circHIPK3 promotes proliferation and migration and invasion via regulation of miR‑637/HDAC4 signaling in osteosarcoma cells

Wen,Yu; Li,Bin; He,Ming; Teng,Songling; Sun,Yuxiu; Wang,Guangbin

doi:10.3892/or.2020.7833

circHIPK3 promotes proliferation and migration and invasion via regulation of miR‑637/HDAC4 signaling in osteosarcoma cells

Authors:
- Yu Wen
- Bin Li
- Ming He
- Songling Teng
- Yuxiu Sun
- Guangbin Wang
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Affiliations: Department of Histology and Embryology, College of Basic Medical Science, Medical University, Shenyang, Liaoning 110122, P.R. China, Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of Internal Medicine, Cancer Hospital of China Medical University/Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110004, P.R. China
Published online on: November 3, 2020 https://doi.org/10.3892/or.2020.7833
Pages: 169-179
Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Accumulating evidence has indicated that circular RNAs (circRNAs) serve crucial roles in the progression of a diverse range of different types of cancer, including osteosarcoma (OS). The present study determined the expression pattern and function of circRNA homeodomain interacting protein kinase 3 (circHIPK3), a novel circular RNA, in OS. It was revealed that circHIPK3 expression was upregulated in OS tissue samples and OS cell lines. A localization assay revealed that circHIPK3 was primarily located in the cytoplasm. Using loss‑of‑function proliferation and Transwell assays, the present study revealed that circHIPK3‑knockdown suppressed OS cell proliferation, migration and invasion. Furthermore, the present study screened potential microRNAs that may interact with circHIPK3. It was revealed that microRNA‑637 (miR‑637) expression was downregulated in OS according to a Gene Expression Omnibus data analysis. In addition, the present study demonstrated that miR‑637 expression was downregulated in OS cell lines. A fluorescence in situ hybridization assay revealed that both miR‑637 and circHIPK3 were located in the cytoplasm. An in‑depth mechanism investigation demonstrated that circHIPK3 expression was inversely correlated with miR‑637 expression, and that circHIPK3 was a target of miR‑637. In addition, it was revealed that histone deacetylase 4 (HDAC4) was another downstream target gene of miR‑637, as demonstrated using a luciferase assay. It was revealed that miR‑637 suppressed OS cell proliferation, migration and invasion via targeting of HDAC4. Finally, the present study demonstrated that circHIPK3 sponged miR‑637 to promote HDAC4 expression and OS cell proliferation, migration and invasion. In conclusion, the present study uncovered the role of the circHIPK3/miR‑637/HDAC4 axis in OS cell proliferation, migration and invasion. It was demonstrated that circHIPK3 promoted OS cell proliferation, migration and invasion by modulating miR‑637/HDAC4 signaling.

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1	Sweetnam R: Osteosarcoma. Ann R Coll Surg Engl. 44:38–58. 1969.
2	Ottaviani G and Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res. 152:3–13. 2009. View Article : Google Scholar
3	Berner K, Johannesen TB, Berner A, Haugland HK, Bjerkehagen B, Bøhler PJ and Bruland ØS: Time-trends on incidence and survival in a nationwide and unselected cohort of patients with skeletal osteosarcoma. Acta Oncol. 54:25–33. 2015. View Article : Google Scholar
4	Friebele JC, Peck J, Pan X, Abdel-Rasoul M and Mayerson JL: Osteosarcoma: A meta-analysis and review of the literature. Am J Orthop (Belle Mead NJ). 44:547–553. 2015.
5	Bishop MW, Janeway KA and Gorlick R: Future directions in the treatment of osteosarcoma. Curr Opin Pediatr. 28:26–33. 2016. View Article : Google Scholar
6	Zamborsky R, Kokavec M, Harsanyi S and Danisovic L: Identification of prognostic and predictive osteosarcoma biomarkers. Med Sci (Basel). 7:282019.
7	Patop IL and Kadener S: circRNAs in cancer. Curr Opin Genet Dev. 48:121–127. 2018. View Article : Google Scholar
8	Kristensen LS, Hansen TB, Venø MT and Kjems J: Circular RNAs in cancer: Opportunities and challenges in the field. Oncogene. 37:555–565. 2018. View Article : Google Scholar
9	Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B, Luo Y, Lyu D, Li Y, Shi G, et al: Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 7:112152016. View Article : Google Scholar
10	Liu N, Zhang J, Zhang LY and Wang L: CircHIPK3 is upregulated and predicts a poor prognosis in epithelial ovarian cancer. Eur Rev Med Pharmacol Sci. 22:3713–3718. 2018.
11	Ke Z, Xie F, Zheng C and Chen D: CircHIPK3 promotes proliferation and invasion in nasopharyngeal carcinoma by abrogating miR-4288-induced ELF3 inhibition. J Cell Physiol. 234:1699–1706. 2019. View Article : Google Scholar
12	Li Y, Zheng F, Xiao X, Xie F, Tao D, Huang C, Liu D, Wang M, Wang L, Zeng F and Jiang G: CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep. 18:1646–1659. 2017. View Article : Google Scholar
13	Yu H, Chen Y and Jiang P: Circular RNA HIPK3 exerts oncogenic properties through suppression of miR-124 in lung cancer. Biochem Biophys Res Commun. 506:455–462. 2018. View Article : Google Scholar
14	Chen G, Shi Y, Liu M and Sun J: circHIPK3 regulates cell proliferation and migration by sponging miR-124 and regulating AQP3 expression in hepatocellular carcinoma. Cell Death Dis. 9:1752018. View Article : Google Scholar
15	Wang Z, Qin G and Zhao TC: HDAC4: Mechanism of regulation and biological functions. Epigenomics. 6:139–150. 2014. View Article : Google Scholar
16	Sun Y and Qin B: Long noncoding RNA MALAT1 regulates HDAC4-mediated proliferation and apoptosis via decoying of miR-140-5p in osteosarcoma cells. Cancer Medicine. 7:4584–4597. 2018. View Article : Google Scholar
17	Zeng LS, Yang XZ, Wen YF, Mail SJ, Wang MH, Zhang MY, Zheng XFS and Wang HY: Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma. Aging (Albany NY). 8:1236–1249. 2016. View Article : Google Scholar
18	Sissons HA: The WHO classification of bone tumors. Recent Results Cancer Res. 104–108. 1976.
19	Kawano M, Tanaka K, Itonaga I, Ikeda S, Iwasaki T and Tsumura H: microRNA-93 promotes cell proliferation via targeting of PTEN in osteosarcoma cells. J Exp Clin Cancer Res. 34:762015. View Article : Google Scholar
20	Namløs HM, Meza-Zepeda LA, Barøy T, Østensen IHG, Kresse SH, Kuijjer ML, Serra M, Bürger H, Cleton-Jansen AM and Myklebost O: Modulation of the osteosarcoma expression phenotype by microRNAs. PLoS One. 7:e480862012. View Article : Google Scholar
21	Davis S and Meltzer PS: GEOquery: A bridge between the gene expression omnibus (GEO) and bioconductor. Bioinformatics. 23:1846–1847. 2007. View Article : Google Scholar
22	Zhang J, Ye Y, Chang DW, Lin SH, Huang M, Tannir NM, Matin S, Karam JA, Wood CG, Chen ZN and Wu X: Global and targeted miRNA expression profiling in clear cell renal cell carcinoma tissues potentially links miR-155-5p and miR-210-3p to both tumorigenesis and recurrence. Am J Pathol. 188:2487–2496. 2018. View Article : Google Scholar
23	Glažar P, Papavasileiou P and Rajewsky N: circBase: A database for circular RNAs. RNA. 20:1666–1670. 2014. View Article : Google Scholar
24	Chang TH, Huang HY, Hsu JB, Weng SL, Horng JT and Huang HD: An enhanced computational platform for investigating the roles of regulatory RNA and for identifying functional RNA motifs. BMC Bioinformatics. 14 (Suppl 2):S42013. View Article : Google Scholar
25	Dudekula DB, Panda AC, Grammatikakis I, De S, Abdelmohsen K and Gorospe M: CircInteractome: A web tool for exploring circular RNAs and their interacting proteins and microRNAs. RNA Biol. 13:34–42. 2016. View Article : Google Scholar
26	Zeng K, Chen X, Xu M, Liu X, Hu X, Xu T, Sun H, Pan Y, He B and Wang S: CircHIPK3 promotes colorectal cancer growth and metastasis by sponging miR-7. Cell Death Dis. 9:4172018. View Article : Google Scholar
27	Cheng Z, Yu C, Cui S, Wang H, Jin H, Wang C, Li B, Qin M, Yang C, He J, et al: circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1. Nat Commun. 10:32002019. View Article : Google Scholar
28	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
29	Zhong S, Wang J, Zhang Q, Xu H and Feng J: CircPrimer: A software for annotating circRNAs and determining the specificity of circRNA primers. BMC Bioinformatics. 19:2922018. View Article : Google Scholar
30	Wang Y, Zeng X, Wang N, Zhao W, Zhang X, Teng S, Zhang Y and Lu Z: Long noncoding RNA DANCR, working as a competitive endogenous RNA, promotes ROCK1-mediated proliferation and metastasis via decoying of miR-335-5p and miR-1972 in osteosarcoma. Mol Cancer. 17:892018. View Article : Google Scholar
31	Wang Y, Lu Z, Wang N, Feng J, Zhang J, Luan L, Zhao W and Zeng X: Long noncoding RNA DANCR promotes colorectal cancer proliferation and metastasis via miR-577 sponging. Exp Mol Med. 50:1–17. 2018. View Article : Google Scholar
32	Wang Y, Zhang Y, Yang T, Zhao W, Wang N, Li P, Zeng X and Zhang W: Long non-coding RNA MALAT1 for promoting metastasis and proliferation by acting as a ceRNA of miR-144-3p in osteosarcoma cells. Oncotarget. 8:59417–59434. 2017. View Article : Google Scholar
33	Yan Y, Wang Z and Qin B: A novel long noncoding RNA, LINC00483 promotes proliferation and metastasis via modulating of FMNL2 in CRC. Biochem Biophys Res Commun. 509:441–447. 2019. View Article : Google Scholar
34	Li X, Yang L and Chen LL: The biogenesis, functions, and challenges of circular RNAs. Mol Cell. 71:428–442. 2018. View Article : Google Scholar
35	Arnaiz E, Sole C, Manterola L, Iparraguirre L, Otaegui D and Lawrie CH: CircRNAs and cancer: Biomarkers and master regulators. Semin Cancer Biol. 58:90–99. 2019. View Article : Google Scholar
36	Chen LL: The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 17:205–211. 2016. View Article : Google Scholar
37	Bach DH, Lee SK and Sood AK: Circular RNAs in cancer. Mol Ther Nucleic Acids. 16:118–129. 2019. View Article : Google Scholar
38	Cai C, Zhi Y, Wang K, Zhang P, Ji Z, Xie C and Sun F: CircHIPK3 overexpression accelerates the proliferation and invasion of prostate cancer cells through regulating miRNA-338-3p. OncoTargets Ther. 12:3363–3372. 2019. View Article : Google Scholar
39	Zhang Y, Li C, Liu X, Wang Y, Zhao R, Yang Y, Zheng X, Zhang Y and Zhang X: circHIPK3 promotes oxaliplatin-resistance in colorectal cancer through autophagy by sponging miR-637. EBioMedicine. 48:277–288. 2019. View Article : Google Scholar
40	Chen X, Mao R, Su W, Yang X, Geng Q, Guo C, Wang Z, Wang J, Kresty LA, Beer DG, et al: Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer. Autophagy. 16:659–671. 2020. View Article : Google Scholar
41	Liu WG and Xu Q: Upregulation of circHIPK3 promotes the progression of gastric cancer via Wnt/β-catenin pathway and indicates a poor prognosis. Eur Rev Med Pharmacol Sci. 23:7905–7912. 2019.
42	Zhong Y, Du Y, Yang X, Mo Y, Fan C, Xiong F, Ren D, Ye X, Li C, Wang Y, et al: Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer. 17:792018. View Article : Google Scholar
43	Cui X, Wang J, Guo Z, Li M, Li M, Liu S, Liu H, Li W, Yin X, Tao J and Xu W: Emerging function and potential diagnostic value of circular RNAs in cancer. Mol Cancer. 17:1232018. View Article : Google Scholar
44	Han TS, Hur K, Cho HS and Ban HS: Epigenetic associations between lncRNA/circRNA and miRNA in hepatocellular carcinoma. Cancers (Basel). 12:E26222020. View Article : Google Scholar
45	Du YM and Wang YB: MiR-637 inhibits proliferation and invasion of hepatoma cells by targeted degradation of AKT1. Eur Rev Med Pharmacol Sci. 23:567–575. 2019.
46	Li JX, Ding XM, Han S, Wang K, Jiao CY and Li XC: mir-637 inhibits the proliferation of cholangiocarcinoma cell QBC939 through interfering CTSB expression. Eur Rev Med Pharmacol Sci. 22:1265–1276. 2018.
47	Zhang J, Liu WL, Zhang L, Ge R, He F, Gao TY, Tian Q, Mu X, Chen LH, Chen W and Li X: MiR-637 suppresses melanoma progression through directly targeting P-REX2a and inhibiting PTEN/AKT signaling pathway. Cell Mol Biol (Noisy-le-Grand). 64:50–57. 2018. View Article : Google Scholar