The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met

Ashley J. Williamson, Michelle E. Doscas, Jin Ye, Katherine B. Heiden, Michael Mingzhao Xing, Yi Li, Richard A. Prinz, Xiulong Xu

Research output: Contribution to journalArticle

Abstract

The sonic hedgehog (Shh) pathway is highly activated in thyroid neoplasms and promotes thyroid cancer stem-like cell phenotype, but whether the Shh pathway regulates thyroid tumor cell motility and invasiveness remains unknown. Here, we report that the motility and invasiveness of two anaplastic thyroid tumor cell lines, KAT-18 and SW1736, were inhibited by two inhibitors of the Shh pathway (cyclopamine and GANT61). Consistently, the cell motility and invasiveness was decreased by Shh and Gli1 knockdown, and was increased by Gli1 overexpression in KAT-18 cells. Mechanistic studies revealed that Akt and c-Met phosphorylation was decreased by a Gli1 inhibitor and by Shh and Gli1 knockdown, but was increased by Gli1 overexpression. LY294002, a PI-3 kinase inhibitor, and a c-Met inhibitor inhibited the motility and invasiveness of Gli1-transfected KAT-18 cells more effectively than the vector-transfected cells. Knockdown of Snail, a transcription factor regulated by the Shh pathway, led to decreased cell motility and invasiveness in KAT-18 and SW1736 cells. However, key epithelial-to-mesenchymal transition (EMT) markers including E-cadherin and vimentin as well as Slug were not affected by cyclopamine and GANT61 in either SW1736 or WRO82, a well differentiated follicular thyroid carcinoma cell line. Our data suggest that the Shh pathway-stimulated thyroid tumor cell motility and invasiveness is largely mediated by AKT and c-Met activation with little involvement of EMT.

Original languageEnglish (US)
Pages (from-to)10472-10485
Number of pages14
JournalOncotarget
Volume7
Issue number9
DOIs
StatePublished - 2016

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Hedgehogs
Cell Movement
Thyroid Gland
Epithelial-Mesenchymal Transition
Thyroid Neoplasms
Follicular Adenocarcinoma
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Gastropoda
Neoplastic Stem Cells
Vimentin
Cadherins
Anaplastic Thyroid Carcinoma
Tumor Cell Line
Phosphatidylinositol 3-Kinases
Neoplasms
Phosphorylation
Phenotype
Cell Line

Keywords

  • C-Met
  • Cell motility and invasion
  • PI-3 kinase
  • Snail
  • Sonic hedgehog signaling pathway

ASJC Scopus subject areas

  • Oncology

Cite this

The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met. / Williamson, Ashley J.; Doscas, Michelle E.; Ye, Jin; Heiden, Katherine B.; Xing, Michael Mingzhao; Li, Yi; Prinz, Richard A.; Xu, Xiulong.

In: Oncotarget, Vol. 7, No. 9, 2016, p. 10472-10485.

Research output: Contribution to journalArticle

Williamson, Ashley J. ; Doscas, Michelle E. ; Ye, Jin ; Heiden, Katherine B. ; Xing, Michael Mingzhao ; Li, Yi ; Prinz, Richard A. ; Xu, Xiulong. / The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met. In: Oncotarget. 2016 ; Vol. 7, No. 9. pp. 10472-10485.
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