title: Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation.
abstract: The sonic hedgehog (SHH) pathway is activated in several types of malignancy and plays an important role in tumor cell proliferation and tumorigenesis. SHH binding to a 12-pass transmembrane receptor, Patched (PTCH), leads to freeing of Smoothened (SMO) and subsequent activation of GLI transcription factors. In the present study, we analyzed the expression of SHH, PTCH, SMO, and GLI1 in 31 follicular thyroid adenomas (FTA), 8 anaplastic thyroid carcinomas (ATC), and 51 papillary thyroid carcinomas (PTC) by immunohistochemical staining. More than 65% of FTA, PTC, and ATC specimens stained positive for SHH, PTCH, SMO, and GLI. However, the expression of the genes encoding these four molecules did not correlate with any clinicopathologic parameters, including the age, gender, the status of BRAF gene mutation, tumor stage, local invasion, and metastasis. Three thyroid tumor cell lines (KAT-18, WRO82, and SW1736) all expressed the genes encoding these four molecules. 5-Bromo-2-deoxyuridine labeling and MTT cell proliferation assays revealed that cyclopamine (CP), an inhibitor of the SHH pathway, was able to inhibit the proliferation of KAT-18 and WRO82 cells more effectively than SW1736 cells. CP led to the arrest of cell cycle or apoptosis. Knockdown of SHH and GLI expression by miRNA constructs that target SHH or GLI mRNA in KAT-18 and SW1736 cells led to the inhibition of cell proliferation. Our results suggest that the SHH pathway is widely activated in thyroid neoplasms and may have potential as an early marker of thyroid cancer or as a potential therapeutic target for thyroid cancer treatment.
authors.affiliation: Department of General Surgery, Rush University Medical Center, Chicago, Illinois 60612, USA. xxu@rush.edu
authors.forename: Xiulong
authors.initials: X
authors.lastname: Xu
authors.forename: Helen
authors.initials: H
authors.lastname: Ding
authors.forename: Geetha
authors.initials: G
authors.lastname: Rao
authors.forename: Shalini
authors.initials: S
authors.lastname: Arora
authors.forename: Constantine P
authors.initials: CP
authors.lastname: Saclarides
authors.forename: Joseph
authors.initials: J
authors.lastname: Esparaz
authors.forename: Paolo
authors.initials: P
authors.lastname: Gattuso
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Solorzano
authors.forename: Richard A
authors.initials: RA
authors.lastname: Prinz
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D016009:Chi-Square Distribution; D005260:Female; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000494:pharmacology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000072086:Smoothened Receptor; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D035683:MicroRNAs; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012334:RNA, Neoplasm; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine