Follicular cells give rise to thyroid cancer. Worldwide thyroid cancer incidence continues to rise in recent decades but the mortality rate remains at a stable level. The discovery of novel molecular mechanisms in the pathogenesis of thyroid cancer will promote new diagnostic or therapeutic strategies. Circular RNA (circRNA) is a type of noncoding RNA which is characterized by the covalently closed loop and non-protein coding capacity. The abnormal expression of circRNAs is an important part during the pathogenesis and development of thyroid cancer. CircTP53 is a novel circRNA, and we aimed to investigate its function in the pathogenesis of thyroid cancer and to further demonstrate the underlying molecular mechanism.
The levels of circTP53, miR-1233-3p, and other relative mRNA were analyzed by qRT-PCR. Protein levels were shown by Western blot. RNA-pulldown assay and luciferase assay were employed to examine the interaction between circTP53 and miR-1233-3p. Cell proliferation was analyzed by the MTT assay.
CircTP53 was a circRNA highly expressed in thyroid cancer tissues. CircTP53 promoted cell proliferation and cell viability of TPC-1 cells. Knockdown of circTP53 inhibited the expression of Mouse double minute 2 (MDM2) and increased the protein level of p53. CircTP53 acted as a target of miR-1233-3p to increase MDM2 expression. p53 expression in thyroid cancer tissue exhibited a negative correlation with circTP53 expression.
In thyroid cancer, overexpressed circTP53 decreased the protein level of p53 via targeting miR-1233-3p/MDM2 axis and promoted cancer cell proliferation.
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Carling T, Udelsman R (2014) Thyroid cancer. Annu Rev Med 65:125–137. https://doi.org/10.1146/annurev-med-061512-105739
Roman BR, Morris LG, Davies L (2017) The thyroid cancer epidemic, 2017 perspective. Curr Opin Endocrinol Diabetes Obes 24:332–336. https://doi.org/10.1097/MED.0000000000000359
Cabanillas ME, McFadden DG, Durante C (2016) Thyroid cancer. Lancet 388:2783–2795. https://doi.org/10.1016/S0140-6736(16)30172-6
Araque DVP, Bleyer A, Brito JP (2017) Thyroid cancer in adolescents and young adults. Future Oncol 13:1253–1261. https://doi.org/10.2217/fon-2017-0024
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66:115–132. https://doi.org/10.3322/caac.21338
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, Loewer A, Ziebold U, Landthaler M, Kocks C, le Noble F, Rajewsky N (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338. https://doi.org/10.1038/nature11928
Xu N, Chen S, Liu Y, Li W, Liu Z, Bian X, Ling C, Jiang M (2018) Profiles and bioinformatics analysis of differentially expressed circrnas in taxol-resistant non-small cell lung cancer cells. Cell Physiol Biochem 48:2046–2060. https://doi.org/10.1159/000492543
Li Y, Hu J, Li L, Cai S, Zhang H, Zhu X, Guan G, Dong X (2018) Upregulated circular RNA circ_0016760 indicates unfavorable prognosis in NSCLC and promotes cell progression through miR-1287/GAGE1 axis. Biochem Biophys Res Commun 503:2089–2094. https://doi.org/10.1016/j.bbrc.2018.07.164
Bi W, Huang J, Nie C, Liu B, He G, Han J, Pang R, Ding Z, Xu J, Zhang J (2018) CircRNA circRNA_102171 promotes papillary thyroid cancer progression through modulating CTNNBIP1-dependent activation of beta-catenin pathway. J Exp Clin Cancer Res 37:275. https://doi.org/10.1186/s13046-018-0936-7
Chen F, Feng Z, Zhu J, Liu P, Yang C, Huang R, Deng Z (2018) Emerging roles of circRNA_NEK6 targeting miR-370-3p in the proliferation and invasion of thyroid cancer via Wnt signaling pathway. Cancer Biol Ther 19:1139–1152. https://doi.org/10.1080/15384047.2018.1480888
Wang M, Chen B, Ru Z, Cong L (2018) CircRNA circ-ITCH suppresses papillary thyroid cancer progression through miR-22-3p/CBL/beta-catenin pathway. Biochem Biophys Res Commun 504:283–288. https://doi.org/10.1016/j.bbrc.2018.08.175
Liu X, Xiao ZD, Han L, Zhang J, Lee SW, Wang W, Lee H, Zhuang L, Chen J, Lin HK, Wang J, Liang H, Gan B (2016) LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress. Nat Cell Biol 18:431–442. https://doi.org/10.1038/ncb3328
Park JY, Yi JW, Park CH, Lim Y, Lee KH, Lee KE, Kim JH (2016) Role of BRAF and RAS mutations in extrathyroidal extension in papillary thyroid cancer. Cancer Genom Proteom 13:171–181
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30. https://doi.org/10.3322/caac.21387
La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F, Negri E (2015) Thyroid cancer mortality and incidence: a global overview. Int J Cancer 136:2187–2195. https://doi.org/10.1002/ijc.29251
Molinaro E, Romei C, Biagini A, Sabini E, Agate L, Mazzeo S, Materazzi G, Sellari-Franceschini S, Ribechini A, Torregrossa L, Basolo F, Vitti P, Elisei R (2017) Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies. Nat Rev Endocrinol 13:644–660. https://doi.org/10.1038/nrendo.2017.76
Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, Evantal N, Memczak S, Rajewsky N, Kadener S (2014) circRNA biogenesis competes with pre-mRNA splicing. Mol Cell 56:55–66. https://doi.org/10.1016/j.molcel.2014.08.019
Li P, Chen S, Chen H, Mo X, Li T, Shao Y, Xiao B, Guo J (2015) Using circular RNA as a novel type of biomarker in the screening of gastric cancer. Clin Chim Acta 444:132–136. https://doi.org/10.1016/j.cca.2015.02.018
Lan X, Xu J, Chen C, Zheng C, Wang J, Cao J, Zhu X, Ge M (2018) The landscape of circular RNA expression profiles in papillary thyroid carcinoma based on RNA sequencing. Cell Physiol Biochem 47:1122–1132. https://doi.org/10.1159/000490188
Wei H, Pan L, Tao D, Li R (2018) Circular RNA circZFR contributes to papillary thyroid cancer cell proliferation and invasion by sponging miR-1261 and facilitating C8orf4 expression. Biochem Biophys Res Commun 503:56–61. https://doi.org/10.1016/j.bbrc.2018.05.174
Li X, Tian Y, Hu Y, Yang Z, Zhang L, Luo J (2018) CircNUP214 sponges miR-145 to promote the expression of ZEB2 in thyroid cancer cells. Biochem Biophys Res Commun 507:168–172. https://doi.org/10.1016/j.bbrc.2018.10.200
Wang H, Yan X, Zhang H, Zhan X (2019) CircRNA circ_0067934 overexpression correlates with poor prognosis and promotes thyroid carcinoma progression. Med Sci Monit 25:1342–1349. https://doi.org/10.12659/MSM.913463
Whibley C, Pharoah PD, Hollstein M (2009) p53 polymorphisms: cancer implications. Nat Rev Cancer 9:95–107. https://doi.org/10.1038/nrc2584
Ou X, Lu Y, Liao L, Li D, Liu L, Liu H, Xu H (2015) Nitidine chloride induces apoptosis in human hepatocellular carcinoma cells through a pathway involving p53, p21, Bax and Bcl-2. Oncol Rep 33:1264–1274. https://doi.org/10.3892/or.2014.3688
Lohr K, Moritz C, Contente A, Dobbelstein M (2003) p21/CDKN1A mediates negative regulation of transcription by p53. J Biol Chem 278:32507–32516. https://doi.org/10.1074/jbc.M212517200
Moll UM, Petrenko O (2003) The MDM2-p53 interaction. Mol Cancer Res 1:1001–1008
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431. https://doi.org/10.1016/j.cell.2009.04.037
Deben C, Wouters A, Op de Beeck K, van Den Bossche J, Jacobs J, Zwaenepoel K, Peeters M, Van Meerbeeck J, Lardon F, Rolfo C, Deschoolmeester V, Pauwels P (2015) The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer. Oncotarget 6:22666–22679. https://doi.org/10.18632/oncotarget.4433
Malaguarnera R, Vella V, Pandini G, Sanfilippo M, Pezzino V, Vigneri R, Frasca F (2008) TAp73 alpha increases p53 tumor suppressor activity in thyroid cancer cells via the inhibition of Mdm2-mediated degradation. Mol Cancer Res 6:64–77. https://doi.org/10.1158/1541-7786.MCR-07-0005
Qiu W, Xia X, Qiu Z, Guo M, Yang Z (2017) RasGRP3 controls cell proliferation and migration in papillary thyroid cancer by regulating the Akt-MDM2 pathway. Gene 633:35–41. https://doi.org/10.1016/j.gene.2017.08.024
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This research was authorized by the ethics committee of The Second Hospital of Hebei Medical University.
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Ma, W., Zhao, P., Zang, L. et al. CircTP53 promotes the proliferation of thyroid cancer via targeting miR-1233-3p/MDM2 axis. J Endocrinol Invest (2020). https://doi.org/10.1007/s40618-020-01317-2
- Thyroid cancer