Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Prognostic Significance and Functional Mechanism of UTS2 in Glioblastoma Multiforme

Author(s): Yanfei Wang, Langping Shen and Mingzhong Sun*

Volume 25, Issue 6, 2025

Published on: 23 January, 2024

Page: [636 - 647] Pages: 12

DOI: 10.2174/0115680096275291231226081320

Price: $65

Abstract

Aim: We aimed to explore the role of urotensin 2 (UTS2) in glioblastoma (GBM).

Background: GBM is the most malignant primary brain cancer with a poor prognosis. Previous studies have suggested that GBM vessels undergo dynamic remodeling modulated by tumor vasodilation and vasoconstriction instead of tumor angiogenesis.

Objective: Here, we have first investigated the expression and function of UTS2, a potent vasoconstrictor, in GBM.

Methods: The mRNA expression profiles and clinical information of GBM patients were obtained from the TCGA database. The clinical relevance of UTS2 was explored by the Mann-Whitney U test and Cox hazard regression survival test. We further explored the role of UTS2 in GBM cell proliferation, migration, and tumor immune microenvironment. Moreover, we established the in vivo mice model to validate its oncogenic effects on GBM progression.

Results: Although we did not find significant correlations between UTS2 expression and patients’ clinical characteristics, UTS2 was identified as a valid independent prognostic indicator according to multivariate survival analysis. Knockdown of UTS2 resulted in decreased GBM cell proliferation and migration. In addition, functional enrichment analysis implied UTS2 to be involved in the regulation of the immune microenvironment. In vivo studies showed that UTS2 knockdown suppressed GBM xenograft growth, highlighting the tumor-promoting effects of UTS2 on GBM.

Conclusion: Our study identified that UTS2 could predict the prognosis of GBM patients and provided evidence regarding its oncogenic effects both in vitro and in vivo.

Keywords: Glioblastoma multiform, vasoconstriction, cell proliferation, survival analysis, immune activation, potent vasoconstrictor.

« Previous Next »
Graphical Abstract

[1]
Omuro, A.; DeAngelis, L.M. Glioblastoma and other malignant gliomas: A clinical review. JAMA, 2013, 310(17), 1842-1850.
[http://dx.doi.org/10.1001/jama.2013.280319] [PMID: 24193082]
[2]
Wen, P.Y.; Reardon, D.A. Progress in glioma diagnosis, classification and treatment. Nat. Rev. Neurol., 2016, 12(2), 69-70.
[http://dx.doi.org/10.1038/nrneurol.2015.242] [PMID: 26782337]
[3]
Melin, B.S.; Barnholtz-Sloan, J.S.; Wrensch, M.R.; Johansen, C.; Il’yasova, D.; Kinnersley, B.; Ostrom, Q.T.; Labreche, K.; Chen, Y.; Armstrong, G.; Liu, Y.; Eckel-Passow, J.E.; Decker, P.A.; Labussière, M.; Idbaih, A.; Hoang-Xuan, K.; Di Stefano, A.L.; Mokhtari, K.; Delattre, J.Y.; Broderick, P.; Galan, P.; Gousias, K.; Schramm, J.; Schoemaker, M.J.; Fleming, S.J.; Herms, S.; Heilmann, S.; Nöthen, M.M.; Wichmann, H.E.; Schreiber, S.; Swerdlow, A.; Lathrop, M.; Simon, M.; Sanson, M.; Andersson, U.; Rajaraman, P.; Chanock, S.; Linet, M.; Wang, Z.; Yeager, M.; Wiencke, J.K.; Hansen, H.; McCoy, L.; Rice, T.; Kosel, M.L.; Sicotte, H.; Amos, C.I.; Bernstein, J.L.; Davis, F.; Lachance, D.; Lau, C.; Merrell, R.T.; Shildkraut, J.; Ali-Osman, F.; Sadetzki, S.; Scheurer, M.; Shete, S.; Lai, R.K.; Claus, E.B.; Olson, S.H.; Jenkins, R.B.; Houlston, R.S.; Bondy, M.L. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nat. Genet., 2017, 49(5), 789-794.
[http://dx.doi.org/10.1038/ng.3823] [PMID: 28346443]
[4]
Sareen, H.; Ma, Y.; Becker, T.M.; Roberts, T.L.; de Souza, P.; Powter, B. Molecular biomarkers in glioblastoma: A systematic review and meta-analysis. Int. J. Mol. Sci., 2022, 23(16), 8835.
[http://dx.doi.org/10.3390/ijms23168835] [PMID: 36012105]
[5]
Ye, H.; Wang, K.; Wang, M.; Liu, R.; Song, H.; Li, N.; Lu, Q.; Zhang, W.; Du, Y.; Yang, W.; Zhong, L.; Wang, Y.; Yu, B.; Wang, H.; Kan, Q.; Zhang, H.; Wang, Y.; He, Z.; Sun, J. Bioinspired nanoplatelets for chemo-photothermal therapy of breast cancer metastasis inhibition. Biomaterials, 2019, 206, 1-12.
[http://dx.doi.org/10.1016/j.biomaterials.2019.03.024] [PMID: 30921730]
[6]
Ye, H.; Wang, K.; Lu, Q.; Zhao, J.; Wang, M.; Kan, Q.; Zhang, H.; Wang, Y.; He, Z.; Sun, J. Nanosponges of circulating tumor-derived exosomes for breast cancer metastasis inhibition. Biomaterials, 2020, 242, 119932.
[http://dx.doi.org/10.1016/j.biomaterials.2020.119932] [PMID: 32169772]
[7]
Zhao, J.; Ye, H.; Lu, Q.; Wang, K.; Chen, X.; Song, J.; Wang, H.; Lu, Y.; Cheng, M.; He, Z.; Zhai, Y.; Zhang, H.; Sun, J. Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs. J. Nanobiotechnology, 2022, 20(1), 62.
[http://dx.doi.org/10.1186/s12951-022-01270-7] [PMID: 35109878]
[8]
Oren, O.; Herrmann, J. Arterial events in cancer patients—the case of acute coronary thrombosis. J. Thorac. Dis., 2018, 10(S35), S4367-S4385.
[http://dx.doi.org/10.21037/jtd.2018.12.79] [PMID: 30701104]
[9]
Zhang, Q.; Liu, H.; Zhu, Q.; Zhan, P.; Zhu, S.; Zhang, J.; Lv, T.; Song, Y. Patterns and functional implications of platelets upon tumor “education”. Int. J. Biochem. Cell Biol., 2017, 90, 68-80.
[http://dx.doi.org/10.1016/j.biocel.2017.07.018] [PMID: 28754316]
[10]
Suematsu, M.; Nakamura, T.; Tokumoto, Y.; Yamamoto, T.; Kajimura, M.; Kabe, Y. CO‐CBS‐H 2 S axis: From vascular mediator to cancer regulator. Microcirculation, 2016, 23(3), 183-190.
[http://dx.doi.org/10.1111/micc.12253] [PMID: 26537442]
[11]
Cook, N.; Brais, R.; Qian, W.; Chan Wah Hak, C.; Corrie, P.G. Endothelin-1 and endothelin B receptor expression in pancreatic adenocarcinoma. J. Clin. Pathol., 2015, 68(4), 309-313.
[http://dx.doi.org/10.1136/jclinpath-2014-202521] [PMID: 25572612]
[12]
Weydert, C.; Esser, A.; Mejia, R.; Drake, J.; Barnes, J.; Henry, M. Endothelin-1 inhibits prostate cancer growth in vivo through vasoconstriction of tumor-feeding arterioles. Cancer Biol. Ther., 2009, 8(8), 720-729.
[http://dx.doi.org/10.4161/cbt.8.8.7922] [PMID: 19242129]
[13]
Svistunov, A.A.; Tarasov, V.V.; Shakhmardanova, S.A.; Sologova, S.S.; Bagaturiya, E.T.; Chubarev, V.N.; Galenko-Yaroshevsky, P.A.; Avila-Rodriguez, M.F.; Barreto, G.E.; Aliev, G.; Urotensin, I.I. Urotensin II: Molecular mechanisms of biological activity. Curr. Protein Pept. Sci., 2018, 19(9), 924-934.
[http://dx.doi.org/10.2174/1389203718666170829162335] [PMID: 28875851]
[14]
Avagimyan, A.; Kajaia, A.; Gabunia, L.; Ghambashidze, K.; Sulashvili, N.; Ratiani, L.; Heshmat-Ghahdarijani, K.; Sheibani, M.; Aznauryan, A. Urotensin-II as a promising key-point of cardiovascular disturbances sequel. Curr. Probl. Cardiol., 2021, 101074
[http://dx.doi.org/10.1016/j.cpcardiol.2021.101074] [PMID: 34848248]
[15]
Gravina, A.G.; Dallio, M.; Tuccillo, C.; Martorano, M.; Abenavoli, L.; Luzza, F.; Stiuso, P.; Lama, S.; Grieco, P.; Merlino, F.; Caraglia, M.; Loguercio, C.; Federico, A. Urotensin II receptor expression in patients with ulcerative colitis: A pilot study. Minerva Gastroenterol. Dietol., 2020, 66(1), 23-28.
[http://dx.doi.org/10.23736/S1121-421X.19.02602-3] [PMID: 31293119]
[16]
Takahashi, K.; Totsune, K.; Murakami, O.; Shibahara, S. Expression of urotensin II and urotensin II receptor mRNAs in various human tumor cell lines and secretion of urotensin II-like immunoreactivity by SW-13 adrenocortical carcinoma cells. Peptides, 2001, 22(7), 1175-1179.
[http://dx.doi.org/10.1016/S0196-9781(01)00441-7] [PMID: 11445248]
[17]
Federico, A.; Zappavigna, S.; Dallio, M.; Misso, G.; Merlino, F.; Loguercio, C.; Novellino, E.; Grieco, P.; Caraglia, M. Urotensin-II receptor: A double identity receptor involved in vasoconstriction and in the development of digestive tract cancers and other tumors. Curr. Cancer Drug Targets, 2017, 17(2), 109-121.
[http://dx.doi.org/10.2174/1568009616666160621101248] [PMID: 27338741]
[18]
Yumrutas, O.; Oztuzcu, S.; Büyükhatipoglu, H.; Bozgeyik, I.; Bozgeyik, E.; Igci, Y.Z.; Bagis, H.; Cevik, M.O.; Kalender, M.E.; Eslik, Z.; Arslan, A. The role of the UTS2 gene polymorphisms and plasma Urotensin-II levels in breast cancer. Tumour Biol., 2015, 36(6), 4427-4432.
[http://dx.doi.org/10.1007/s13277-015-3082-2] [PMID: 25604143]
[19]
Takahashi, K.; Totsune, K.; Kitamuro, T.; Sone, M.; Murakami, O.; Shibahara, S. Three vasoactive peptides, endothelin-1, adrenomedullin and urotensin-II, in human tumour cell lines of different origin: expression and effects on proliferation. Clin. Sci., 2002, 103(s2002 (S48)), 35S-38S.
[http://dx.doi.org/10.1042/CS103S035S] [PMID: 12193050]
[20]
Takahashi, K.; Totsune, K.; Murakami, O.; Arihara, Z.; Noshiro, T.; Hayashi, Y.; Shibahara, S. Expression of urotensin II and its receptor in adrenal tumors and stimulation of proliferation of cultured tumor cells by urotensin II. Peptides, 2003, 24(2), 301-306.
[http://dx.doi.org/10.1016/S0196-9781(03)00039-1] [PMID: 12668216]
[21]
Shenouda, A.; Douglas, S.A.; Ohlstein, E.H.; Giaid, A. Localization of urotensin-II immunoreactivity in normal human kidneys and renal carcinoma. J. Histochem. Cytochem., 2002, 50(7), 885-889.
[http://dx.doi.org/10.1177/002215540205000702] [PMID: 12070267]
[22]
Ye, H.; Wang, K.; Zhao, J.; Lu, Q.; Wang, M.; Sun, B.; Shen, Y.; Liu, H.; Pané, S.; Chen, X.Z.; He, Z.; Sun, J. In situ sprayed nanovaccine suppressing exosomal PD-L1 by golgi apparatus disorganization for postsurgical melanoma immunotherapy. ACS Nano, 2023, 17(11), 10637-10650.
[http://dx.doi.org/10.1021/acsnano.3c01733] [PMID: 37213184]
[23]
Morimoto, R.; Satoh, F.; Murakami, O.; Totsune, K.; Arai, Y.; Suzuki, T.; Sasano, H.; Ito, S.; Takahashi, K. Immunolocalization of urotensin II and its receptor in human adrenal tumors and attached non-neoplastic adrenal tissues. Peptides, 2008, 29(5), 873-880.
[http://dx.doi.org/10.1016/j.peptides.2007.06.025] [PMID: 17686550]
[24]
Giuliani, L.; Lenzini, L.; Antonello, M.; Aldighieri, E.; Belloni, A.S.; Fassina, A.; Gomez-Sanchez, C.; Rossi, G.P. Expression and functional role of urotensin-II and its receptor in the adrenal cortex and medulla: novel insights for the pathophysiology of primary aldosteronism. J. Clin. Endocrinol. Metab., 2009, 94(2), 684-690.
[http://dx.doi.org/10.1210/jc.2008-1131] [PMID: 19001524]
[25]
Zeng, Z.P.; Liu, G.Q.; Li, H.Z.; Fan, X.R.; Liu, D.M.; Tong, L.; Zheng, X.; Liu, C. The effects of urotensin-II on proliferation of pheochromocytoma cells and mRNA expression of urotensin-II and its receptor in pheochromocytoma tissues. Ann. N. Y. Acad. Sci., 2006, 1073(1), 284-289.
[http://dx.doi.org/10.1196/annals.1353.032] [PMID: 17102097]
[26]
De Cobelli, O.; Buonerba, C.; Terracciano, D.; Bottero, D.; Lucarelli, G.; Bove, P.; Altieri, V.; Coman, I.; Perdonà, S.; Facchini, G.; Berretta, M.; Di Lorenzo, G.; Grieco, P.; Novellino, E.; Franco, R.; Caraglia, M.; Manini, C.; Mirone, V.; De Placido, S.; Sonpavde, G.; Ferro, M. Urotensin II receptor on preoperative biopsy is associated with upstaging and upgrading in prostate cancer. Future Oncol., 2015, 11(22), 3091-3098.
[http://dx.doi.org/10.2217/fon.15.249] [PMID: 26381851]
[27]
Franco, R.; Zappavigna, S.; Gigantino, V.; Luce, A.; Cantile, M.; Cerrone, M.; Facchini, G.; Perdonà, S.; Pignata, S.; Di Lorenzo, G.; Chieffi, S.; Vitale, G.; De Sio, M.; Sgambato, A.; Botti, G.; Yousif, A.M.; Novellino, E.; Grieco, P.; Caraglia, M. Urotensin II receptor determines prognosis of bladder cancer regulating cell motility/invasion. J. Exp. Clin. Cancer Res., 2014, 33(1), 48.
[http://dx.doi.org/10.1186/1756-9966-33-48] [PMID: 24893613]
[28]
Wu, YQ.; Song, Z.; Zhou, CH.; Xing, SH.; Pei, DS.; Zheng, JN. Expression of urotensin II and its receptor in human lung adenocarcinoma A549 cells and the effect of urotensin II on lung adenocarcinoma growth in vitro and in vivo. Oncol Rep., 2010, 24, 1179-1184.
[http://dx.doi.org/10.3892/or_00000970] [PMID: 220878108]
[29]
Federico, A.; Zappavigna, S.; Romano, M.; Grieco, P.; Luce, A.; Marra, M.; Gravina, A.G.; Stiuso, P.; D’Armiento, F.P.; Vitale, G.; Tuccillo, C.; Novellino, E.; Loguercio, C.; Caraglia, M. Urotensin‐ II receptor is over‐expressed in colon cancer cell lines and in colon carcinoma in humans. Eur. J. Clin. Invest., 2014, 44(3), 285-294.
[http://dx.doi.org/10.1111/eci.12231] [PMID: 24372535]
[30]
Camci, C.; Kalender, M.E.; Suner, A.; Cengiz, B.; Oztuzcu, S.; Bayraktar, R.; Borazan, E.; Babacan, T.; Camci, C. The relationship between urotensin II and its receptor and the clinicopathological parameters of breast cancer. Med. Sci. Monit., 2014, 20, 1419-1425.
[http://dx.doi.org/10.12659/MSM.890459] [PMID: 25112588]
[31]
Liu, D.G.; Chen, J.; Wang, H.X.; Li, B.X. Increased expression of urotensin II is associated with poor prognosis in hepatocellular carcinoma. Oncol. Lett., 2016, 12(6), 4961-4968.
[http://dx.doi.org/10.3892/ol.2016.5344] [PMID: 28105202]
[32]
Le Joncour, V.; Guichet, P.O.; Dembélé, K.P.; Mutel, A.; Campisi, D.; Perzo, N.; Desrues, L.; Modzelewski, R.; Couraud, P.O.; Honnorat, J.; Ferracci, F.X.; Marguet, F.; Laquerrière, A.; Vera, P.; Bohn, P.; Langlois, O.; Morin, F.; Gandolfo, P.; Castel, H. Targeting the urotensin ii/ut g protein-coupled receptor to counteract angiogenesis and mesenchymal hypoxia/necrosis in glioblastoma. Front. Cell Dev. Biol., 2021, 9, 652544.
[http://dx.doi.org/10.3389/fcell.2021.652544] [PMID: 33937253]
[33]
Yu, X.T.; Wang, P.Y.; Shi, Z.M.; Dong, K.; Feng, P.; Wang, H.X.; Wang, X.J. Up-regulation of urotensin II and its receptor contributes to human hepatocellular carcinoma growth via activation of the PKC, ERK1/2, and p38 MAPK signaling pathways. Molecules, 2014, 19(12), 20768-20779.
[http://dx.doi.org/10.3390/molecules191220768] [PMID: 25514221]
[34]
Li, Y.; Shi, Z.; Yu, X.; Feng, P.; Wang, X.J. The effects of urotensin II on migration and invasion are mediated by NADPH oxidase-derived reactive oxygen species through the c-Jun N-terminal kinase pathway in human hepatoma cells. Peptides, 2017, 88, 106-114.
[http://dx.doi.org/10.1016/j.peptides.2016.12.005] [PMID: 27988353]
[35]
Coly, P.M.; Perzo, N.; Le Joncour, V.; Lecointre, C.; Schouft, M.T.; Desrues, L.; Tonon, M.C.; Wurtz, O.; Gandolfo, P.; Castel, H.; Morin, F. Chemotactic G protein-coupled receptors control cell migration by repressing autophagosome biogenesis. Autophagy, 2016, 12(12), 2344-2362.
[http://dx.doi.org/10.1080/15548627.2016.1235125] [PMID: 27715446]
[36]
Lecointre, C.; Desrues, L.; Joubert, J.E.; Perzo, N.; Guichet, P-O.; Le Joncour, V.; Brulé, C.; Chabbert, M.; Leduc, R.; Prézeau, L.; Laquerrière, A.; Proust, F.; Gandolfo, P.; Morin, F.; Castel, H. Signaling switch of the urotensin II vasosactive peptide GPCR: Prototypic chemotaxic mechanism in glioma. Oncogene, 2015, 34(39), 5080-5094.
[http://dx.doi.org/10.1038/onc.2014.433] [PMID: 25597409]
[37]
Herrmann, J. Vascular toxic effects of cancer therapies. Nat. Rev. Cardiol., 2020, 17(8), 503-522.
[http://dx.doi.org/10.1038/s41569-020-0347-2] [PMID: 32218531]
[38]
Cleary, J.F.; Anderson, B.M.; Eickhoff, J.C.; Khuntia, D.; Fahl, W.E. Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor. Radiat. Oncol., 2017, 12(1), 201.
[http://dx.doi.org/10.1186/s13014-017-0940-7] [PMID: 29273054]
[39]
Soref, C.M.; Fahl, W.E. A new strategy to prevent chemotherapy and radiotherapy-induced alopecia using topically applied vasoconstrictor. Int. J. Cancer, 2015, 136(1), 195-203.
[http://dx.doi.org/10.1002/ijc.28961] [PMID: 24811525]
[40]
Guo, X.; Wang, G. Advances in research on immune escape mechanism of glioma. CNS Neurosci. Ther., 2023, 29(7), 1709-1720.
[http://dx.doi.org/10.1111/cns.14217] [PMID: 37088950]
[41]
Andersen, R.S.; Anand, A.; Harwood, D.S.L.; Kristensen, B.W. Tumor-associated microglia and macrophages in the glioblastoma microenvironment and their implications for therapy. Cancers, 2021, 13(17), 4255.
[http://dx.doi.org/10.3390/cancers13174255] [PMID: 34503065]
[42]
Li, M.; Xu, H.; Qi, Y.; Pan, Z.; Li, B.; Gao, Z.; Zhao, R.; Xue, H.; Li, G. Tumor-derived exosomes deliver the tumor suppressor miR-3591-3p to induce M2 macrophage polarization and promote glioma progression. Oncogene, 2022, 41(41), 4618-4632.
[http://dx.doi.org/10.1038/s41388-022-02457-w] [PMID: 36085418]
[43]
Lin, Y.J.; Wei, K.C.; Chen, P.Y.; Lim, M.; Hwang, T.L. Roles of neutrophils in glioma and brain metastases. Front. Immunol., 2021, 12, 701383.
[http://dx.doi.org/10.3389/fimmu.2021.701383] [PMID: 34484197]
[44]
Basheer, A.S.; Abas, F.; Othman, I.; Naidu, R. Role of inflammatory mediators, macrophages, and neutrophils in glioma maintenance and progression: Mechanistic understanding and potential therapeutic applications. Cancers, 2021, 13(16), 4226.
[http://dx.doi.org/10.3390/cancers13164226] [PMID: 34439380]
[45]
Srivastava, S.; Jackson, C.; Kim, T.; Choi, J.; Lim, M. A characterization of dendritic cells and their role in immunotherapy in glioblastoma: from preclinical studies to clinical trials. Cancers, 2019, 11(4), 537.
[http://dx.doi.org/10.3390/cancers11040537] [PMID: 30991681]
[46]
Hu, J.L.; Omofoye, O.A.; Rudnick, J.D.; Kim, S.; Tighiouart, M.; Phuphanich, S.; Wang, H.; Mazer, M.; Ganaway, T.; Chu, R.M.; Patil, C.G.; Black, K.L.; Shiao, S.L.; Wang, R.; Yu, J.S. A phase I study of autologous dendritic cell vaccine pulsed with allogeneic stem-like cell line lysate in patients with newly diagnosed or recurrent glioblastoma. Clin. Cancer Res., 2022, 28(4), 689-696.
[http://dx.doi.org/10.1158/1078-0432.CCR-21-2867] [PMID: 34862245]

Rights & Permissions Print Cite
Article Metrics
21
1
Wayfinder Image
© 2025 Bentham Science Publishers | Privacy Policy