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

Alex Shimura Yamashita1, Murilo Vieira Geraldo, Cesar Seigi Fuziwara

  • 1Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, Sã Paulo, Brazil.

Translational Oncology
|April 2, 2013
PubMed

Insights

Mitogen-activated protein kinase (MAPK) pathway activation drives papillary thyroid cancer (PTC) by upregulating Notch signaling. Inhibiting Notch or MAPK pathways suppressed PTC cell growth, suggesting Notch as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Papillary thyroid carcinomas (PTCs) frequently exhibit activated mitogen-activated protein kinase (MAPK) signaling due to genetic alterations in RET, RAS, or BRAF.
  • The impact of MAPK pathway activation on other oncogenic pathways, like Notch signaling, in PTC remains largely uncharacterized.

Purpose of the Study:

  • To investigate if the MAPK pathway regulates Notch signaling in PTC.
  • To determine the role of Notch signaling in PTC cell proliferation.

Main Methods:

  • Conditional induction of MAPK signaling oncogenes (RET/PTC3, BRAF(T1799A)) in rat thyroid cells.
  • Pharmacological inhibition of MAPK and Notch signaling (using γ-secretase inhibitor - GSI).
  • Analysis of Notch1 and Hes1 expression in cell lines and tumor samples; assessment of PTC cell proliferation.

Main Results:

  • MAPK activation (RET/PTC3, BRAF(T1799A)) led to increased Notch signaling, evidenced by elevated Notch1 receptor and Hes1 expression.
  • MAPK inhibition reduced Notch signaling in PTC cells.
  • High Notch1 expression was observed in BRAF(T1799A) transgenic mouse tumors and human PTC samples.
  • Down-regulating Notch signaling (via GSI or NOTCH1 RNA interference) decreased PTC cell proliferation.
  • Combined GSI and MAPK inhibition synergistically suppressed PTC cell growth.

Conclusions:

  • RET/PTC and BRAF(T1799A) oncogenes activate Notch signaling, contributing to thyroid follicular cell tumor growth.
  • Notch signaling represents a potential therapeutic target for adjuvant therapy in papillary thyroid cancer.

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