Downregulation of the long non‑coding RNA FOXD2‑AS1 inhibits cell proliferation, migration and invasion in osteosarcoma

Zhang,Haomeng; Lu,Yao; Wang,Jun; Zhang,Tian; Dong,Chuan; Li,Xiaoxiang; Wang,Xinli; Ma,Qiong; Yang,Tongtao; Zhou,Yong

doi:10.3892/mmr.2019.10254

Downregulation of the long non‑coding RNA FOXD2‑AS1 inhibits cell proliferation, migration and invasion in osteosarcoma

Authors:
- Haomeng Zhang
- Yao Lu
- Jun Wang
- Tian Zhang
- Chuan Dong
- Xiaoxiang Li
- Xinli Wang
- Qiong Ma
- Tongtao Yang
- Yong Zhou
View Affiliations

Affiliations: Department of Orthopedic Oncology Institute, Tangdu Hospital, The Second Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710038, P.R. China, Department of Orthopedic Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710054, P.R. China, Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, The First Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Pharmacy, Tangdu Hospital, The Second Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: May 16, 2019 https://doi.org/10.3892/mmr.2019.10254
Pages: 292-302
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Increasing amounts of long noncoding RNAs (lncRNAs) have been shown to be involved in the development of cancer. Recently, aberrant expression of the lncRNA forkhead box D2 adjacent opposite strand RNA1 (FOXD2‑AS1) has been reported to be involved in the progression of several types of human cancer. However, the function and mechanism of FOXD2‑AS1 in osteosarcoma (OS) are currently unclear. The present study aimed to investigate the function and mechanism of FOXD2‑AS1 in OS. Firstly, it was revealed that the expression levels of FOXD2‑AS1 were significantly upregulated in OS tissues and cells, compared with in adjacent tissues and normal cells, as determined using reverse transcription‑quantitative polymerase chain reaction. Notably, the overall survival of patients with relatively high FOXD2‑AS1 expression in OS tissues was significantly lower than that of patients with relatively low expression, as determined using Kaplan‑Meier analysis. In addition, loss‑of‑function experiments were performed in vivo and in vitro to study the biological effects of FOXD2‑AS1. The SOSP‑9607 and U2OS OS cell lines were infected with lentivirus‑mediated FOXD2‑AS1 short hairpin RNA; subsequently, the alterations in cell phenotype and downstream molecules were evaluated. Knockdown of FOXD2‑AS1 inhibited the proliferation, migration and invasion of OS cells. Furthermore, the number of cells in the S phase was significantly decreased, which was consistent with the results of the Cell Counting kit 8 proliferation assay. The expression levels of ribonucleotide reductase regulatory subunit M2 and phosphoglycerate dehydrogenase were decreased, as determined by western blotting, following FOXD2‑AS1 knockdown. Finally, in a nude mouse model of tumorigenesis, it was revealed that, when FOXD2‑AS1 expression was downregulated, tumor growth was significantly reduced and pulmonary metastatic nodules were markedly reduced. The results of the present study suggested that decreased FOXD2‑AS1 expression may inhibit the growth, migration and invasion of tumor cells, and it may regulate downstream gene expression. In conclusion, these findings indicated that FOXD2‑AS1 may be used as a potential therapeutic target and early tumor marker for the diagnosis and prognosis of OS.

View Figures

View References

1	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 : PubMed/NCBI
2	Yang Z, Li X, Yang Y, He Z, Qu X and Zhang Y: Long noncoding RNAs in the progression, metastasis, and prognosis of osteosarcoma. Cell Death Dis. 7:e23892016. View Article : Google Scholar : PubMed/NCBI
3	Lee C and Kikyo N: Strategies to identify long noncoding RNAs involved in gene regulation. Cell Biosci. 2:372012. View Article : Google Scholar : PubMed/NCBI
4	Mattick JS: Non-coding RNAs: The architects of eukaryotic complexity. EMBO Rep. 2:986–991. 2001. View Article : Google Scholar : PubMed/NCBI
5	Di Gesualdo F, Capaccioli S and Lulli M: A pathophysiological view of the long non-coding RNA world. Oncotarget. 5:10976–10996. 2014. View Article : Google Scholar : PubMed/NCBI
6	Chang L, Li C, Lan T, Wu L, Yuan Y, Liu Q and Liu Z: Decreased expression of long non-coding RNA GAS5 indicates a poor prognosisand promotes cell proliferation and invasion in hepatocellular carcinoma by regulating vimentin. Mol Med Rep. 13:1541–1550. 2016. View Article : Google Scholar : PubMed/NCBI
7	Lalevee S and Feil R: Long noncoding RNAs in human disease: Emerging mechanisms and therapeutic strategies. Epigenomics. 7:877–879. 2015. View Article : Google Scholar : PubMed/NCBI
8	Gutschner T and Diederichs S: The hallmarks of cancer: A long non-coding RNA point of view. RNA Biol. 9:703–719. 2012. View Article : Google Scholar : PubMed/NCBI
9	Smolle MA and Pichler M: The role of long non-coding RNAs in osteosarcoma. Noncoding RNA. 4(pii): E72018.PubMed/NCBI
10	Su F, He W, Chen C, Liu M, Liu H, Xue F, Bi J, Xu D, Zhao Y, Huang J, et al: The long non-coding RNA FOXD2-AS1 promotes bladder cancer progression and recurrence through a positive feedback loop with Akt and E2F1. Cell Death Dis. 9:2332018. View Article : Google Scholar : PubMed/NCBI
11	Xiong Y, Wang T, Wang M, Zhao J, Li X, Zhang Z, Zhou Y, Liu J, Jia L and Han Y: Long non-coding RNAs function as novel predictors and targets of non-small cell lung cancer: A systematic review and meta-analysis. Oncotarget. 9:11377–11386. 2018. View Article : Google Scholar : PubMed/NCBI
12	Zhang J, Fan D, Jian Z, Chen GG and Lai PB: Cancer specific long noncoding RNAs show differential expression patterns and competing endogenous RNA potential in hepatocellular carcinoma. PLoS One. 10:e1410422015.
13	Chen X, Yang TT, Wang W, Sun HH, Ma BA, Li CX, Ma Q, Yu Z and Fan QY: Establishment and characterization of human osteosarcoma cell lines with different pulmonary metastatic potentials. Cytotechnology. 61:37–44. 2009. View Article : Google Scholar : PubMed/NCBI
14	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 : PubMed/NCBI
15	Benjamin RS: Osteosarcoma: Better treatment through better trial design. Lancet Oncol. 16:12–13. 2015. View Article : Google Scholar : PubMed/NCBI
16	Durnali A, Alkis N, Cangur S, Yukruk FA, Inal A, Tokluoglu S, Seker MM, Bal O, Akman T, Inanc M, et al: Prognostic factorsfor teenage and adult patients with high-grade osteosarcoma: An analysis of 240 patients. Med Oncol. 30:6242013. View Article : Google Scholar : PubMed/NCBI
17	Miller BJ, Cram P, Lynch CF and Buckwalter JA: Risk factors for metastatic disease at presentation with osteosarcoma: An analysis of the SEER database. J Bone Joint Surg Am. 95:e892013. View Article : Google Scholar : PubMed/NCBI
18	Chan JJ and Tay Y: Noncoding RNA: RNA regulatory networks in cancer. Int J Mol Sci. 19(pii): E13102018. View Article : Google Scholar : PubMed/NCBI
19	Wang YL, Shao J, Wu X, Li T, Xu M and Shi D: A long non-coding RNA signature for predicting survival in patients with colorectal cancer. Oncotarget. 9:21687–21695. 2017.PubMed/NCBI
20	Tuo YL, Li XM and Luo J: Long noncoding RNA UCA1 modulates breast cancer cell growth and apoptosis through decreasing tumor suppressive miR-143. Eur Rev Med Pharmacol Sci. 19:3403–3411. 2015.PubMed/NCBI
21	Nie W, Ge HJ, Yang XQ, Sun X, Huang H, Tao X, Chen WS and Li B: LncRNA-UCA1 exerts oncogenic functions in non-small cell lung cancer by targeting miR-193a-3p. Cancer Lett. 371:99–106. 2016. View Article : Google Scholar : PubMed/NCBI
22	Arab K, Park YJ, Lindroth AM, Schäfer A, Oakes C, Weichenhan D, Lukanova A, Lundin E, Risch A, Meister M, et al: Long noncoding RNA TARID directs demethylation and activation of the tumor suppressor TCF21 via GADD45A. Mol Cell. 55:604–614. 2014. View Article : Google Scholar : PubMed/NCBI
23	Chen F, Mo J and Zhang L: Long noncoding RNA BCAR4 promotes osteosarcoma progression through activating GLI2-dependent gene transcription. Tumour Biol. 37:13403–13412. 2016. View Article : Google Scholar : PubMed/NCBI
24	Sun XH, Yang LB, Geng XL, Wang R and Zhang ZC: Increased expression of lncRNA HULC indicates a poor prognosis and promotes cell metastasis in osteosarcoma. Int J Clin Exp Pathol. 8:2994–3000. 2015.PubMed/NCBI
25	Cao L, Wang Y, Wang Q and Huang J: LncRNA FOXD2-AS1 regulates chondrocyte proliferation in osteoarthritis by acting as a sponge of miR-206 to modulate CCND1 expression. Biomed Pharmacother. 106:1220–1226. 2018. View Article : Google Scholar : PubMed/NCBI
26	Yang X, Duan B and Zhou X: Long non-coding RNA FOXD2-AS1 functions as a tumor promoter in colorectal cancer by regulating EMT and Notch signaling pathway. Eur Rev Med Pharmacol Sci. 21:3586–3591. 2017.PubMed/NCBI
27	Hainaut P and Plymoth A: Targeting the hallmarks of cancer: Towards a rational approach to next-generation cancer therapy. Curr Opin Oncol. 25:50–51. 2013. View Article : Google Scholar : PubMed/NCBI
28	Ou Y, Wang SJ, Jiang L, Zheng B and Gu W: p53 Protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. J Biol Chem. 290:457–466. 2015. View Article : Google Scholar : PubMed/NCBI
29	Jing Z, Heng W, Xia L, Ning W, Yafei Q, Yao Z and Shulan Z: Downregulation of phosphoglycerate dehydrogenase inhibits proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma cells by regulating Bcl-2 and caspase-3. Cancer Biol Ther. 16:541–548. 2015. View Article : Google Scholar : PubMed/NCBI
30	Fellenberg J, Bernd L, Delling G, Witte D and Zahlten- Hinguranage A: Prognostic significance of drug-regulated genes in high-grade osteosarcoma. Mod Pathol. 20:1085–1094. 2007. View Article : Google Scholar : PubMed/NCBI
31	Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U, Karreth F, Poliseno L, Provero P, Di Cunto F, et al: Coding-independentregulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell. 147:344–357. 2011. View Article : Google Scholar : PubMed/NCBI
32	Salmena L, Poliseno L, Tay Y, Kats L and Pandolfi PP: A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language. Cell. 146:353–358. 2011. View Article : Google Scholar : PubMed/NCBI