Notch Pathway Is Activated by MAPK Signaling and Influences Papillary Thyroid Cancer Proliferation
| Autor: | Celso U. M. Friguglietti, Gilson S. Baia, Murilo Vieira Geraldo, Alex Shimura Yamashita, Cesar Seigi Fuziwara, Marco Aurélio Vamondes Kulcsar, Ricardo Borges da Costa, Edna Teruko Kimura |
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| Jazyk: | angličtina |
| Předmět: |
MAPK/ERK pathway
Cancer Research medicine.medical_specialty endocrine system endocrine system diseases business.industry Notch signaling pathway medicine.disease Follicular cell Papillary thyroid cancer Endocrinology Oncology Hes3 signaling axis Internal medicine medicine Cancer research Cyclin-dependent kinase 8 HES1 Signal transduction business |
| Zdroj: | Translational Oncology. (2):197-IN22 |
| ISSN: | 1936-5233 |
| DOI: | 10.1593/tlo.12442 |
| Popis: | Mutually exclusive genetic alterations in the RET, RAS, or BRAF genes, which result in constitutively active mitogen-activated 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. |
| Databáze: | OpenAIRE |
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