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EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy

Oncogene volume 42, pages 861–868 (2023)Cite this article

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Abstract

Experimental studies on immunoglobulin superfamily (IgSF) member EWI2 reveal that it suppresses a variety of solid malignant tumors including brain, lung, skin, and prostate cancers in animal models and inhibits tumor cell movement and growth in vitro. While EWI2 appears to support myeloid leukemia in mouse models and maintain leukemia stem cells. Bioinformatics analyses suggest that EWI2 gene expression is downregulated in glioblastoma but upregulated in melanoma, pancreatic cancer, and liver cancer. The mechanism of action for EWI2 is linked to its inhibition of growth factor receptors and cell adhesion proteins through its associated tetraspanin-enriched membrane domains (TEMDs), by altering the cell surface clustering and endolysosome trafficking/turnover of these transmembrane proteins. Recent studies also show that EWI2 modulates the nuclear translocation of ERK and TFEB to change the activities of these gene expression regulators. For EWI2 relatives including FPRP, IgSF3, and CD101, although their roles in malignant diseases are not fully clear and remain to be determined experimentally, FPRP and IgSF3 likely promote the progression of solid malignant tumors while CD101 seems to modulate immune cells of tumor microenvironment. Distinctive from other tumor regulators, the impacts of EWI subfamily members on solid malignant tumors are likely to be context dependent. In other words, the effect of a given EWI subfamily member on a tumor probably depends on the molecular network and composition of TEMDs in that tumor. Collectively, EWI2 and its relatives are emerged as important regulators of malignant diseases with promising potentials to become anti-cancer therapeutics and cancer therapy targets.

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Fig. 1: EWI IgSF proteins and TEMD.
Fig. 2: Gene expression levels of EWI subfamily members, using TCGA samples (normal & cancer), bolstered with normal tissue samples from GTEX.
Fig. 3: Functional enrichment analysis of the genes co-expressed with four EWI Ig subfamily members in human prostate cancer.
Fig. 4: IgSF3 gene expression and solid malignant tumors.
Fig. 5

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Data availability

The data that support the findings of this study are openly available from STRING database at https://string-db.org/, reference number 35, and TCGA database at https://www.cancer.gov/structural-genomics/tcga.

References

  1. Charrin S, Le Naour F, Labas V, Billard M, Le Caer JP, Emile JF, et al. EWI-2 is a new component of the tetraspanin web in hepatocytes and lymphoid cells. Biochem J. 2003;373:409–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Clark KL, Zeng Z, Langford AL, Bowen SM, Todd SC. PGRL is a major CD81-associated protein on lymphocytes and distinguishes a new family of cell surface proteins. J Immunol. 2001;167:5115–21.

    Article  CAS  PubMed  Google Scholar 

  3. Stipp CS, Kolesnikova TV, Hemler ME. EWI-2 is a major CD9 and CD81 partner and member of a novel Ig protein subfamily. J Biol Chem. 2001;276:40545–54.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang XA, Lane WS, Charrin S, Rubinstein E, Liu L. EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res. 2003;63:2665–74.

    CAS  PubMed  Google Scholar 

  5. He B, Zhang YH, Richardson MM, Zhang JS, Rubinstein E, Zhang XA. Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL. Biochem J. 2011;437:399–411.

    Article  CAS  PubMed  Google Scholar 

  6. Kolesnikova TV, Stipp CS, Rao RM, Lane WS, Luscinskas FW, Hemler ME. EWI-2 modulates lymphocyte integrin alpha4beta1 functions. Blood. 2004;103:3013–9.

    Article  CAS  PubMed  Google Scholar 

  7. Yang XH, Kovalenko OV, Kolesnikova TV, Andzelm MM, Rubinstein E, Strominger JL, et al. Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. J Biol Chem. 2006;281:12976–85.

    Article  CAS  PubMed  Google Scholar 

  8. Charrin S, Jouannet S, Boucheix C, Rubinstein E. Tetraspanins at a glance. J Cell Sci. 2014;127:3641–8.

    CAS  PubMed  Google Scholar 

  9. Richardson MM, Jennings LK, Zhang XA. Tetraspanins and tumor progression. Clin Exp Metastasis. 2011;28:261–70.

    Article  CAS  PubMed  Google Scholar 

  10. van Deventer SJ, Dunlock VE, van Spriel AB. Molecular interactions shaping the tetraspanin web. Biochem Soc Trans. 2017;45:741–50.

    Article  PubMed  Google Scholar 

  11. Yanez-Mo M, Barreiro O, Gordon-Alonso M, Sala-Valdes M, Sanchez-Madrid F. Tetraspanin-enriched microdomains: a functional unit in cell plasma membranes. Trends Cell Biol. 2009;19:434–46.

    Article  CAS  PubMed  Google Scholar 

  12. Hemler ME. Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer. 2014;14:49–60.

    Article  CAS  PubMed  Google Scholar 

  13. Vences-Catalan F, Levy S. Immune Targeting of Tetraspanins Involved in Cell Invasion and Metastasis. Front Immunol. 2018;9:1277.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wang HX, Sharma C, Knoblich K, Granter SR, Hemler ME. EWI-2 negatively regulates TGF-beta signaling leading to altered melanoma growth and metastasis. Cell Res. 2015;25:370–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang J, Wren JD, Ding Y, Chen J, Mittal N, Xu C, et al. EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer. Cancer Lett. 2022;536:215641.

    Article  CAS  PubMed  Google Scholar 

  16. Fu C, Wang J, Pallikkuth S, Ding Y, Chen J, Wren JD, et al. EWI2 prevents EGFR from clustering and endocytosis to reduce tumor cell movement and proliferation. Cell Mol Life Sci. 2022;79:389.

    Article  CAS  PubMed  Google Scholar 

  17. Feng J, Huang C, Wren JD, Wang DW, Yan J, Zhang J, et al. Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity. Cancer Metastasis Rev. 2015;34:619–33.

    Article  CAS  PubMed  Google Scholar 

  18. Fu C, Zhang Q, Wang A, Yang S, Jiang Y, Bai L, et al. EWI-2 controls nucleocytoplasmic shuttling of EGFR signaling molecules and miRNA sorting in exosomes to inhibit prostate cancer cell metastasis. Mol Oncol. 2021;15:1543–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Levina E, Ji H, Chen M, Baig M, Oliver D, Ohouo P, et al. Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells. Oncotarget. 2015;6:13088–104.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kolesnikova TV, Kazarov AR, Lemieux ME, Lafleur MA, Kesari S, Kung AL, et al. Glioblastoma inhibition by cell surface immunoglobulin protein EWI-2, in vitro and in vivo. Neoplasia. 2009;11:77–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang C, Fu C, Wren JD, Wang X, Zhang F, Zhang YH, et al. Tetraspanin-enriched microdomains regulate digitation junctions. Cell Mol Life Sci. 2018;75:3423–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sala-Valdes M, Ursa A, Charrin S, Rubinstein E, Hemler ME, Sanchez-Madrid F, et al. EWI-2 and EWI-F link the tetraspanin web to the actin cytoskeleton through their direct association with ezrin-radixin-moesin proteins. J Biol Chem. 2006;281:19665–75.

    Article  CAS  PubMed  Google Scholar 

  23. Stipp CS, Kolesnikova TV, Hemler ME. EWI-2 regulates alpha3beta1 integrin-dependent cell functions on laminin-5. J Cell Biol. 2003;163:1167–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gordon-Alonso M, Sala-Valdes M, Rocha-Perugini V, Perez-Hernandez D, Lopez-Martin S, Ursa A, et al. EWI-2 association with alpha-actinin regulates T cell immune synapses and HIV viral infection. J Immunol. 2012;189:689–700.

    Article  CAS  PubMed  Google Scholar 

  25. Liang Y, Eng WS, Colquhoun DR, Dinglasan RR, Graham DR, Mahal LK. Complex N-linked glycans serve as a determinant for exosome/microvesicle cargo recruitment. J Biol Chem. 2014;289:32526–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jimbo K, Nakajima-Takagi Y, Ito T, Koide S, Nannya Y, Iwama A, et al. Immunoglobulin superfamily member 8 maintains myeloid leukemia stem cells through inhibition of beta-catenin degradation. Leukemia. 2022;36:1550–62.

    Article  CAS  PubMed  Google Scholar 

  27. Beckwith KA, Byrd JC, Muthusamy N. Tetraspanins as therapeutic targets in hematological malignancy: a concise review. Front Physiol. 2015;6:91.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Suwatthanarak T, Tanaka M, Miyamoto Y, Miyado K, Okochi M. Inhibition of cancer-cell migration by tetraspanin CD9-binding peptide. Chem Commun (Camb). 2021;57:4906–9.

    Article  CAS  PubMed  Google Scholar 

  29. Claas C, Wahl J, Orlicky DJ, Karaduman H, Schnolzer M, Kempf T, et al. The tetraspanin D6.1A and its molecular partners on rat carcinoma cells. Biochem J. 2005;389:99–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Colin S, Guilmain W, Creoff E, Schneider C, Steverlynck C, Bongaerts M, et al. A truncated form of CD9-partner 1 (CD9P-1), GS-168AT2, potently inhibits in vivo tumour-induced angiogenesis and tumour growth. Br J Cancer. 2011;105:1002–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aguila B, Morris AB, Spina R, Bar E, Schraner J, Vinkler R, et al. The Ig superfamily protein PTGFRN coordinates survival signaling in glioblastoma multiforme. Cancer Lett. 2019;462:33–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen S, Sun Y, Jin Z, Jing X. Functional and biochemical studies of CD9 in fibrosarcoma cell line. Mol Cell Biochem. 2011;350:89–99.

    Article  CAS  PubMed  Google Scholar 

  33. Sheng P, Zhu H, Zhang W, Xu Y, Peng W, Sun J, et al. The immunoglobulin superfamily member 3 (IGSF3) promotes hepatocellular carcinoma progression through activation of the NF-kappaB pathway. Ann Transl Med. 2020;8:378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Erfani S, Hua H, Pan Y, Zhou BP, Yang XH. The context-dependent impact of integrin-associated CD151 and other tetraspanins on cancer development and progression: A class of versatile mediators of cellular function and signaling, tumorigenesis and metastasis. Cancers. 2021;13:2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ramovs V, Te Molder L, Sonnenberg A. The opposing roles of laminin-binding integrins in cancer. Matrix Biol: J Int Soc Matrix Biol. 2017;57-58:213–43.

    Article  CAS  Google Scholar 

  36. Liu Y, Yao R, Shi Y, Liu Y, Liu H, Liu J, et al. Identification of CD101 in Glioma: A novel prognostic indicator expressed on M2 macrophages. Front Immunol. 2022;13:845223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhou J, Wang W, Liang Z, Ni B, He W, Wang D. Clinical significance of CD38 and CD101 expression in PD-1(+)CD8(+) T cells in patients with epithelial ovarian cancer. Oncol Lett. 2020;20:724–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bobrowicz M, Kubacz M, Slusarczyk A, Winiarska M. CD37 in B cell derived tumors-more than just a docking point for monoclonal antibodies. Int J Mol Sci. 2020;21:9531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. de Winde CM, Elfrink S, van Spriel AB. Novel insights into membrane targeting of B cell lymphoma. Trends cancer. 2017;3:442–53.

    Article  PubMed  Google Scholar 

  40. Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic acids Res. 2021;49:D605–D612.

    Article  CAS  PubMed  Google Scholar 

  41. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic acids Res. 2017;45:W98–W102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic acids Res. 2019;47:W556–W560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cancer Genome Atlas Research N, Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, et al. The cancer genome atlas Pan-Cancer analysis project. Nat Genet. 2013;45:1113–20.

    Article  Google Scholar 

  45. Yu G, Wang LG, Han Y, He QY. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Uhlen M, Zhang C, Lee S, Sjostedt E, Fagerberg L, Bidkhori G, et al. A pathology atlas of the human cancer transcriptome. Science. 2017;357:eaan2507.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by National Institutes of Health grant GM135547 and the research grants from OCAST and PHF to XAZ. XAZ is an Oklahoma TSET Cancer Research Scholar. We thank Ms. Kathy Kyler for English editing.

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  1. These authors contributed equally: Yingjun Ding, Junxiong Chen.

Authors and Affiliations

  1. University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Yingjun Ding, Junxiong Chen, Shuping Li, Jie Wang, Takemi Tanaka, Heather C. Rice, Franklin A. Hays & Xin A. Zhang

  2. Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Jonathan D. Wren

  3. University of Tennessee Health Science Center, Memphis, TN, USA

    Akhilesh K. Bajpai & Lu Lu

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Contributions

YD, JXC, SL, JDW, and AKB performed analysis and wrote the manuscript; LL and XAZ supervised the study; XAZ conceived and designed the study; and YD, JXC, JDW, AKB, JW, TT, HCR, FAH, and XAZ wrote the manuscript.

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Correspondence to Xin A. Zhang.

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Ding, Y., Chen, J., Li, S. et al. EWI2 and its relatives in Tetraspanin-enriched membrane domains regulate malignancy. Oncogene 42, 861–868 (2023). https://doi.org/10.1038/s41388-023-02623-8

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