Hsa_circ_0002111/miR-557/DUSP14 axis mediates euthyrox-resistance in papillary thyroid cancer

  • Jing Zhou The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
  • Jing Liu The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
  • Weiyuan Ma The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
  • Pengxin Zhao The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
Keywords: miR-557, Circ_0002111, Euthyrox resistant, DUSP14, Umael


As one of the most commonly used chemotherapeutic drug for papillary thyroid cancer (PTC), euthyrox affects the therapeutic outcome due to the resistance of euthyrox. Hsa_circ_0002111 is highly expressed in euthyrox-resistant PTC patients, and this study intends to explore its role in euthyrox drug resistance. PTC patient samples were used to screen for Circ_0002111 expression. TPC-1 and K1 PTC cell lines and their corresponding euthyrox-resistant cell lines (TPC-1/euthyrox and K1/euthyrox), and a benign human thyroid follicular cell line (Nthy-ori 3-1) were used in in vitro experiments. Circ_0002111 was knocked down in euthyrox-resistant cell lines, and cell viability and colony formation were detected. Caspase-3 activity assay and nucleosomal fragmentation assay were used for the detection of apoptosis. Luciferase reporter assay and biotin-labeled RNA pulldown assay were used to analyze interactions between Circ_0002111 and miR-557, or miR-557 and DUSP14. The upregulation of Circ_0002111 was found in PTC patient samples and associated with euthyrox-resistance in poor prognosis of PTC patients. Experiments in cell lines showed that Circ_0002111 regulates euthyrox-resistance in PTC cells. Mechanistic studies showed that Circ_0002111 promoted DUSP14 expression through miR-557, and euthyrox-resistance in PTC cells depended on the regulation via miR-557/DUSP14 signaling pathways. In conclusion, Hsa_circ_0002111 promotes euthyrox-resistance of PTC cells by adsorption miR-557 upregulation, suggesting Circ_0002111 might be a potential diagnostic marker and therapeutic target for euthyrox-resistant PTC patients.


Download data is not yet available.


Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet 2016; 388: 2783–95. doi: 10.1016/S0140-6736(16)30172-6

Wiltshire JJ, Drake TM, Uttley L, Balasubramanian SP. Systematic review of trends in the incidence rates of thyroid cancer. Thyroid 2016; 26: 1541–52. doi: 10.1089/thy.2016.0100

Mao YS, Xing MZ. Recent incidences and differential trends of thyroid cancer in the USA. Endocr Relat Cancer 2016; 23: 313–22. doi: 10.1530/ERC-15-0445

Aragon Han P, Weng CH, Khawaja HT, Nagarajan N, Schneider EB, Umbricht CB, et al. MicroRNA expression and association with clinicopathologic features in papillary thyroid cancer: a systematic review. Thyroid 2015; 25: 1322–9. doi: 10.1089/thy.2015.0193

Kunavisarut T. Diagnostic biomarkers of differentiated thyroid cancer. Endocrine 2013; 44: 616–22. doi: 10.1007/s12020-013-9974-2

Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case-control study. Cancer 2006; 106: 524–31. doi: 10.1002/cncr.21653

Fiore E, Rago T, Latrofa F, Provenzale MA, Piaggi P, Delitala A, et al. Hashimoto’s thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with L-thyroxine. Endocr Relat Cancer 2011; 18: 429–37. doi: 10.1530/ERC-11-0028

Han B, Chao J, Yao HH. Circular RNA and its mechanisms in disease: from the bench to the clinic. Pharmacol Ther 2018; 187: 31–44. doi: 10.1016/j.pharmthera.2018.01.010

Nicolet BP, Engels S, Aglialoro F, van den Akker E, von Lindern M, Wolkers MC. Circular RNA expression in human hematopoietic cells is widespread and cell-type specific. Nucleic Acids Res 2018; 46: 8168–80. doi: 10.1093/nar/gky721

Salzman J. Circular RNA Expression: its potential regulation and function. Trends Genet 2016; 32: 309–16. doi: 10.1016/j.tig.2016.03.002

Jin XY, Wang ZY, Pang WY, Zhou J, Liang Y, Yang JJ, et al. Upregulated hsa_circ_0004458 contributes to progression of papillary thyroid carcinoma by inhibition of miR-885-5p and activation of RAC1. Med Sci Monit 2018; 24: 5488–500. doi: 10.12659/MSM.911095

Tian XF, Zhang L, Jiao Y, Chen JS, Shan Y, Yang WF. CircABCB10 promotes nonsmall cell lung cancer cell proliferation and migration by regulating the miR-1252/FOXR2 axis. J Cell Biochem 2019; 120: 3765–72. doi: 10.1002/jcb.27657

Yao Y, Chen XY, Yang H, Chen W, Qian YC, Yan ZY, et al. Hsa_circ_0058124 promotes papillary thyroid cancer tumorigenesis and invasiveness through the NOTCH3/GATAD2A axis. J Exp Clin Cancer Res 2019; 38: 318. doi: 10.1186/s13046-019-1321-x

Li QD, Wang YC, Wu S, Zhou Z, Ding XJ, Shi RH, et al. CircACC1 regulates assembly and activation of AMPK complex under metabolic stress. Cell Metab 2019; 30: 157–73.e7. doi: 10.1016/j.cmet.2019.05.009

Zhao HD, Tang HL, Huang QK, Qiu B, Liu XM, Fan D, et al. MiR-101 targets USP22 to inhibit the tumorigenesis of papillary thyroid carcinoma. Am J Cancer Res 2016; 6: 2575–86.

Wang Z. Editorial (hot topic: miRNAs as legitimate targets for cancer therapy). Curr Drug Targets 2013; 14: 1093. doi: 10.2174/1389450111314100001

Shao H, Zhang Y, Yan J, Ban X, Fan X, Chang X, et al. Upregulated MicroRNA-483-3p is an early event in pancreatic ductal adenocarcinoma (PDAC) and as a powerful liquid biopsy biomarker in PDAC. Onco Targets Ther 2021; 14: 2163–75. doi: 10.2147/OTT.S288936

Panda AC. Circular RNAs act as miRNA sponges. Adv Exp Med Biol 2018; 1087: 67–79. doi: 10.1007/978-981-13-1426-1_6

Qiu J, Hao Y, Huang S, Ma Y, Li X, Li D, et al. MiR-557 works as a tumor suppressor in human lung cancers by negatively regulating LEF1 expression. Tumour Biol 2017; 39: 1010428317709467. doi: 10.1177/1010428317709467

Yang Y, Sun KK, Shen XJ, Wu XY, Li DC. miR-557 inhibits the proliferation and invasion of pancreatic cancer cells by targeting EGFR. Int J Clin Exp Pathol 2019; 12: 1333–41.

Kia V, Paryan M, Mortazavi Y, Biglari A, Mohammadi-Yeganeh S. Evaluation of exosomal miR-9 and miR-155 targeting PTEN and DUSP14 in highly metastatic breast cancer and their effect on low metastatic cells. J Cell Biochem 2019; 120: 5666–76. doi: 10.1002/jcb.27850

Mabrouk NMK, Elkaffash DM, Abdel-Hadi M, Abdelmoneim SE, Saad ElDeen S, Gewaifel G, et al. Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4. Drug Target Insights 2020; 14: 1–11. doi: 10.33393/dti.2020.1548

Wei Y, Wang G, Wang C, Zhou Y, Zhang J, Xu K. Upregulation of DUSP14 affects proliferation, invasion and metastasis, potentially via epithelial-mesenchymal transition and is associated with poor prognosis in pancreatic cancer. Cancer Manag Res 2020; 12: 2097–108. doi: 10.2147/CMAR.S240040

Yan F, Ying L, Li X, Qiao B, Meng Q, Yu L, et al. Overexpression of the transcription factor ATF3 with a regulatory molecular signature associates with the pathogenic development of colorectal cancer. Oncotarget 2017; 8: 47020–36. doi: 10.18632/oncotarget.16638

Ashraf S, Hegazy YK, Harmancey R. Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to beta-adrenergic stimulation in adult rat cardiomyocytes. Am J Physiol Cell Physiol 2019; 317: C513–24. doi: 10.1152/ajpcell.00526.2018

Douglas T, Saleh M. Post-translational modification of OTULIN regulates ubiquitin dynamics and cell death. Cell Rep 2019; 29: 3652–63.e5. doi: 10.1016/j.celrep.2019.11.014

Jianrong S, Yanjun Z, Chen Y, Jianwen X. DUSP14 rescues cerebral ischemia/reperfusion (IR) injury by reducing inflammation and apoptosis via the activation of Nrf-2. Biochem Biophys Res Commun 2019; 509: 713–21. doi: 10.1016/j.bbrc.2018.12.170

How to Cite
ZhouJ., LiuJ., MaW., & ZhaoP. (2022). Hsa_circ_0002111/miR-557/DUSP14 axis mediates euthyrox-resistance in papillary thyroid cancer. STEMedicine, 3(2), e127. https://doi.org/10.37175/stemedicine.v3i2.127
Research articles