title: GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers.
abstract: A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin-embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414-13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674-18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292-13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097-14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers, as well as novel therapeutic targets.
authors.affiliation: From the Department of Surgery (JL, CRL, S-WK, JJJ, K-HN, WYC); and Department of Internal Medicine (SJ, CRK, DYS, EJL, YSJ), Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jandee
authors.initials: J
authors.lastname: Lee
authors.forename: Seonhyang
authors.initials: S
authors.lastname: Jeong
authors.forename: Cho Rok
authors.initials: CR
authors.lastname: Lee
authors.forename: Cheol Ryong
authors.initials: CR
authors.lastname: Ku
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Jong Ju
authors.initials: JJ
authors.lastname: Jeong
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Nam
authors.forename: Dong Yeob
authors.initials: DY
authors.lastname: Shin
authors.forename: Woong Youn
authors.initials: WY
authors.lastname: Chung
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
mesh_terms: D000328:Adult; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1