title: The sonic hedgehog signaling pathway stimulates anaplastic thyroid cancer cell motility and invasiveness by activating Akt and c-Met.
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.
authors: Rush Medical College, Rush University Medical Center, Chicago, IL, USA.
authors: Ashley J
authors: AJ
authors: Williamson
authors: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors: Michelle E
authors: ME
authors: Doscas
authors: Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.
authors: Jin
authors: J
authors: Ye
authors: Department of General Surgery, Rush University Medical Center, Chicago, IL, USA.
authors: Katherine B
authors: KB
authors: Heiden
authors: Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Mingzhao
authors: M
authors: Xing
authors: Lester and Sue Smith Breast Center and Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA.
authors: Yi
authors: Y
authors: Li
authors: Department of Surgery, NorthShore University Health System, Evanston, IL, USA.
authors: Richard A
authors: RA
authors: Prinz
authors: Center for Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China.|Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL, USA.|Department of General Surgery, Rush University Medical Center, Chicago, IL, USA.
authors: Xiulong
authors: X
authors: Xu
mesh_terms: D015820:Cadherins / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors / Q000187:drug effects / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000473:pathology*; D014704:Veratrum Alkaloids / Q000494:pharmacology; D014746:Vimentin / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D002867:Chromones; C551027:GANT 61; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C509239:SHH protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014704:Veratrum Alkaloids; D014746:Vimentin; D000071676:Zinc Finger Protein GLI1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; C000541:cyclopamine
keywords: PI-3 kinase; Snail; c-Met; cell motility and invasion; sonic hedgehog signaling pathway