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Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Glioblastoma | Research

EMP3 as a prognostic biomarker correlates with EMT in GBM

Authors: Li Li, Siyu Xia, Zitong Zhao, Lili Deng, Hanbing Wang, Dongbo Yang, Yizhou Hu, Jingjing Ji, Dayong Huang, Tao Xin

Published in: BMC Cancer | Issue 1/2024

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Abstract

Background

Glioblastoma (GBM) is the most aggressive malignant central nervous system tumor with a poor prognosis.The malignant transformation of glioma cells via epithelial-mesenchymal transition (EMT) has been observed as a main obstacle for glioblastoma treatment. Epithelial membrane protein 3 (EMP3) is significantly associated with the malignancy of GBM and the prognosis of patients. Therefore, exploring the possible mechanisms by which EMP3 promotes the growth of GBM has important implications for the treatment of GBM.

Methods

We performed enrichment and correlation analysis in 5 single-cell RNA sequencing datasets. Differential expression of EMP3 in gliomas, Kaplan–Meier survival curves, diagnostic accuracy and prognostic prediction were analyzed by bioinformatics in the China Glioma Genome Atlas (CGGA) database and The Cancer Genome Atlas (TCGA) database. EMP3-silenced U87 and U251 cell lines were obtained by transient transfection with siRNA. The effect of EMP3 on glioblastoma proliferation was examined using the CCK-8 assay. Transwell migration assay and wound healing assay were used to assess the effect of EMP3 on glioblastoma migration. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect the mRNA and protein expression levels of EMT-related transcription factors and mesenchymal markers.

Results

EMP3 is a EMT associated gene in multiple types of malignant cancer and in high-grade glioblastoma. EMP3 is enriched in high-grade gliomas and isocitrate dehydrogenase (IDH) wild-type gliomas.EMP3 can be used as a specific biomarker for diagnosing glioma patients. It is also an independent prognostic factor for glioma patients' overall survival (OS). In addition, silencing EMP3 reduces the proliferation and migration of glioblastoma cells. Mechanistically, EMP3 enhances the malignant potential of tumor cells by promoting EMT.

Conclusion

EMP3 promotes the proliferation and migration of GBM cells, and the mechanism may be related to EMP3 promoting the EMT process in GBM; EMP3 may be an independent prognostic factor in GBM.
Appendix
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Literature
2.
go back to reference Luo X, Yang F. Section: neurosurgery bioinformatics analysis reveals that IGFBP2, EMP3, PDPN, and MCUB genes were potential biomarkers for Glioblastoma. Int J Contemp Med Res. 2020;7:1. Luo X, Yang F. Section: neurosurgery bioinformatics analysis reveals that IGFBP2, EMP3, PDPN, and MCUB genes were potential biomarkers for Glioblastoma. Int J Contemp Med Res. 2020;7:1.
4.
go back to reference Thornton N, Karamatic Crew V, Tilley L, Green CA, Tay CL, Griffiths RE, Singleton BK, Spring F, Walser P, Alattar AG, Jones B, Laundy R, Storry JR, Möller M, Wall L, Charlewood R, Westhoff CM, Lomas-Francis C, Yahalom V, Feick U, Seltsam A, Mayer B, Olsson ML, Anstee DJ. Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype. Nat Commun. 2020;11:3569. https://doi.org/10.1038/s41467-020-17060-4.CrossRefPubMedPubMedCentral Thornton N, Karamatic Crew V, Tilley L, Green CA, Tay CL, Griffiths RE, Singleton BK, Spring F, Walser P, Alattar AG, Jones B, Laundy R, Storry JR, Möller M, Wall L, Charlewood R, Westhoff CM, Lomas-Francis C, Yahalom V, Feick U, Seltsam A, Mayer B, Olsson ML, Anstee DJ. Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype. Nat Commun. 2020;11:3569. https://​doi.​org/​10.​1038/​s41467-020-17060-4.CrossRefPubMedPubMedCentral
6.
go back to reference Alaminos M, Dávalos V, Ropero S, Setién F, Paz MF, Herranz M, Fraga MF, Mora J, Cheung NK, Gerald WL, Esteller M. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res. 2005;65:2565–71. https://doi.org/10.1158/0008-5472.Can-04-4283.CrossRefPubMed Alaminos M, Dávalos V, Ropero S, Setién F, Paz MF, Herranz M, Fraga MF, Mora J, Cheung NK, Gerald WL, Esteller M. EMP3, a myelin-related gene located in the critical 19q13.3 region, is epigenetically silenced and exhibits features of a candidate tumor suppressor in glioma and neuroblastoma. Cancer Res. 2005;65:2565–71. https://​doi.​org/​10.​1158/​0008-5472.​Can-04-4283.CrossRefPubMed
12.
go back to reference Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, Daenen KL, Partouns-Hendriks IE, Stessels F, Louwagie J, Smits KM, Weijenberg MP, Sanduleanu S, Khalid-de Bakker CA, Oort FA, Meijer GA, Jonkers DM, Herman JG, de Bruïne AP, van Engeland M. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst. 2009;101:916–27. https://doi.org/10.1093/jnci/djp131.CrossRefPubMed Melotte V, Lentjes MH, van den Bosch SM, Hellebrekers DM, de Hoon JP, Wouters KA, Daenen KL, Partouns-Hendriks IE, Stessels F, Louwagie J, Smits KM, Weijenberg MP, Sanduleanu S, Khalid-de Bakker CA, Oort FA, Meijer GA, Jonkers DM, Herman JG, de Bruïne AP, van Engeland M. N-Myc downstream-regulated gene 4 (NDRG4): a candidate tumor suppressor gene and potential biomarker for colorectal cancer. J Natl Cancer Inst. 2009;101:916–27. https://​doi.​org/​10.​1093/​jnci/​djp131.CrossRefPubMed
20.
go back to reference Hu Y, Jiang Y, Behnan J, Ribeiro MM, Kalantzi C, Zhang MD, Lou D, Häring M, Sharma N, Okawa S, Del Sol A, Adameyko I, Svensson M, Persson O, Ernfors P. Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages. Sci Adv. 2022;8:abm6340. https://doi.org/10.1126/sciadv.abm6340.CrossRef Hu Y, Jiang Y, Behnan J, Ribeiro MM, Kalantzi C, Zhang MD, Lou D, Häring M, Sharma N, Okawa S, Del Sol A, Adameyko I, Svensson M, Persson O, Ernfors P. Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages. Sci Adv. 2022;8:abm6340. https://​doi.​org/​10.​1126/​sciadv.​abm6340.CrossRef
21.
go back to reference Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, Neftel C, Desai N, Nyman J, Izar B, Luo CC, Francis JM, Patel AA, Onozato ML, Riggi N, Livak KJ, Gennert D, Satija R, Nahed BV, Curry WT, Martuza RL, Mylvaganam R, Iafrate AJ, Frosch MP, Golub TR, Rivera MN, Getz G, Rozenblatt-Rosen O, Cahill DP, Monje M, Bernstein BE, Louis DN, Regev A, Suvà ML. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539:309–13. https://doi.org/10.1038/nature20123.CrossRefPubMedPubMedCentral Tirosh I, Venteicher AS, Hebert C, Escalante LE, Patel AP, Yizhak K, Fisher JM, Rodman C, Mount C, Filbin MG, Neftel C, Desai N, Nyman J, Izar B, Luo CC, Francis JM, Patel AA, Onozato ML, Riggi N, Livak KJ, Gennert D, Satija R, Nahed BV, Curry WT, Martuza RL, Mylvaganam R, Iafrate AJ, Frosch MP, Golub TR, Rivera MN, Getz G, Rozenblatt-Rosen O, Cahill DP, Monje M, Bernstein BE, Louis DN, Regev A, Suvà ML. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539:309–13. https://​doi.​org/​10.​1038/​nature20123.CrossRefPubMedPubMedCentral
22.
go back to reference Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, Hovestadt V, Escalante LE, Shaw ML, Rodman C, Gillespie SM, Dionne D, Luo CC, Ravichandran H, Mylvaganam R, Mount C, Onozato ML, Nahed BV, Wakimoto H, Curry WT, Iafrate AJ, Rivera MN, Frosch MP, Golub TR, Brastianos PK, Getz G, Patel AP, Monje M, Cahill DP, Rozenblatt-Rosen O, Louis DN, Bernstein BE, Regev A, Suvà ML. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017;355:eaa18478. https://doi.org/10.1126/science.aai8478.CrossRef Venteicher AS, Tirosh I, Hebert C, Yizhak K, Neftel C, Filbin MG, Hovestadt V, Escalante LE, Shaw ML, Rodman C, Gillespie SM, Dionne D, Luo CC, Ravichandran H, Mylvaganam R, Mount C, Onozato ML, Nahed BV, Wakimoto H, Curry WT, Iafrate AJ, Rivera MN, Frosch MP, Golub TR, Brastianos PK, Getz G, Patel AP, Monje M, Cahill DP, Rozenblatt-Rosen O, Louis DN, Bernstein BE, Regev A, Suvà ML. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017;355:eaa18478. https://​doi.​org/​10.​1126/​science.​aai8478.CrossRef
24.
go back to reference Bell EH, Pugh SL, McElroy JP, Gilbert MR, Mehta M, Klimowicz AC, Magliocco A, Bredel M, Robe P, Grosu AL, Stupp R, Curran W Jr, Becker AP, Salavaggione AL, Barnholtz-Sloan JS, Aldape K, Blumenthal DT, Brown PD, Glass J, Souhami L, Lee RJ, Brachman D, Flickinger J, Won M, Chakravarti A. Molecular-based recursive partitioning analysis model for Glioblastoma in the Temozolomide era: a correlative analysis based on NRG oncology RTOG 0525. Jama Oncol. 2017;3:784–92. https://doi.org/10.1001/jamaoncol.2016.6020.CrossRefPubMedPubMedCentral Bell EH, Pugh SL, McElroy JP, Gilbert MR, Mehta M, Klimowicz AC, Magliocco A, Bredel M, Robe P, Grosu AL, Stupp R, Curran W Jr, Becker AP, Salavaggione AL, Barnholtz-Sloan JS, Aldape K, Blumenthal DT, Brown PD, Glass J, Souhami L, Lee RJ, Brachman D, Flickinger J, Won M, Chakravarti A. Molecular-based recursive partitioning analysis model for Glioblastoma in the Temozolomide era: a correlative analysis based on NRG oncology RTOG 0525. Jama Oncol. 2017;3:784–92. https://​doi.​org/​10.​1001/​jamaoncol.​2016.​6020.CrossRefPubMedPubMedCentral
25.
go back to reference Linz U. Commentary on Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (Lancet Oncol. 2009;10:459–466). Cancer. 2010;116:1844–6. https://doi.org/10.1002/cncr.24950.CrossRefPubMed Linz U. Commentary on Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (Lancet Oncol. 2009;10:459–466). Cancer. 2010;116:1844–6. https://​doi.​org/​10.​1002/​cncr.​24950.CrossRefPubMed
28.
go back to reference Ernst A, Hofmann S, Ahmadi R, Becker N, Korshunov A, Engel F, Hartmann C, Felsberg J, Sabel M, Peterziel H, Durchdewald M, Hess J, Barbus S, Campos B, Starzinski-Powitz A, Unterberg A, Reifenberger G, Lichter P, Herold-Mende C, Radlwimmer B. Genomic and expression profiling of glioblastoma stem cell-like spheroid cultures identifies novel tumor-relevant genes associated with survival. Clin Cancer Res. 2009;15:6541–50. https://doi.org/10.1158/1078-0432.Ccr-09-0695.CrossRefPubMed Ernst A, Hofmann S, Ahmadi R, Becker N, Korshunov A, Engel F, Hartmann C, Felsberg J, Sabel M, Peterziel H, Durchdewald M, Hess J, Barbus S, Campos B, Starzinski-Powitz A, Unterberg A, Reifenberger G, Lichter P, Herold-Mende C, Radlwimmer B. Genomic and expression profiling of glioblastoma stem cell-like spheroid cultures identifies novel tumor-relevant genes associated with survival. Clin Cancer Res. 2009;15:6541–50. https://​doi.​org/​10.​1158/​1078-0432.​Ccr-09-0695.CrossRefPubMed
29.
go back to reference Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MA, Motta FJ, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, Marie SK, Tone LG. 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. 2008;88:281–91. https://doi.org/10.1007/s11060-008-9579-4.CrossRefPubMed Scrideli CA, Carlotti CG Jr, Okamoto OK, Andrade VS, Cortez MA, Motta FJ, Lucio-Eterovic AK, Neder L, Rosemberg S, Oba-Shinjo SM, Marie SK, Tone LG. 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. 2008;88:281–91. https://​doi.​org/​10.​1007/​s11060-008-9579-4.CrossRefPubMed
38.
go back to reference Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH, Turski A, Azodi Y, Yang Y, Doucette T, Colman H, Sulman EP, Lang FF, Rao G, Copray S, Vaillant BD, Aldape KD. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 2011;25:2594–609. https://doi.org/10.1101/gad.176800.111.CrossRefPubMedPubMedCentral Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH, Turski A, Azodi Y, Yang Y, Doucette T, Colman H, Sulman EP, Lang FF, Rao G, Copray S, Vaillant BD, Aldape KD. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 2011;25:2594–609. https://​doi.​org/​10.​1101/​gad.​176800.​111.CrossRefPubMedPubMedCentral
39.
go back to reference Wu L, Wu W, Zhang J, Zhao Z, Li L, Zhu M, Wu M, Wu F, Zhou F, Du Y, Chai RC, Zhang W, Qiu X, Liu Q, Wang Z, Li J, Li K, Chen A, Jiang Y, Xiao X, Zou H, Srivastava R, Zhang T, Cai Y, Liang Y, Huang B, Zhang R, Lin F, Hu L, Wang X, Qian X, Lv S, Hu B, Zheng S, Hu Z, Shen H, You Y, Verhaak RGW, Jiang T, Wang Q. Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma. Cancer Discov. 2022;12:2820–37. https://doi.org/10.1158/2159-8290.Cd-22-0196.CrossRefPubMedPubMedCentral Wu L, Wu W, Zhang J, Zhao Z, Li L, Zhu M, Wu M, Wu F, Zhou F, Du Y, Chai RC, Zhang W, Qiu X, Liu Q, Wang Z, Li J, Li K, Chen A, Jiang Y, Xiao X, Zou H, Srivastava R, Zhang T, Cai Y, Liang Y, Huang B, Zhang R, Lin F, Hu L, Wang X, Qian X, Lv S, Hu B, Zheng S, Hu Z, Shen H, You Y, Verhaak RGW, Jiang T, Wang Q. Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma. Cancer Discov. 2022;12:2820–37. https://​doi.​org/​10.​1158/​2159-8290.​Cd-22-0196.CrossRefPubMedPubMedCentral
51.
go back to reference Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RYJ, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21:341–52. https://doi.org/10.1038/s41580-020-0237-9.CrossRefPubMedPubMedCentral Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RYJ, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP, Sheng G. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21:341–52. https://​doi.​org/​10.​1038/​s41580-020-0237-9.CrossRefPubMedPubMedCentral
53.
go back to reference Soundararajan R, Fradette JJ, Konen JM, Moulder S, Zhang X, Gibbons DL, Varadarajan N, Wistuba II, Tripathy D, Bernatchez C, Byers LA, Chang JT, Contreras A, Lim B, Parra ER, Roarty EB, Wang J, Yang F, Barton M, Rosen JM, Mani SA. Targeting the interplay between Epithelial-to-Mesenchymal-transition and the immune system for effective immunotherapy. Cancers (Basel). 2019;11:714. https://doi.org/10.3390/cancers11050714.CrossRefPubMed Soundararajan R, Fradette JJ, Konen JM, Moulder S, Zhang X, Gibbons DL, Varadarajan N, Wistuba II, Tripathy D, Bernatchez C, Byers LA, Chang JT, Contreras A, Lim B, Parra ER, Roarty EB, Wang J, Yang F, Barton M, Rosen JM, Mani SA. Targeting the interplay between Epithelial-to-Mesenchymal-transition and the immune system for effective immunotherapy. Cancers (Basel). 2019;11:714. https://​doi.​org/​10.​3390/​cancers11050714.CrossRefPubMed
Metadata
Title
EMP3 as a prognostic biomarker correlates with EMT in GBM
Authors
Li Li
Siyu Xia
Zitong Zhao
Lili Deng
Hanbing Wang
Dongbo Yang
Yizhou Hu
Jingjing Ji
Dayong Huang
Tao Xin
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-11796-0

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