GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers

Jandee Lee, Seonhyang Jeong, Cho Rok Lee, Cheol Ryong Ku, Sang Wook Kang, Jong Ju Jeong, Kee Hyun Nam, Dong Yeob Shin, Woong Youn Chung, Eunjig Lee, Young Suk Jo

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)e998
JournalMedicine (United States)
Volume94
Issue number25
DOIs
Publication statusPublished - 2015 Jun 9

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Transcription Factors
Odds Ratio
Confidence Intervals
Lymph Nodes
Neoplasms
Neoplasm Metastasis
Oncogenes
Glioma
RNA
Staining and Labeling
Gene Expression
Information Centers
Polymerase Chain Reaction
Telomerase
Thyroidectomy
Biotechnology
Paraffin
Genes
Thyroid Gland
Papillary Thyroid cancer

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Lee, J., Jeong, S., Lee, C. R., Ku, C. R., Kang, S. W., Jeong, J. J., ... Jo, Y. S. (2015). GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers. Medicine (United States), 94(25), e998. https://doi.org/10.1097/MD.0000000000000998
Lee, Jandee ; Jeong, Seonhyang ; Lee, Cho Rok ; Ku, Cheol Ryong ; Kang, Sang Wook ; Jeong, Jong Ju ; Nam, Kee Hyun ; Shin, Dong Yeob ; Chung, Woong Youn ; Lee, Eunjig ; Jo, Young Suk. / GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers. In: Medicine (United States). 2015 ; Vol. 94, No. 25. pp. e998.
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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.",
author = "Jandee Lee and Seonhyang Jeong and Lee, {Cho Rok} and Ku, {Cheol Ryong} and Kang, {Sang Wook} and Jeong, {Jong Ju} and Nam, {Kee Hyun} and Shin, {Dong Yeob} and Chung, {Woong Youn} and Eunjig Lee and Jo, {Young Suk}",
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Lee, J, Jeong, S, Lee, CR, Ku, CR, Kang, SW, Jeong, JJ, Nam, KH, Shin, DY, Chung, WY, Lee, E & Jo, YS 2015, 'GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers', Medicine (United States), vol. 94, no. 25, pp. e998. https://doi.org/10.1097/MD.0000000000000998

GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers. / Lee, Jandee; Jeong, Seonhyang; Lee, Cho Rok; Ku, Cheol Ryong; Kang, Sang Wook; Jeong, Jong Ju; Nam, Kee Hyun; Shin, Dong Yeob; Chung, Woong Youn; Lee, Eunjig; Jo, Young Suk.

In: Medicine (United States), Vol. 94, No. 25, 09.06.2015, p. e998.

Research output: Contribution to journalArticle

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T1 - GLI1 transcription factor affects tumor aggressiveness in patients with papillary thyroid cancers

AU - Lee, Jandee

AU - Jeong, Seonhyang

AU - Lee, Cho Rok

AU - Ku, Cheol Ryong

AU - Kang, Sang Wook

AU - Jeong, Jong Ju

AU - Nam, Kee Hyun

AU - Shin, Dong Yeob

AU - Chung, Woong Youn

AU - Lee, Eunjig

AU - Jo, Young Suk

PY - 2015/6/9

Y1 - 2015/6/9

N2 - 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.

AB - 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.

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