Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO

Abstract

Glioma is the most common malignant primary brain tumor with aggressiveness and poor prognosis. Although extracellular vesicles (EVs)-based cell-to-cell communication mediates glioma progression, the key molecular mediators of this process are still not fully understood. Herein, we elucidated an EVs-mediated transfer of suprabasin (SBSN), leading to the aggressiveness and progression of glioma. High levels of SBSN were positively correlated with clinical grade, predicting poor clinical prognosis of patients. Upregulation of SBSN promoted, while silencing of SBSN suppressed tumorigenesis and aggressiveness of glioma cells in vivo. EVs-mediated transfer of SBSN resulted in an increase in SBSN levels, which promoted the aggressiveness of glioma cells by enhancing migration, invasion, and angiogenesis of recipient glioma cells. Mechanistically, SBSN activated NF-κB signaling by interacting with annexin A1, which further induced Lys63-linked and Met1-linear polyubiquitination of NF-κB essential modulator (NEMO). In conclusion, the communication of SBSN-containing EVs within glioma cells drives the formation and development of tumors by activating NF-κB pathway, which may provide potential therapeutic target for clinical intervention in glioma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SBSN is upregulated in glioma and associates with glioma progression.
Fig. 2: SBSN enhances glioma aggressiveness in vivo.
Fig. 3: SBSN enhances glioma aggressiveness in vitro.
Fig. 4: EVs-transferred SBSN promotes glioma aggressiveness.
Fig. 5: EVs-transferred SBSN activates NF-κB signaling pathway.
Fig. 6: EVs-transferred SBSN activates NF-κB through ANXA1.
Fig. 7: EVs-transferred SBSN activates NF-κB through ANXA1-dependent NEMO ubiquitination.

Similar content being viewed by others

Data availability

For survival analysis of glioma patients, the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets were used. All other data supporting the findings of this study are available within the article and its Supplementary information files and on reasonable request from the corresponding author.

References

  1. Lapointe S, Perry A, Butowski NA. Primary brain tumours in adults. Lancet. 2018;392:432–46.

    Article  PubMed  Google Scholar 

  2. Delgado-Lopez PD, Corrales-Garcia EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18:1062–71.

    Article  CAS  PubMed  Google Scholar 

  3. Alexander BM, Cloughesy TF. Adult glioblastoma. J Clin Oncol. 2017;35:2402–09.

    Article  CAS  PubMed  Google Scholar 

  4. Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-mediated metastasis: communication from a distance. Dev Cell. 2019;49:347–60.

    Article  CAS  PubMed  Google Scholar 

  5. Mathieu M, Martin-Jaular L, Lavieu G, Thery C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.

    Article  CAS  PubMed  Google Scholar 

  6. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79.

    Article  CAS  PubMed  Google Scholar 

  7. Liu Y, Ye G, Huang L, Zhang C, Sheng Y, Wu B, et al. Single-cell transcriptome analysis demonstrates inter-patient and intra-tumor heterogeneity in primary and metastatic lung adenocarcinoma. Aging (Albany NY). 2020;12:21559–81.

    Article  CAS  PubMed  Google Scholar 

  8. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016;30:836–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cheng J, Meng J, Zhu L, Peng Y. Exosomal noncoding RNAs in Glioma: biological functions and potential clinical applications. Mol Cancer. 2020;19:66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gao X, Zhang Z, Mashimo T, Shen B, Nyagilo J, Wang H, et al. Gliomas interact with non-glioma brain cells via extracellular vesicles. Cell Rep. 2020;30:2489–500 e5.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Q, Lenardo MJ, Baltimore D. 30 Years of NF-kappaB: a blossoming of relevance to human pathobiology. Cell. 2017;168:37–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hayden MS, Ghosh S. NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev. 2012;26:203–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6.

    Article  CAS  PubMed  Google Scholar 

  14. Taniguchi K, Karin M. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24.

    Article  CAS  PubMed  Google Scholar 

  15. Cahill KE, Morshed RA, Yamini B. Nuclear factor-kappaB in glioblastoma: insights into regulators and targeted therapy. Neuro Oncol. 2016;18:329–39.

    Article  CAS  PubMed  Google Scholar 

  16. Chen J, Chen ZJ. Regulation of NF-kappaB by ubiquitination. Curr Opin Immunol. 2013;25:4–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hinz M, Scheidereit C. The IkappaB kinase complex in NF-kappaB regulation and beyond. EMBO Rep. 2014;15:46–61.

    Article  CAS  PubMed  Google Scholar 

  18. Park GT, Lim SE, Jang SI, Morasso MI. Suprabasin, a novel epidermal differentiation marker and potential cornified envelope precursor. J Biol Chem. 2002;277:45195–202.

    Article  CAS  PubMed  Google Scholar 

  19. Pribyl M, Hodny Z, Kubikova I. Suprabasin–a review. Genes (Basel). 2021;12:108.

  20. Matsui T, Hayashi-Kisumi F, Kinoshita Y, Katahira S, Morita K, Miyachi Y, et al. Identification of novel keratinocyte-secreted peptides dermokine-alpha/-beta and a new stratified epithelium-secreted protein gene complex on human chromosome 19q13.1. Genomics. 2004;84:384–97.

    Article  CAS  PubMed  Google Scholar 

  21. Pribyl M, Hubackova S, Moudra A, Vancurova M, Polackova H, Stopka T, et al. Aberrantly elevated suprabasin in the bone marrow as a candidate biomarker of advanced disease state in myelodysplastic syndromes. Mol Oncol. 2020;14:2403–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aoshima M, Phadungsaksawasdi P, Nakazawa S, Iwasaki M, Sakabe JI, Umayahara T, et al. Decreased expression of suprabasin induces aberrant differentiation and apoptosis of epidermal keratinocytes: possible role for atopic dermatitis. J Dermatol Sci. 2019;95:107–12.

    Article  CAS  PubMed  Google Scholar 

  23. Yanovich-Arad G, Ofek P, Yeini E, Mardamshina M, Danilevsky A, Shomron N, et al. Proteogenomics of glioblastoma associates molecular patterns with survival. Cell Rep. 2021;34:108787.

    Article  CAS  PubMed  Google Scholar 

  24. Lauko A, Lo A, Ahluwalia MS, Lathia JD. Cancer cell heterogeneity & plasticity in glioblastoma and brain tumors. Semin Cancer Biol. 2022;82:162–75.

  25. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schafer R, Beerling E, et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161:1046–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Raychaudhuri B, Han Y, Lu T, Vogelbaum MA. Aberrant constitutive activation of nuclear factor kappaB in glioblastoma multiforme drives invasive phenotype. J Neurooncol. 2007;85:39–47.

    Article  CAS  PubMed  Google Scholar 

  28. Ji J, Ding K, Luo T, Zhang X, Chen A, Zhang D, et al. TRIM22 activates NF-kappaB signaling in glioblastoma by accelerating the degradation of IkappaBalpha. Cell Death Differ. 2021;28:367–81.

    Article  CAS  PubMed  Google Scholar 

  29. Wang SS, Feng L, Hu BG, Lu YF, Wang WM, Guo W, et al. miR-133a promotes TRAIL resistance in glioblastoma via suppressing death receptor 5 and activating NF-kappaB signaling. Mol Ther Nucleic Acids. 2017;8:482–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Srivastava C, Irshad K, Gupta Y, Sarkar C, Suri A, Chattopadhyay P, et al. NFkappaB is a critical transcriptional regulator of atypical cadherin FAT1 in glioma. BMC Cancer. 2020;20:62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sarkar S, Yong VW. Inflammatory cytokine modulation of matrix metalloproteinase expression and invasiveness of glioma cells in a 3-dimensional collagen matrix. J Neurooncol. 2009;91:157–64.

    Article  CAS  PubMed  Google Scholar 

  32. Bond M, Fabunmi RP, Baker AH, Newby AC. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-kappa B. FEBS Lett. 1998;435:29–34.

    Article  CAS  PubMed  Google Scholar 

  33. Wei S, Wang D, Li H, Bi L, Deng J, Zhu G, et al. Fatty acylCoA synthetase FadD13 regulates proinflammatory cytokine secretion dependent on the NF-kappaB signalling pathway by binding to eEF1A1. Cell Microbiol. 2019;21:e13090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bist P, Leow SC, Phua QH, Shu S, Zhuang Q, Loh WT, et al. Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-kappaB: implication in breast cancer metastasis. Oncogene. 2011;30:3174–85.

    Article  CAS  PubMed  Google Scholar 

  35. Wu Y, Kang J, Zhang L, Liang Z, Tang X, Yan Y, et al. Ubiquitination regulation of inflammatory responses through NF-kappaB pathway. Am J Transl Res. 2018;10:881–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Song K, Cai X, Dong Y, Wu H, Wei Y, Shankavaram U, et al. Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development. J Clin Invest. 2020;131:e129374.

    Article  Google Scholar 

  37. Rahighi S, Ikeda F, Kawasaki M, Akutsu M, Suzuki N, Kato R, et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-kappaB activation. Cell. 2009;136:1098–109.

    Article  CAS  PubMed  Google Scholar 

  38. Wertz IE, Dixit VM. Signaling to NF-kappaB: regulation by ubiquitination. Cold Spring Harb Perspect Biol. 2010;2:a003350.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chen ZJ, Sun LJ. Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell. 2009;33:275–86.

    Article  CAS  PubMed  Google Scholar 

  40. Yamamoto M, Okamoto T, Takeda K, Sato S, Sanjo H, Uematsu S, et al. Key function for the Ubc13 E2 ubiquitin-conjugating enzyme in immune receptor signaling. Nat Immunol. 2006;7:962–70.

    Article  CAS  PubMed  Google Scholar 

  41. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell. 2006;22:245–57.

    Article  CAS  PubMed  Google Scholar 

  42. Lee IY, Lim JM, Cho H, Kim E, Kim Y, Oh HK, et al. MST1 negatively regulates TNFalpha-induced NF-kappaB signaling through modulating LUBAC activity. Mol Cell. 2019;73:1138–49.e6.

    Article  CAS  PubMed  Google Scholar 

  43. Tokunaga F, Sakata S, Saeki Y, Satomi Y, Kirisako T, Kamei K, et al. Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol. 2009;11:123–32.

    Article  CAS  PubMed  Google Scholar 

  44. Yang Y, Schmitz R, Mitala J, Whiting A, Xiao W, Ceribelli M, et al. Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Disco. 2014;4:480–93.

    Article  CAS  Google Scholar 

  45. Niu J, Shi Y, Iwai K, Wu ZH. LUBAC regulates NF-kappaB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. EMBO J. 2011;30:3741–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Prasetyanti PR, Medema JP. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Cancer. 2017;16:41.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl J Med. 2012;366:883–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Oushy S, Hellwinkel JE, Wang M, Nguyen GJ, Gunaydin D, Harland TA, et al. Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype. Philos Trans R Soc Lond B Biol Sci. 2018;373:20160477.

  49. Abels ER, Broekman MLD, Breakefield XO, Maas SLN. Glioma EVs contribute to immune privilege in the brain. Trends Cancer. 2019;5:393–96.

    Article  PubMed  PubMed Central  Google Scholar 

  50. de Vrij J, Maas SL, Kwappenberg KM, Schnoor R, Kleijn A, Dekker L, et al. Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int J Cancer. 2015;137:1630–42.

    Article  PubMed  Google Scholar 

  51. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Basic and Applied Research Projects of Guangzhou Science and Technology Bureau (202002030067), the Natural Science Foundation of China (82273464, 81972619, 81672874, and 81972399), the Natural Science Foundation of Guangdong Province (2021A1515012477 and 2022A1515012260), the Key Discipline of Guangzhou Education Bureau (Basic Medicine) (201851839), the Natural Science Foundation research team of Guangdong Province (2018B030312001), the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital (202011-202), the Innovative Academic Team of Guangzhou Education System (1201610014), and the Guangzhou key medical discipline construction project fun.

Author information

Authors and Affiliations

Authors

Contributions

LJ and JL developed the original idea, designed the study, analyzed data, and wrote the manuscript. HC, XC, ZZ and WB contributed to the development of the protocol and performed most of the experiments and data analysis. ZG, DL, XX, PZ, CY and ZZ contributed to the in vitro biological experiments and data analysis. HC, ZZ, ZG and XX performed the in vivo experiments and data analysis. ZZ, JP, XK, DZ, JY and LW contributed to clinical data collection and statistical analysis. RT, ZF, LZ and HH provided the bioinformatics analysis. DT assisted in data interpretation and edited the manuscript.

Corresponding authors

Correspondence to Jinbao Liu or Lili Jiang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Investigation has been conducted in accordance with the ethical standards according to the Declaration of Helsinki and national and international guidelines and has been approved by the authors’ Institutional Review Board.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, H., Chen, X., Zhang, Z. et al. Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO. Oncogene 41, 5253–5265 (2022). https://doi.org/10.1038/s41388-022-02520-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02520-6

This article is cited by

Search

Quick links