UBDP1 pseudogene and UBD network competitively bind miR‑6072 to promote glioma progression

Hong,Fan; Gong,Zhenyu; Chen,Chao; Hua,Tianzhen; Huang,Qilin; Liu,Yu'e; Ma,Peipei; Zhang,Xu; Wang,Hongxiang; Chen,Juxiang

doi:10.3892/ijo.2024.5617

UBDP1 pseudogene and UBD network competitively bind miR‑6072 to promote glioma progression

Authors:
- Fan Hong
- Zhenyu Gong
- Chao Chen
- Tianzhen Hua
- Qilin Huang
- Yu'e Liu
- Peipei Ma
- Xu Zhang
- Hongxiang Wang
- Juxiang Chen
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Affiliations: Department of Neurosurgery, Second Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui 230601, P.R. China, Department of Neurosurgery, Klinikum rechts der Isar, Technical University of Munich, D‑81675 Munich, Germany, Department of Neurosurgery, Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China, Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, P.R. China
Published online on: January 22, 2024 https://doi.org/10.3892/ijo.2024.5617
Article Number: 29
Copyright: © Hong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Increasing evidence suggests that pseudogenes play crucial roles in various cancers, yet their functions and regulatory mechanisms in glioma pathogenesis remain enigmatic. In the present study, a novel pseudogene was identified, UBDP1, which is significantly upregulated in glioblastoma and positively correlated with the expression of its parent gene, UBD. Additionally, high levels of these paired genes are linked with a poor prognosis for patients. In the present study, clinical samples were collected followed by various analyses including microarray for long non‑coding RNAs, reverse transcription‑quantitative PCR, fluorescence in situ hybridization and western blotting. Cell lines were authenticated and cultured then subjected to various assays for proliferation, migration, and invasion to investigate the molecular mechanisms. Bioinformatic tools identified miRNA targets, and luciferase reporter assays validated these interactions. A tumor xenograft model in mice was used for in vivo studies. In vitro and in vivo studies have demonstrated that UBDP1, localized in the cytoplasm, functions as a tumor‑promoting factor influencing cell proliferation, migration, invasion and tumor growth. Mechanistic investigations have indicated that UBDP1 exerts its oncogenic effects by decoying miR‑6072 from UBD mRNA, thus forming a competitive endogenous RNA network, which results in the enhanced oncogenic activity of UBD. The present findings offered new insights into the role of pseudogenes in glioma progression, suggesting that targeting the UBDP1/miR‑6072/UBD network may serve as a potential therapeutic strategy for glioma patients.

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1	Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, et al: Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: A secondary analysis of a randomized clinical trial. JAMA Oncol. 4:495–504. 2018.
2	Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, et al: Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA. 318:2306–2316. 2017.
3	Pink RC and Carter DRF: Pseudogenes as regulators of biological function. Essays Biochem. 54:103–112. 2013.
4	Lou W, Ding B and Fu P: Pseudogene-derived lncRNAs and Their miRNA sponging mechanism in human cancer. Front Cell Dev Biol. 8:852020.
5	Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ and Pandolfi PP: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 465:1033–1038. 2010.
6	Chan JJ, Kwok ZH, Chew XH, Zhang B, Liu C, Soong TW, Yang H and Tay Y: A FTH1 gene:Pseudogene:microRNA network regulates tumorigenesis in prostate cancer. Nucleic Acids Res. 46:1998–2011. 2018.
7	Karreth FA, Reschke M, Ruocco A, Ng C, Chapuy B, Léopold V, Sjoberg M, Keane TM, Verma A, Ala U, et al: The BRAF pseudogene functions as a competitive endogenous RNA and induces lymphoma in vivo. Cell. 161:319–332. 2015.
8	Zhou D, Ren K, Wang M, Wang J, Li E, Hou C, Su Y, Jin Y, Zou Q, Zhou P and Liu X: Long non-coding RNA RACGAP1P promotes breast cancer invasion and metastasis via miR-345-5p/RACGAP1-mediated mitochondrial fission. Mol Oncol. 15:543–559. 2021.
9	Gao KM, Chen XC, Zhang JX, Wang Y, Yan W and You YP: A pseudogene-signature in glioma predicts survival. J Exp Clin Cancer Res. 34:232015.
10	Wang Y, Liu X, Guan G, Xiao Z, Zhao W and Zhuang M: Identification of a five-pseudogene signature for predicting survival and its ceRNA network in glioma. Front Oncol. 9:10592019.
11	Wang S, Qi Y, Gao X, Qiu W, Liu Q, Guo X, Qian M, Chen Z, Zhang Z, Wang H, et al: Hypoxia-induced lncRNA PDIA3P1 promotes mesenchymal transition via sponging of miR-124-3p in glioma. Cell Death Dis. 11:1682020.
12	Liao K, Qian Z, Zhang S, Chen B, Li Z, Huang R, Cheng L, Wang T, Yang R, Lan J, et al: The LGMN pseudogene promotes tumor progression by acting as a miR-495-3p sponge in glioblastoma. Cancer Lett. 490:111–123. 2020.
13	Du P, Liao Y, Zhao H, Zhang J, Muyiti Keremu and Mu K: ANXA2P2/miR-9/LDHA axis regulates Warburg effect and affects glioblastoma proliferation and apoptosis. Cell Signal. 74:1097182020.
14	Theng SS, Wang W, Mah WC, Chan C, Zhuo J, Gao Y, Qin H, Lim L, Chong SS, Song J and Lee CG: Disruption of FAT10-MAD2 binding inhibits tumor progression. Proc Natl Acad Sci USA. 111:E5282–E5291. 2014.
15	Yuan R, Wang K, Hu J, Yan C, Li M, Yu X, Liu X, Lei J, Guo W, Wu L, et al: Ubiquitin-like protein FAT10 promotes the invasion and metastasis of hepatocellular carcinoma by modifying β-catenin degradation. Cancer Res. 74:5287–5300. 2014.
16	Ma C, Zhang Z, Cui Y, Yuan H and Wang F: Silencing Fat10 inhibits metastasis of osteosarcoma. Int J Oncol. 49:666–674. 2016.
17	Zou Y, Ouyang Q, Wei W, Yang S, Zhang Y and Yang W: FAT10 promotes the invasion and migration of breast cancer cell through stabilization of ZEB2. Biochem Biophys Res Commun. 506:563–570. 2018.
18	Xue F, Zhu L, Meng QW, Wang L, Chen XS, Zhao YB, Xing Y, Wang XY and Cai L: FAT10 is associated with the malignancy and drug resistance of non-small-cell lung cancer. Onco Targets Ther. 9:4397–4409. 2016.
19	Yuan J, Tu Y, Mao X, He S, Wang L, Fu G, Zong J and Zhang Y: Increased expression of FAT10 is correlated with progression and prognosis of human glioma. Pathol Oncol Res. 18:833–839. 2012.
20	Dai B, Zhang Y, Zhang P, Pan C, Xu C, Wan W, Wu Z, Zhang J and Zhang L: Upregulation of p-Smad2 contributes to FAT10-induced oncogenic activities in glioma. Tumour Biol. 37:8621–8631. 2016.
21	Yan Y, Zhang L, Jiang Y, Xu T, Mei Q, Wang H, Qin R, Zou Y, Hu G, Chen J and Lu Y: LncRNA and mRNA interaction study based on transcriptome profiles reveals potential core genes in the pathogenesis of human glioblastoma multiforme. J Cancer Res Clin Oncol. 141:827–838. 2015.
22	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.
23	Zhou J, Wang H, Hong F, Hu S, Su X, Chen J and Chu J: CircularRNA circPARP4 promotes glioblastoma progression through sponging miR-125a-5p and regulating FUT4. Am J Cancer Res. 11:138–156. 2021.
24	He H, Wang Y, Ye P, Yi D, Cheng Y, Tang H, Zhu Z, Wang X and Jin S: Long noncoding RNA ZFPM2-AS1 acts as a miRNA sponge and promotes cell invasion through regulation of miR-139/GDF10 in hepatocellular carcinoma. J Exp Clin Cancer Res. 39:1592020.
25	Cui Y, Yi L, Zhao JZ and Jiang YG: Long noncoding RNA HOXA11-AS functions as miRNA sponge to promote the glioma tumorigenesis through targeting miR-140-5p. DNA Cell Biol. 36:822–828. 2017.
26	Zhang JY, Wang M, Tian L, Genovese G, Yan P, Wilson JG, Thadhani R, Mottl AK, Appel GB, Bick AG, et al: UBD modifies APOL1-induced kidney disease risk. Proc Natl Acad Sci USA. 115:3446–3451. 2018.
27	Aichem A and Groettrup M: The ubiquitin-like modifier FAT10 in cancer development. Int J Biochem Cell Biol. 79:451–461. 2016.
28	Liu X, Chen L, Ge J, Yan C, Huang Z, Hu J, Wen C, Li M, Huang D, Qiu Y, et al: The ubiquitin-like protein FAT10 stabilizes eEF1A1 expression to promote tumor proliferation in a complex manner. Cancer Res. 76:4897–4907. 2016.
29	Wu D, Wang L, Yang Y, Huang J, Hu Y, Shu Y, Zhang J and Zheng J: MAD2-p31^comet axis deficiency reduces cell proliferation, migration and sensitivity of microtubule-interfering agents in glioma. Biochem Biophys Res Commun. 498:157–163. 2018.
30	Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MAA, Motta FJN, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, et al: Gene expression profile analysis of primary glioblastomas and non-neoplastic brain tissue: Identification of potential target genes by oligonucleotide microarray and real-time quantitative PCR. J Neurooncol. 88:281–291. 2008.
31	Biterge-Sut B: Alterations in eukaryotic elongation factor complex proteins (EEF1s) in cancer and their implications in epigenetic regulation. Life Sci. 238:1169772019.
32	Choi Y, Kim JK and Yoo JY: NFκB and STAT3 synergistically activate the expression of FAT10, a gene counteracting the tumor suppressor p53. Mol Oncol. 8:642–655. 2014.
33	Wang H, Xu T, Jiang Y, Xu H, Yan Y, Fu D and Chen J: The challenges and the promise of molecular targeted therapy in malignant gliomas. Neoplasia. 17:239–255. 2015.
34	Yan J, Lei J, Chen L, Deng H, Dong D, Jin T, Liu X, Yuan R, Qiu Y, Ge J, et al: Human leukocyte antigen F locus adjacent transcript 10 overexpression disturbs WISP1 protein and mRNA expression to promote hepatocellular carcinoma progression. Hepatology. 68:2268–2284. 2018.
35	Jing D, Zhang Q, Yu H, Zhao Y and Shen L: Identification of WISP1 as a novel oncogene in glioblastoma. Int J Oncol. 51:1261–1270. 2017.
36	Tao W, Chu C, Zhou W, Huang Z, Zhai K, Fang X, Huang Q, Zhang A, Wang X, Yu X, et al: Dual role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Nat Commun. 11:30152020.
37	He L, Zhou H, Zeng Z, Yao H, Jiang W and Qu H: Wnt/β-catenin signaling cascade: A promising target for glioma therapy. J Cell Physiol. 234:2217–2228. 2019.
38	Allen M, Bjerke M, Edlund H, Nelander S and Westermark B: Origin of the U87MG glioma cell line: Good news and bad news. Sci Transl Med. 8:354re32016.
39	Chen X, Wan L, Wang W, Xi WJ, Yang AG and Wang T: Re-recognition of pseudogenes: From molecular to clinical applications. Theranostics. 10:1479–1499. 2020.
40	Johnsson P, Ackley A, Vidarsdottir L, Lui WO, Corcoran M, Grandér D and Morris KV: A pseudogene long-noncoding-RNA network regulates PTEN transcription and translation in human cells. Nat Struct Mol Biol. 20:440–446. 2013.
41	Xu Y, Yu X, Wei C, Nie F, Huang M and Sun M: Over-expression of oncigenic pesudogene DUXAP10 promotes cell proliferation and invasion by regulating LATS1 and β-catenin in gastric cancer. J Exp Clin Cancer Res. 37:132018.
42	Lee CGL, Ren J, Cheong ISY, Ban KHK, Ooi LLPJ, Yong Tan S, Kan A, Nuchprayoon I, Jin R, Lee KH, et al: Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers. Oncogene. 22:2592–2603. 2003.
43	Lukasiak S, Schiller C, Oehlschlaeger P, Schmidtke G, Krause P, Legler DF, Autschbach F, Schirmacher P, Breuhahn K and Groettrup M: Proinflammatory cytokines cause FAT10 upregulation in cancers of liver and colon. Oncogene. 27:6068–6074. 2008.
44	Buerger S, Herrmann VL, Mundt S, Trautwein N, Groettrup M and Basler M: The ubiquitin-like modifier FAT10 is selectively expressed in medullary thymic epithelial cells and modifies T cell selection. J Immunol. 195:4106–4116. 2015.
45	Canaan A, Yu X, Booth CJ, Lian J, Lazar I, Gamfi SL, Castille K, Kohya N, Nakayama Y, Liu YC, et al: FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences. Mol Cell Biol. 26:5180–1589. 2006.
46	Basler M, Buerger S and Groettrup M: The ubiquitin-like modifier FAT10 in antigen processing and antimicrobial defense. Mol Immunol. 68:129–132. 2015.
47	Kandel-Kfir M, Garcia-Milan R, Gueta I, Lubitz I, Ben-Zvi I, Shaish A, Shir L, Harats D, Mahajan M, Canaan A and Kamari Y: IFNγ potentiates TNFα/TNFR1 signaling to induce FAT10 expression in macrophages. Mol Immunol. 117:101–109. 2020.