Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2021 | Glioblastoma | Research

Novel LncRNA OXCT1-AS1 indicates poor prognosis and contributes to tumorigenesis by regulating miR-195/CDC25A axis in glioblastoma

Authors: Chen Zhong, Qian Yu, Yucong Peng, Shengjun Zhou, Zhendong Liu, Yong Deng, Leiguang Guo, Shiguang Zhao, Gao Chen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Long noncoding RNAs (lncRNAs) contribute to multiple biological processes in human glioblastoma (GBM). However, identifying a specific lncRNA target remains a challenge. In this study, bioinformatics methods and competing endogenous RNA (ceRNA) network regulatory rules were used to identify GBM-related lncRNAs and revealed that OXCT1 antisense RNA 1 (OXCT1-AS1) is a potential therapeutic target for the treatment of glioma.

Methods

Based on the Gene Expression Omnibus (GEO) dataset, we identified differential lncRNAs, microRNAs and mRNAs and constructed an lncRNA-associated ceRNA network.

The novel lncRNA OXCT1-AS1 was proposed to function as a ceRNA, and its potential target miRNAs were predicted through the database LncBase Predicted v.2. The expression patterns of OXCT1-AS1 in glioma and normal tissue samples were measured. The effect of OXCT1-AS1 on glioma cells was checked using the Cell Counting Kit 8 assay, cell colony formation assay, Transwell assay and flow cytometry in vitro. The dual-luciferase activity assay was performed to investigate the potential mechanism of the ceRNA network. Finally, orthotopic mouse models of glioma were created to evaluate the influence of OXCT1-AS1 on tumour growth in vivo.

Results

In this study, it was found that the expression of lncRNA OXCT1-AS1 was upregulated in both The Cancer Genome Atlas (TCGA) GBM patients and GBM tissue samples, and high expression of OXCT1-AS1 predicted a poor prognosis. Suppressing OXCT1-AS1 expression significantly decreased GBM cell proliferation and inhibited cell migration and invasion. We further investigated the potential mechanism and found that OXCT1-AS1 may act as a ceRNA of miR-195 to enhance CDC25A expression and promote glioma cell progression. Finally, knocking down OXCT1-AS1 notably attenuated the severity of glioma in vivo.

Conclusion

OXCT1-AS1 inhibits glioma progression by regulating the miR-195-5p/CDC25A axis and is a specific tumour marker and a novel potential therapeutic target for glioma treatment.

Available only for authorised users

Mary D. Glioblastoma: overview of disease and treatment. Clin J Oncol Nurs. 2016;20(5 Suppl):S2–8.

Brandner S, Jaunmuktane Z. Neurological update: gliomas and other primary brain tumours in adults. J Neurol. 2018;265(3):717–27. https://doi.org/10.1007/s00415-017-8652-3.CrossRefPubMed

Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma subclassifications and their clinical significance. Neurotherapeutics. 2017;14(2):1–14.CrossRef

Alan O, Telli TA, Tuylu TB, Arikan R, Demircan NC, Ercelep O, et al. Prognostic factors in progressive high-grade glial tumors treated with systemic approach: A single center experience. J Oncol Pharm Pract. 2020;0(0):1078155220920684.

Jiang HH, Lin S. Current status and prospect in the treatment of glioblastoma. Zhonghua wai ke za zhi Chinese J Surg. 2020;58(1):70–4. https://doi.org/10.3760/cma.j.issn.0529-5815.2020.01.015.CrossRef

Chen RS-CM, Cohen AL, Colman H. Molecular profiling of gliomas: potential therapeutic implications. Expert Rev Anticancer Ther. 2015;15(8):955–62.CrossRef

Zhou L, Tang H, Wang F, Chen L, Ou S, Wu T, et al. Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in glioblastoma. Mol Med Rep. 2018;18(5):4185–96. https://doi.org/10.3892/mmr.2018.9411.

Dragomir MP, Kopetz S, Ajani JA, Calin GA. Non-coding RNAs in GI cancers: from cancer hallmarks to clinical utility. Gut. 2020;69(4):748–63. https://doi.org/10.1136/gutjnl-2019-318279.CrossRefPubMed

Grillone K, Riillo C, Scionti F, Rocca R, Tassone P. Non-coding RNAs in cancer: platforms and strategies for investigating the genomic “dark matter”. J Exp Clin Cancer Res. 2020;39(1):117. https://doi.org/10.1186/s13046-020-01622-x.CrossRefPubMedPubMedCentral

10.

Liao Y, Jung SH, Kim T. A-to-I RNA editing as a tuner of noncoding RNAs in cancer. Cancer Lett. 2020;494:88–93. https://doi.org/10.1016/j.canlet.2020.08.004.CrossRefPubMed

11.

Costa FF. Non-coding RNAs: meet thy masters. Bioessays. 2010;32(7):599–608. https://doi.org/10.1002/bies.200900112.CrossRefPubMed

12.

Choudhari R, Sedano MJ, Harrison AL, Subramani R, Lin KY, Ramos EI, et al. Long noncoding RNAs in cancer: from discovery to therapeutic targets. Adv Clin Chem. 2020;95:105–47.CrossRef

13.

Zhang X-Z, Liu H, Chen S-R. Mechanisms of Long non-coding RNAs in cancers and their dynamic regulations. Cancers. 2020;12(5):1245. https://doi.org/10.3390/cancers12051245.CrossRefPubMedCentral

14.

Peng Z, Liu C, Wu M. New insights into long noncoding RNAs and their roles in glioma. Mol Cancer. 2018;17(1):61. https://doi.org/10.1186/s12943-018-0812-2.CrossRefPubMedPubMedCentral

15.

Tay Y, Rinn J, Pandolfi PP. The multilayered complexity of ceRNA crosstalk and competition. Nature. 2014;505(7483):344–52. https://doi.org/10.1038/nature12986.CrossRefPubMedPubMedCentral

16.

Chen W, Li Q, Zhang G, Wang H, Zhu Z, Chen L. LncRNA HOXA-AS3 promotes the malignancy of glioblastoma through regulating miR-455-5p/USP3 axis. J Cell Mol Med. 2020;24(20):11755–67. https://doi.org/10.1111/jcmm.15788.CrossRefPubMedPubMedCentral

17.

Yu M, Xue Y, Zheng J, Liu X, Yu H, Liu L, et al. Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway. Mol Cancer. 2017;16(1):110. https://doi.org/10.1186/s12943-017-0677-9.

18.

Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell. 2006;9(4):287–300. https://doi.org/10.1016/j.ccr.2006.03.003.

19.

TE Gulluoglu S, Sahin M, Kuskucu A, Kaan Yaltirik C, Ture U, Kucukkaraduman B, et al. Simultaneous miRNA and mRNA Transcriptome profiling of Glioblastoma samples reveals a novel set of OncomiR candidates and their target genes. Brain Res. 2018;1700:199–210.

20.

Feng F, Wu J, Gao Z, Yu S, Cui Y. Screening the key microRNAs and transcription factors in prostate cancer based on microRNA functional synergistic relationships. Medicine (Baltimore). 2017;96(1):e5679. https://doi.org/10.1097/MD.0000000000005679.CrossRef

21.

Zhang J, Zhou YJ, Yu ZH, Chen AX, Cao XC. Identification of core genes and clinical roles in pregnancy-associated breast cancer based on integrated analysis of different microarray profile datasets. Bioence Reports. 2019;39(6):BSR20190019.

22.

Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11(10):R106. https://doi.org/10.1186/gb-2010-11-10-r106.CrossRefPubMedPubMedCentral

23.

Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, et al. Integration of biological networks and gene expression data using Cytoscape. Nat Protoc. 2007;2(10):2366–82. https://doi.org/10.1038/nprot.2007.324.

24.

Yin J, Zeng X, Ai Z, Yu M, Yo W, Li S. Construction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in oral cancer. BMC Med Genet. 2020;13(1):84.

25.

von Mering CHM, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31(1):258–61. https://doi.org/10.1093/nar/gkg034.CrossRef

26.

Yi F, Sun M, Dai G, Ramani K. The intrinsic geometric structure of protein-protein interaction networks for protein interaction prediction. IEEE/ACM Trans Comput Biol Bioinform. 2016;13(1):76–85.CrossRef

27.

Ana M. María, Blanco-Prieto, João, Sousa, et al. breaching barriers in glioblastoma. Part I: molecular pathways and novel treatment approaches. Int J Pharm. 2017;531(1):372–88.CrossRef

28.

Taylor OG, Brzozowski JS, Skelding KA. Glioblastoma Multiforme: an overview of emerging therapeutic targets. Front Oncol. 2019;9:963. https://doi.org/10.3389/fonc.2019.00963.CrossRefPubMedPubMedCentral

29.

Athina K-S, Kleita M, Andreas S, et al. Long Noncoding RNAs in Digestive System Malignancies: A Novel Class of Cancer Biomarkers and Therapeutic Targets? Gastroenterol Res Pract. 2015;2015:319861.

30.

Fatima R, Akhade VS, Pal D, Rao SM. Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol Cell Ther. 2015;3(1):5. https://doi.org/10.1186/s40591-015-0042-6.CrossRefPubMedPubMedCentral

31.

Wang L, Cho KB, Li Y, Tao G, Guo B. Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal Cancer. Int J Mol Ences. 2019;20(22):5758.CrossRef

32.

Cheng B, Rong A, Zhou Q, Li W. LncRNA LINC00662 promotes colon cancer tumor growth and metastasis by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway. J Exp Clin Cancer Res. 2020;39(1):5. https://doi.org/10.1186/s13046-019-1510-7.CrossRefPubMedPubMedCentral

33.

Zhang H, Zhu C, He Z, Chen S, Li L, Sun C. LncRNA PSMB8-AS1 contributes to pancreatic cancer progression via modulating miR-382-3p/STAT1/PD-L1 axis. J Exp Clin Cancer Res. 2020;39(1):179. https://doi.org/10.1186/s13046-020-01687-8.CrossRefPubMedPubMedCentral

34.

Liao K, Lin Y, Gao W, Xiao Z, Guo L. Blocking lncRNA MALAT1/miR-199a/ZHX1 axis inhibits glioblastoma proliferation and progression. Mol Ther Nucleic Acids. 2019;18:388–99. https://doi.org/10.1016/j.omtn.2019.09.005.CrossRefPubMedPubMedCentral

35.

Jin M, Wang L, Zheng T, Yu J, Sheng R, Zhu H. MiR-195-3p inhibits cell proliferation in cervical cancer by targeting BCDIN3D. J Reprod Immunol. 2020;143:103211.

36.

Liu X, Zhou Y, Ning YE, Gu H, Tong Y, Wang N. MiR-195-5p inhibits malignant progression of cervical Cancer by targeting YAP1. Oncotargets Ther. 2020;13:931–44. https://doi.org/10.2147/OTT.S227826.

37.

Long Z, Wang Y. miR-195-5p Suppresses Lung Cancer Cell Proliferation, Migration, and Invasion Via FOXK1. Technol Cancer Res Treatment. 2020;19:1533033820922587.

38.

Cai C, Chen QB, Han ZD, Zhang YQ, He HC, Chen JH, et al. miR-195 inhibits tumor progression by targeting RPS6KB1 in human prostate Cancer. Clin Cancer Res. 2015;21(21):4922–34. https://doi.org/10.1158/1078-0432.CCR-15-0217.

39.

Singh R, Yadav V, Kumar S, Saini N. MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1. Sci Rep. 2015;5(1):17454. https://doi.org/10.1038/srep17454.

40.

Sadeghi H, Golalipour M, Yamchi A, Farazmandfar T, Shahbazi M. CDC25A pathway toward tumorigenesis: molecular targets of CDC25A in cell-cycle regulation. J Cell Biochem. 2019;120(3):2919–28. https://doi.org/10.1002/jcb.26838.CrossRefPubMed

41.

Blomberg I, Hoffmann I. Ectopic expression of Cdc25A accelerates the G1/S transition and leads to premature activation of Cyclin E- and Cyclin A-dependent kinases. Mol Cell Biol. 1999;19(9):6183–94. https://doi.org/10.1128/MCB.19.9.6183.CrossRefPubMedPubMedCentral

42.

Kabakci Z, Käppeli S, Cantù C, Jensen LD, König C, Toggweiler J, et al. Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression. Sci Rep. 2019;9(1):1335. https://doi.org/10.1038/s41598-019-38579-7.CrossRefPubMedPubMedCentral

Title: Novel LncRNA OXCT1-AS1 indicates poor prognosis and contributes to tumorigenesis by regulating miR-195/CDC25A axis in glioblastoma
Authors: Chen Zhong
Qian Yu
Yucong Peng
Shengjun Zhou
Zhendong Liu
Yong Deng
Leiguang Guo
Shiguang Zhao
Gao Chen
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Glioblastoma
Glioma
Glioma
Glioblastoma
Glioblastoma
Glioma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01928-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Circulating tumor DNA tracking through driver mutations as a liquid biopsy-based biomarker for uveal melanoma

LINC00460/DHX9/IGF2BP2 complex promotes colorectal cancer proliferation and metastasis by mediating HMGA1 mRNA stability depending on m6A modification

ZIP10 is a negative determinant for anti-tumor effect of mannose in thyroid cancer by activating phosphate mannose isomerase

Pyroptosis: a new paradigm of cell death for fighting against cancer

Circ_0119872 promotes uveal melanoma development by regulating the miR-622/G3BP1 axis and downstream signalling pathways

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor

Keynote webinar | Spotlight on antibody–drug conjugates in cancer