MicroRNA-592 suppresses the malignant phenotypes of thyroid cancer by regulating lncRNA NEAT1 and downregulating NOVA1

Luo,Yiqiang; Hao,Tianwei; Zhang,Jian; Zhang,Ming; Sun,Peng; Wu,Lei

doi:10.3892/ijmm.2019.4278

MicroRNA-592 suppresses the malignant phenotypes of thyroid cancer by regulating lncRNA NEAT1 and downregulating NOVA1

Authors:
- Yiqiang Luo
- Tianwei Hao
- Jian Zhang
- Ming Zhang
- Peng Sun
- Lei Wu
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Affiliations: Department of Breast and Thyroid Surgery, Jilin Central General Hospital, Chuanying, Jilin 132000, P.R. China
Published online on: July 16, 2019 https://doi.org/10.3892/ijmm.2019.4278
Pages: 1172-1182

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Abstract

Numerous studies have demonstrated that various microRNAs (miRs) are aberrantly expressed in thyroid cancer and play critical roles in thyroid cancer malignancy. The aberrant expression of miR‑592 has frequently been reported in multiple human cancer types; however, its expression profile and functions in thyroid cancer remain poorly understood. Reverse transcription‑quantitative polymerase chain reaction was carried out to determine the expression profile of miR‑592 in thyroid cancer tissues and cell lines. The regulatory effects of miR‑592 upregulation on thyroid cancer cell proliferation, migration, and invasion in vitro, and tumor growth in vivo were investigated using a CCK‑8 assay, migration and invasion assays, and a xenograft tumor model, respectively. Furthermore, the mechanisms underlying miR‑592‑mediated suppression of the aggressive phenotypes of thyroid cancer cells were explored in detail. The results indicated that miR‑592 was significantly downregulated in thyroid cancer samples, and its downregulation was associated with lymph node metastasis and tumor‑node‑metastasis stage. Patients with thyroid cancer and low miR‑592 expression exhibited shorter overall survival than patients with high miR‑592 expression. Overexpression of miR‑592 resulted in decreased cell proliferation, migration, and invasion in thyroid cancer. In addition, neuro‑oncological ventral antigen 1 (NOVA1) was identified as a novel target gene of miR‑592 in thyroid cancer cells. Furthermore, ectopic NOVA1 expression may effectively abolish the tumor‑suppressing effects of miR‑592 overexpression in thyroid cancer cells. Notably, the lncRNA NEAT1 was proposed to function as a sponge of miR‑592 in thyroid cancer cells, thereby regulating NOVA1 expression. Finally, resuming miR‑592 expression significantly impaired thyroid cancer tumor growth in vivo. The results indicated that the NEAT1/miR‑592/NOVA1 pathway may play regulatory roles in thyroid cancer malignancy in vitro and in vivo. Our findings may provide novel insight into the pathogenesis of thyroid cancer. Therefore, this pathway may be an effective target for treating patients with this disease.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
3	La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F and Negri E: Thyroid cancer mortality and incidence: A global overview. Int J Cancer. 136:2187–2195. 2015. View Article : Google Scholar
4	Xing M: Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 13:184–199. 2013. View Article : Google Scholar : PubMed/NCBI
5	Fröhlich E and Wahl R: The current role of targeted therapies to induce radioiodine uptake in thyroid cancer. Cancer Treat Rev. 40:665–674. 2014. View Article : Google Scholar : PubMed/NCBI
6	Shi X, Liu R, Basolo F, Giannini R, Shen X, Teng D, Guan H, Shan Z, Teng W, Musholt TJ, et al: Differential clinicopathological risk and prognosis of major papillary thyroid cancer variants. J Clin Endocrinol Metab. 101:264–274. 2016. View Article : Google Scholar :
7	Kim WW, Ha TK and Bae SK: Clinical implications of the BRAF mutation in papillary thyroid carcinoma and chronic lymphocytic thyroiditis. J Otolaryngol Head Neck Surg. 47:42018. View Article : Google Scholar
8	Kim VN, Han J and Siomi MC: Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 10:126–139. 2009. View Article : Google Scholar : PubMed/NCBI
9	Huang W: MicroRNAs: Biomarkers, diagnostics, and therapeutics. Methods Mol Biol. 1617:57–67. 2017. View Article : Google Scholar : PubMed/NCBI
10	Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M and Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:2999–3004. 2004. View Article : Google Scholar : PubMed/NCBI
11	Gao X, Chen Z, Li A, Zhang X and Cai X: miR-129 regulates growth and invasion by targeting MAL2 in papillary thyroid carcinoma. Biomed Pharmacother. 105:1072–1078. 2018. View Article : Google Scholar : PubMed/NCBI
12	Xu CB, Liu XS, Li JQ, Zhao X, Xin D and Yu D: MicroRNA-539 functions as a tumor suppressor in papillary thyroid carcinoma via the transforming growth factor β1/Smads signaling pathway by targeting secretory leukocyte protease inhibitor. J Cell Biochem. 120:10830–10846. 2019. View Article : Google Scholar : PubMed/NCBI
13	Gao XB, Chen CL, Tian ZL, Yuan FK and Jia GL: MicroRNA-791 is an independent prognostic factor of papillary thyroid carcinoma and inhibits the proliferation of PTC cells. Eur Rev Med Pharmacol Sci. 22:5562–5568. 2018.PubMed/NCBI
14	Yi T, Zhou X, Sang K, Zhou J and Ge L: MicroRNA-1270 modulates papillary thyroid cancer cell development by regulating SCAI. Biomed Pharmacother. 109:2357–2364. 2019. View Article : Google Scholar
15	Diao Y, Fu H and Wang Q: miR-221 exacerbate cell proliferation and invasion by targeting TIMP3 in papillary thyroid carcinoma. Am J Ther. 24:e317–e328. 2017. View Article : Google Scholar :
16	Huang Y, Yu S, Cao S, Yin Y, Hong S, Guan H, Li Y and Xiao H: MicroRNA-222 promotes invasion and metastasis of papillary thyroid cancer through targeting protein phosphatase 2 regulatory subunit B alpha expression. Thyroid. 28:1162–1173. 2018. View Article : Google Scholar : PubMed/NCBI
17	Fang L, Kong D and Xu W: MicroRNA-625-3p promotes the proliferation, migration and invasion of thyroid cancer cells by up-regulating astrocyte elevated gene 1. Biomed Pharmacother. 102:203–211. 2018. View Article : Google Scholar : PubMed/NCBI
18	Ponting CP, Oliver PL and Reik W: Evolution and functions of long noncoding RNAs. Cell. 136:629–641. 2009. View Article : Google Scholar : PubMed/NCBI
19	Huang F, Zhang Q, Chen W, Zhang H, Lu G, Chen J and Qiu C: Long noncoding RNA cancer susceptibility candidate 2 suppresses papillary thyroid carcinoma growth by inactivating the AKT/ERK1/2 signaling pathway. J Cell Biochem. 120:10380–10390. 2019. View Article : Google Scholar : PubMed/NCBI
20	Liu C, Feng Z, Chen T, Lv J, Liu P, Jia L, Zhu J, Chen F, Yang C and Deng Z: Downregulation of NEAT1 reverses the radioactive iodine resistance of papillary thyroid carcinoma cell via miR-101-3p/FN1/PI3K-AKT signaling pathway. Cell Cycle. 18:167–203. 2019. View Article : Google Scholar : PubMed/NCBI
21	Li X, Zhong W, Xu Y, Yu B and Liu H: Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-204-3p/CDC23 axis. Biochem Biophys Res Commun. 508:1145–1148. 2019. View Article : Google Scholar
22	Chan JJ and Tay Y: Noncoding RNA:RNA regulatory networks in cancer. Int J Mol Sci. 19:2018. View Article : Google Scholar
23	Li Z, Li B, Niu L and Ge L: miR-592 functions as a tumor suppressor in human non-small cell lung cancer by targeting SOX9. Oncol Rep. 37:297–304. 2017. View Article : Google Scholar
24	Hou W, Zhang H, Bai X, Liu X, Yu Y, Song L and Du Y: Suppressive role of miR-592 in breast cancer by repressing TGF-β2. Oncol Rep. 38:3447–3454. 2017.PubMed/NCBI
25	Gao S, Chen J, Wang Y, Zhong Y, Dai Q, Wang Q and Tu J: miR-592 suppresses the development of glioma by regulating Rho-associated protein kinase. Neuroreport. 29:1391–1399. 2018. View Article : Google Scholar : PubMed/NCBI
26	Peng T, Zhou L, Qi H, Wang G, Luan Y and Zuo L: miR-592 functions as a tumor suppressor in glioma by targeting IGFBP2. Tumour Biol. 39:10104283177192732017. View Article : Google Scholar : PubMed/NCBI
27	Wang W, Zhang H, Tang M, Liu L, Zhou Z, Zhang S and Wang L: MicroRNA-592 targets IGF-1R to suppress cellular proliferation, migration and invasion in hepatocellular carcinoma. Oncol Lett. 13:3522–3528. 2017. View Article : Google Scholar : PubMed/NCBI
28	Jia YY, Zhao JY, Li BL, Gao K, Song Y, Liu MY, Yang XJ, Xue Y, Wen AD and Shi L: miR-592/WSB1/HIF-1α axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth. Oncotarget. 7:35257–35269. 2016. View Article : Google Scholar : PubMed/NCBI
29	Li X, Zhang W, Zhou L, Yue D and Su X: MicroRNA-592 targets DEK oncogene and suppresses cell growth in the hepatocellular carcinoma cell line HepG2. Int J Clin Exp Pathol. 8:12455–12463. 2015.
30	Lv Z, Rao P and Li W: miR-592 represses FOXO3 expression and promotes the proliferation of prostate cancer cells. Int J Clin Exp Med. 8:15246–15253. 2015.PubMed/NCBI
31	Liu M, Zhi Q, Wang W, Zhang Q, Fang T and Ma Q: Up-regulation of miR-592 correlates with tumor progression and poor prognosis in patients with colorectal cancer. Biomed Pharmacother. 69:214–220. 2015. View Article : Google Scholar : PubMed/NCBI
32	Fu Q, Du Y, Yang C, Zhang D, Zhang N, Liu X, Cho WC and Yang Y: An oncogenic role of miR-592 in tumorigenesis of human colorectal cancer by targeting Forkhead Box O3A (FoxO3A). Expert Opin Ther Targets. 20:771–782. 2016. View Article : Google Scholar : PubMed/NCBI
33	Schmid KW, Synoracki S, Dralle H and Wittekind C: Proposal for an extended pTNM classification of thyroid carcinoma: Commentary on deficits of the 8th edition of the TNM classification. Pathologe. 40:18–24. 2019. View Article : Google Scholar
34	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
35	Sun W, Lan X, Zhang H, Wang Z, Dong W, He L, Zhang T, Zhang P, Liu J and Qin Y: NEAT1_2 functions as a competing endogenous RNA to regulate ATAD2 expression by sponging microRNA-106b-5p in papillary thyroid cancer. Cell Death Dis. 9:3802018. View Article : Google Scholar : PubMed/NCBI
36	Li JH, Zhang SQ, Qiu XG, Zhang SJ, Zheng SH and Zhang DH: Long non-coding RNA NEAT1 promotes malignant progression of thyroid carcinoma by regulating miRNA-214. Int J Oncol. 50:708–716. 2017. View Article : Google Scholar
37	Zhang H, Cai Y, Zheng L, Zhang Z, Lin X and Jiang N: Long noncoding RNA NEAT1 regulate papillary thyroid cancer progression by modulating miR-129-5p/KLK7 expression. J Cell Physiol. 233:6638–6648. 2018. View Article : Google Scholar : PubMed/NCBI
38	Liu Y, Li J, Li M, Li F, Shao Y and Wu L: MicroRNA-510-5p promotes thyroid cancer cell proliferation, migration, and invasion through suppressing SNHG15. J Cell Biochem. 2019.
39	Chen J, Yin J, Liu J, Zhu RX, Zheng Y and Wang XL: miR-202-3p-functions as a tumor suppressor and reduces cell migration and invasion in papillary thyroid carcinoma. Eur Rev Med Pharmacol Sci. 23:1145–1150. 2019.PubMed/NCBI
40	Ma Y and Sun Y: miR-29a-3p inhibits growth, proliferation, and invasion of papillary thyroid carcinoma by suppressing NF-κB signaling via direct targeting of OTUB2. Cancer Manag Res. 11:13–23. 2018. View Article : Google Scholar :
41	Zembska A, Jawiarczyk-Przybyłowska A, Wojtczak B and Bolanowski M: MicroRNA expression in the progression and aggressiveness of papillary thyroid carcinoma. Anticancer Res. 39:33–40. 2019. View Article : Google Scholar
42	Jia M, Shi Y, Li Z, Lu X and Wang J: MicroRNA-146b-5p as an oncomiR promotes papillary thyroid carcinoma development by targeting CCDC6. Cancer Lett. 443:145–156. 2019. View Article : Google Scholar
43	Yuan LY, Zhou M, Lv H, Qin X, Zhou J, Mao X, Li X, Xu Y, Liu Y and Xing H: Involvement of NEAT1/miR-133a axis in promoting cervical cancer progression via targeting SOX4. J Cell Physiol. 2019. View Article : Google Scholar
44	Ji Y, Wang M, Li X and Cui F: The long noncoding RNA NEAT1 targets miR-34a-5p and drives nasopharyngeal carcinoma progression via Wnt/β-catenin signaling. Yonsei Med J. 60:336–345. 2019. View Article : Google Scholar : PubMed/NCBI
45	Shin VY, Chen J, Cheuk IW, Siu MT, Ho CW, Wang X, Jin H and Kwong A: Long non-coding RNA NEAT1 confers oncogenic role in triple-negative breast cancer through modulating chemo-resistance and cancer stemness. Cell Death Dis. 10:2702019. View Article : Google Scholar
46	Li B, Gu W and Zhu X: NEAT1 mediates paclitaxel-resistance of non-small cell of lung cancer through activation of Akt/mTOR signalling pathway. J Drug Target. 1–7. 2019.
47	Zhu Z, Du S, Yin K, Ai S, Yu M, Liu Y, Shen Y, Liu M, Jiao R, Chen X and Guan W: Knockdown long noncoding RNA nuclear paraspeckle assembly transcript 1 suppresses colorectal cancer through modulating miR-193a-3p/KRAS. Cancer Med. 8:261–275. 2019. View Article : Google Scholar
48	Yu HM, Wang C, Yuan Z, Chen GL, Ye T and Yang BW: LncRNA NEAT1 promotes the tumorigenesis of colorectal cancer by sponging miR-193a-3p. Cell Prolif. 52:e125262019. View Article : Google Scholar
49	Liu X, Shang W and Zheng F: Long non-coding RNA NEAT1 promotes migration and invasion of oral squamous cell carcinoma cells by sponging microRNA-365. Exp Ther Med. 16:2243–2250. 2018.PubMed/NCBI
50	Jin L, Li H, Wang J, Lin D, Yin K, Lin L, Lin Z, Lin G, Wang H, Ying X, et al: MicroRNA-193a-5p exerts a tumor suppressor role in glioblastoma via modulating NOVA1. J Cell Biochem. 120:6188–6197. 2019. View Article : Google Scholar
51	Yu X, Zheng H, Chan MTV and Wu WKK: NOVA1 acts as an oncogene in melanoma via regulating FOXO3a expression. J Cell Mol Med. 22:2622–2630. 2018. View Article : Google Scholar : PubMed/NCBI
52	Shen B, Zhang Y, Yu S, Yuan Y, Zhong Y, Lu J and Feng J: MicroRNA-339, an epigenetic modulating target is involved in human gastric carcinogenesis through targeting NOVA1. FEBS Lett. 589:3205–3211. 2015. View Article : Google Scholar : PubMed/NCBI