The sonic hedgehog signaling pathway maintains the cancer stem cell self-renewal of anaplastic thyroid cancer by inducing snail expression

Katherine B. Heiden, Ashley J. Williamson, Michelle E. Doscas, Jin Ye, Yimin Wang, Dingxie Liu, Mingzhao Xing, Richard A. Prinz, Xiulong Xu

Research output: Contribution to journalArticlepeer-review

Abstract

Context: Cancer stem cells (CSCs) have been recently identified in thyroid neoplasm. Anaplastic thyroid cancer (ATC) contains a higher percentage of CSCs than well-differentiated thyroid cancer. The signaling pathways and the transcription factors that regulate thyroid CSC self-renewal remain poorly understood.

Objective: The objective of this study is to use two ATC cell lines (KAT-18 and SW1736) as a model to study the role of the sonic hedgehog (Shh) pathway in maintaining thyroid CSC self-renewal and to understand its underlying molecular mechanisms.

Design: The expression and activity of aldehyde dehydrogenase (ALDH), a marker for thyroid CSCs, was analyzed by Western blot and ALDEFLUOR assay, respectively. The effect of three Shh pathway inhibitors (cyclopamine, HhAntag, GANT61), Shh, Gli1, Snail knockdown, and Gli1 overexpression on thyroid CSC self-renewal was analyzed by ALDEFLUOR assay and thyrosphere formation. The sensitivity of transfected KAT-18 cells to radiation was evaluated by a colony survival assay.

Results: Western blot analysis revealed that ALDH protein levels in five thyroid cancer cell lines (WRO82, a follicular thyroid cancer cell line; BCPAP and TPC1, two papillary thyroid cancer cell lines; KAT-18andSW1736, twoATCcell lines) correlated with the percentage of the ALDHHigh cells as well as Gli1 and Snail expression. The Shh pathway inhibitors, Shh and Gli1 knockdown, in KAT-18 cells decreased thyroid CSC self-renewal and increased radiation sensitivity. In contrast, Gli1 overexpression led to increased thyrosphere formation, an increased percentage of ALDHHigh cells, and increased radiation resistance in KAT-18 cells. Inhibition of the Shh pathway by three specific inhibitors led to decreased Snail expression and a decreased number of ALDHHigh cells in KAT-18 and SW1736. Snail gene knockdown decreased the number of ALDHHigh cells in KAT-18 and SW1736 cells.

Conclusions: The Shh pathway promotes the CSC self-renewal inATCcell lines by Gli1-induced Snail expression.

Original languageEnglish (US)
Pages (from-to)E2178-E2187
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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