title: Sirt1 induction confers resistance to etoposide-induced genotoxic apoptosis in thyroid cancers.
abstract: 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.
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Kweon
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Cho Rok
authors.initials: CR
authors.lastname: Lee
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Jung
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Ban
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Jong Ju
authors.initials: JJ
authors.lastname: Jeong
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Kee-Hyun
authors.initials: KH
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Jo
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Jandee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Surgery, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Woong Youn
authors.initials: WY
authors.lastname: Chung
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005047:Etoposide / Q000008:administration & dosage; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics; D056566:Sirtuin 3 / Q000096:biosynthesis* / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005047:Etoposide; C447939:SIRT1 protein, human; C466093:SIRT3 protein, human; D056564:Sirtuin 1; D056566:Sirtuin 3