Downregulation of miR-519d-3p is Associated with Poor Outcomes and Facilitates Tumor Progression in Papillary Thyroid Cancer by Regulating FOXQ1

Abstract

MicroRNA-519d-3p (miR-519d-3p) has emerged as a tumor suppressor in several human cancers. But whether miR-519d-3p is involved in papillary thyroid cancer (PTC) remains elusive. In this study, we investigated the potential relevance of miR-miR-519d-3p in PTC. A retrospective study of 119 PTCs was carried out. The RT-qPCR analysis was used to measure the expression of miR-519d-3p and FOXQ1 in PTC tissues and cells. Chi-square test, Kaplan–Meier curve analysis, and multivariate Cox regression analyses were performed to assess the clinical and prognostic value of miR-519d-3p in PTC. Then cellular experiments were used to explore its biological effects on PTC cells. Finally, the Pearson correlation coefficient, dual-luciferase reporter assay, and rescue experiments were used to analyze the association between miR-519d-3p and FOXQ1. miR-519d-3p was significantly downregulated in PTC tissues and cell lines. The decreased expression of miR-519d-3p was associated with reduced overall survival and progression-free survival of patients. The proliferative, migratory, and invasive abilities of cells were blocked or elevated after upregulation or downregulation of miR-519d-3p, while FOXQ1 reversed these cellular behaviors caused after upregulation or knockdown of miR-519d-3p. In conclusion, miR-519d-3p was downregulated in PTC and associated with OS and PFS of patients. MiR-519d-3p may be a tumor-inhibiting miRNA in PTC, and that miR-519d-3p/FOXQ1 axis mediated PTC tumor progression from cell proliferation, migration, and invasion in PTC cells.

Key words

miR-519d-3p - FOXQ1 - OS - PFS - papillary thyroid cancer - progression

• References

• 1 Lim H, Devesa SS, Sosa JA. et al. Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA 2017; 317: 1338-1348
• 2 Lavarello RJ, Ridgway WR, Sarwate SS. et al. Characterization of thyroid cancer in mouse models using high-frequency quantitative ultrasound techniques. Ultrasound Med Biol 2013; 39: 2333-2341
• 3 Huang J, Harris EJ, Lorch JH. Treatment of agressive thyroid cancer. Surg Pathol Clin 2019; 12: 943-950
• 4 Kreissl MC, Janssen MJR, Nagarajah J. Current treatment strategies in metastasized differentiated thyroid cancer. J Nucl Med 2019; 60: 9-15
• 5 Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017; 16: 203-222
• 6 Petrovic N, Ergun S. miRNAs as Potential treatment targets and treatment options in cancer. Mol Diagn Ther 2018; 22: 157-168
• 7 Vishnoi A, Rani S. MiRNA Biogenesis and regulation of diseases: an overview. Methods Mol Biol 2017; 1509: 1-10
• 8 Liu B, Li J, Cairns MJ. Identifying miRNAs, targets and functions. Brief Bioinform 2014; 15: 1-19
• 9 Qiu Z, Li H, Wang J. et al. miR-146a and miR-146b in the diagnosis and prognosis of papillary thyroid carcinoma. Oncol Rep 2017; 38: 2735-2740
• 10 Sun Y, Sun W, Hua H. et al. Overexpression of miR-127 predicts poor prognosis and contributes to the progression of papillary thyroid cancer by targeting REPIN1. Horm Metab Res 2021; 53: 197-203
• 11 Ye X, Lv H. MicroRNA-519d-3p inhibits cell proliferation and migration by targeting TROAP in colorectal cancer. Biomed Pharmacother 2018; 105: 879-886
• 12 Hua KT, Hong JB, Sheen YS. et al. miR-519d promotes melanoma progression by downregulating EphA4. Cancer Res 2018; 78: 216-229
• 13 Xu Y, Chen J, Yang Z. et al. Identification of RNA expression profiles in thyroid cancer to construct a competing endogenous RNA (ceRNA) network of mRNAs, long noncoding RNAs (lncRNAs), and microRNAs (miRNAs). Med Sci Monit 2019; 25: 1140-1154
• 14 Liu JY, Wu XY, Wu GN. et al. FOXQ1 promotes cancer metastasis by PI3K/AKT signaling regulation in colorectal carcinoma. Am J Transl Res 2017; 9: 2207-2218
• 15 Zhang J, Liu Y, Zhang J. et al. FOXQ1 promotes gastric cancer metastasis through upregulation of Snail. Oncol Rep 2016; 35: 3607-3613
• 16 Xu J, You Q, Wei Z. et al. miR-519 inhibits epithelial-mesenchymal transition and biologic behavior of gastric cancer cells by down-regulating FOXQ1. Int J Clin Exp Pathol 2020; 13: 425-436
• 17 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
• 18 Tang X, Sun G, He Q. et al. Circular noncoding RNA circMBOAT2 is a novel tumor marker and regulates proliferation/migration by sponging miR-519d-3p in colorectal cancer. 2020; 11: 625
• 19 Wang A, Zhang H, Wang J. et al. MiR-519d targets HER3 and can be used as a potential serum biomarker for non-small cell lung cancer. Aging (Albany NY) 2020; 12: 4866-4878
• 20 Yan CQ, Lu YH, Tang SM. et al. MiR-519d inhibits prostate cancer cell proliferation, cycle and invasion via targeting NRBP1. Eur Rev Med Pharmacol Sci 2018; 22: 2985-2990
• 21 Liu F, Lou K, Zhao X. et al. miR-214 regulates papillary thyroid carcinoma cell proliferation and metastasis by targeting PSMD10. Int J Mol Med 2018; 42: 3027-3036
• 22 Chen J, Xu Z, Yu C. et al. MiR-758-3p regulates papillary thyroid cancer cell proliferation and migration by targeting TAB1. Pharmazie 2019; 74: 235-238
• 23 Li D, Song H, Wu T. et al. MiR-519d-3p suppresses breast cancer cell growth and motility via targeting LIM domain kinase 1. 2018; 444: 169–178
• 24 Fang L, Li YY, Shao JP. et al. miR-519d-3p inhibits cell proliferation and invasion of gastric cancer by downregulating B-cell lymphoma 6. Mol Cell Biochem 2018; 154: 12-19
• 25 Chu C, Liu X, Bai X. et al. MiR-519d suppresses breast cancer tumorigenesis and metastasis via targeting MMP3. Int J Biol Sci 2018; 14: 228-236
• 26 Jin Y, Li Y, Wang X. et al. Dysregulation of miR-519d affects oral squamous cell carcinoma invasion and metastasis by targeting MMP3. J Cancer 2019; 10: 2720-2734
• 27 Li YY, Shao JP, Zhang SP. et al. miR-519d-3p inhibits cell proliferation and invasion of gastric cancer by downregulating B-cell lymphoma 6. Cytogenet Genome Res 2018; 154: 12-19
• 28 Zhang G, Hu Y, Yuan W. et al. miR-519d-3p overexpression inhibits P38 and PI3K/AKT pathway via targeting VEGFA to attenuate the malignant biological behavior of non-small cell lung cancer. Onco Targets Ther 2020; 13: 10257-10266
• 29 Pei Y, Wang P, Liu H. et al. FOXQ1 promotes esophageal cancer proliferation and metastasis by negatively modulating CDH1. Biomed Pharmacother 2015; 74: 89-94
• 30 Li Y, Wang HQ, Wang AC. et al. Overexpression of forkhead box Q1 correlates with poor prognosis in papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2019; 90: 334-342
• 31 Christensen J, Bentz S, Sengstag T. et al. FOXQ1, a novel target of the Wnt pathway and a new marker for activation of Wnt signaling in solid tumors. PLoS One 2013; 8: e60051