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Sirt1 induction confers resistance to etoposide-induced genotoxic apoptosis in thyroid cancers

 Ki Hwan Kweon  ;  Cho Rok Lee  ;  Soo Jung Jung  ;  Eun Jeong Ban  ;  Sang-Wook Kang  ;  Jong Ju Jeong  ;  Kee-Hyun Nam  ;  Young Suk Jo  ;  Jandee Lee  ;  Woong Youn Chung 
 INTERNATIONAL JOURNAL OF ONCOLOGY, Vol.45(5) : 2065-2075, 2014 
Journal Title
Issue Date
Apoptosis/drug effects ; Carcinogenesis/drug effects ; Carcinogenesis/genetics ; Cell Line, Tumor ; Cell Survival ; DNA Damage/drug effects ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Etoposide/administration & dosage ; Forkhead Transcription Factors/biosynthesis* ; Forkhead Transcription Factors/genetics ; Humans ; Signal Transduction/drug effects ; Sirtuin 1/biosynthesis* ; Sirtuin 1/genetics ; Sirtuin 3/biosynthesis* ; Sirtuin 3/genetics ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/genetics* ; Thyroid Neoplasms/pathology
Despite the favorable therapeutic outcomes reported in differentiated thyroid cancer (DTC), a significant proportion of DTC patients present with refractory behavior to conventional therapy. The sirtuin (Sirt) family has recently been implicated in the maintenance of cellular homeostasis under genotoxic stress. Here, we investigated the induction of Sirt1 expression by etoposide-induced genotoxic stress to gain insights into thyroid carcinogenesis and identify novel therapeutic targets. Immunohistochemical staining analyses of Sirt1 and Sirt3 were performed using human thyroid cancer tissues and matched normal tissues, and bioinformatic analyses were done using public repositories, including the Human Protein Atlas, BioGPS, NCBI Gene Expression Omnibus (GEO) profiles, and GeneNetwork. TPC1, FTC133 and FRO cells were used for molecular biological experiments including apoptosis assays, MTT, immunofluorescence staining and qRT-PCR assays. The IHC data and public repositories data consistently showed variable Sirt1 and Sirt3 expression patterns in normal thyroid follicular cells and papillary thyroid cancer cells. The induction of Sirt1 and Sirt3 was cell type-specific and the expression levels of these genes correlated with apoptotic cell death and cell viability after etoposide-induced genotoxic stress. Sirt1‑Foxp3 signaling-mediated regulation of Bax and p21 mRNA expression was a signature molecular event in TPC1 cells, which showed remarkable resistance to etoposide-induced genotoxic stress. The induction of Sirt1 and Sirt3 may be a determinant of thyroid cancer cell survival under genotoxic stress conditions. Further examination of the Sirt1-Foxp3 signal may improve our understanding of thyroid carcinogenesis and help identify new druggable targets.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Sang Wook(강상욱) ORCID logo https://orcid.org/0000-0001-5355-833X
Nam, Kee Hyun(남기현) ORCID logo https://orcid.org/0000-0002-6852-1190
Ban, Eun Jeong(반은정)
Lee, Jan Dee(이잔디) ORCID logo https://orcid.org/0000-0003-4090-0049
Lee, Cho Rok(이초록) ORCID logo https://orcid.org/0000-0001-7848-3709
Jung, Soo Jung(정수정)
Chung, Woong Youn(정웅윤)
Jeong, Jong Ju(정종주) ORCID logo https://orcid.org/0000-0002-4155-6035
Jo, Young Suk(조영석) ORCID logo https://orcid.org/0000-0001-9926-8389
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