Kimura

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)197-205
Number of pages9
JournalTranslational Oncology
Volume6
Issue number2
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Yamashita, A. S., Geraldo, M. V., Fuziwara, C. S., Kulcsar, M. A. V., Friguglietti, C. U. M., da Costa, R. B., Baia, G. S., & Kimura, E. T. (2013). Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Translational Oncology, 6(2), 197-205. https://doi.org/10.1593/tlo.12442