Su In Lee1, Dae Kyoung Kim1, Eun Jin Seo1, Eun Jung Choi1, Yang Woo Kwon1, Il Ho Jang2, Jin Choon Lee3, Hyun Yul Kim4,5, Minho Shong6, Jae Ho Kim1,5, Seong-Jang Kim7. 1. 1 Department of Physiology, School of Medicine, Pusan National University , Yangsan, Republic of Korea. 2. 2 Department of Oral Biochemistry and Molecular Biology, School of Dentistry, Pusan National University , Yangsan, Republic of Korea. 3. 3 Department of Otolaryngology, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea. 4. 4 Department of Surgery, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea. 5. 5 Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea. 6. 6 Division of Endocrinology, Department of Internal Medicine, Chungnam National University School of Medicine , Daejeon, Republic of Korea. 7. 7 Department of Nuclear Medicine, Pusan National University Yangsan Hospital , Yangsan, Republic of Korea.
Abstract
BACKGROUND: Anaplastic thyroid cancer (ATC) has a very poor prognosis due to its aggressive nature and resistance to conventional treatment. Radiotherapy and chemotherapy are not fully effective because of the undifferentiated phenotype and enhanced drug resistance of ATC. The objective of this study was to evaluate the involvement of Krüppel-like factor 4 (KLF4), a stemness-associated transcription factor, in the undifferentiated phenotype and drug resistance of ATC. METHODS: ATC cells were compared to papillary thyroid cancer cells in drug resistance and gene expression. The effects of KLF4 knockdown in ATC cells on in vitro and in vivo drug resistance were measured. The effects of KLF4 overexpression and knockdown on ABC transporter activity were determined. RESULTS: ATC cells, such as HTH83, 8505C, and SW1736, exhibited higher resistance to the anticancer drug paclitaxel and higher expression of KLF4 than TPC-1 papillary thyroid cancer cells. Knockdown of KLF4 expression in ATC cells increased the expression of the thyroid-specific differentiation genes, such as thyrotropin receptor, thyroid peroxidase, thyroglobulin, and sodium-iodide symporter. Knockdown of KLF4 expression in ATC cells decreased the resistance to doxorubicin and paclitaxel, and reduced ABC transporter expression. Luciferase reporter assay results showed that KLF4 overexpression increased ABCG2 promoter activity, which was abolished by KLF4 knockdown. A tumorigenicity assay showed that the combination of paclitaxel treatment and KLF4 knockdown significantly decreased tumor mass originated from HTH83 cells in mice. CONCLUSIONS: ATC cells show high expression of KLF4, and KLF4 expression is necessary for maintaining the undifferentiated phenotype and drug resistance in vitro and in vivo. The present study identifies KLF4 as a potential therapeutic target for eliminating ATC cells.
BACKGROUND:Anaplastic thyroid cancer (ATC) has a very poor prognosis due to its aggressive nature and resistance to conventional treatment. Radiotherapy and chemotherapy are not fully effective because of the undifferentiated phenotype and enhanced drug resistance of ATC. The objective of this study was to evaluate the involvement of Krüppel-like factor 4 (KLF4), a stemness-associated transcription factor, in the undifferentiated phenotype and drug resistance of ATC. METHODS: ATC cells were compared to papillary thyroid cancer cells in drug resistance and gene expression. The effects of KLF4 knockdown in ATC cells on in vitro and in vivo drug resistance were measured. The effects of KLF4 overexpression and knockdown on ABC transporter activity were determined. RESULTS: ATC cells, such as HTH83, 8505C, and SW1736, exhibited higher resistance to the anticancer drug paclitaxel and higher expression of KLF4 than TPC-1papillary thyroid cancer cells. Knockdown of KLF4 expression in ATC cells increased the expression of the thyroid-specific differentiation genes, such as thyrotropin receptor, thyroid peroxidase, thyroglobulin, and sodium-iodide symporter. Knockdown of KLF4 expression in ATC cells decreased the resistance to doxorubicin and paclitaxel, and reduced ABC transporter expression. Luciferase reporter assay results showed that KLF4 overexpression increased ABCG2 promoter activity, which was abolished by KLF4 knockdown. A tumorigenicity assay showed that the combination of paclitaxel treatment and KLF4 knockdown significantly decreased tumor mass originated from HTH83 cells in mice. CONCLUSIONS: ATC cells show high expression of KLF4, and KLF4 expression is necessary for maintaining the undifferentiated phenotype and drug resistance in vitro and in vivo. The present study identifies KLF4 as a potential therapeutic target for eliminating ATC cells.
Entities:
Keywords:
KLF4; anaplastic thyroid cancer; cancer stem cell; chemoresistance
Authors: Tomeka L Suber; Ina Nikolli; Michael E O'Brien; James Londino; Jing Zhao; Kong Chen; Rama K Mallampalli; Yutong Zhao Journal: Respir Res Date: 2018-10-25