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Glioma pathogenesis-related protein 1 performs dual functions in tumor cells

Cancer Gene Therapy volume 29, pages 253–263 (2022)Cite this article

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Abstract

Glioma pathogenesis-related protein 1 (GLIPR1) was identified as an oncoprotein in some cancer types including gliomas, breast cancers, melanoma cancers, and Wilms tumors, but as a tumor suppressor in some other types of cancers, such as prostate cancers, lung cancers, bladder cancers, and thyroid cancers. In gliomas, GLIPR1 promotes the migration and invasion of glioma cells by interaction with the actin polymerization regulator Neural Wiskott–Aldrich syndrome protein (N-WASP) and then abolishes the negative effects of Heterogeneous nuclear ribonuclear protein K (hnRNPK). In prostate cancers, high levels of GLIPR1 induce apoptosis and destruction of oncoproteins. In lung cancers, overexpression of GLIPR1 inhibits the growth of lung cancer cells partially through inhibiting the V-ErbB avian erythroblastic leukemia viral oncogene homolog3 (ErbB3) pathway. However, the mechanisms that GLIPR1 performs its function in other tumors still remain unclear. The tumor suppressing role of GLIPR1 has been explored to the cancer treatment. The adenoviral vector-mediated Glipr1 (AdGlipr1) gene therapy and the GLIPR1-transmembrane domain deleted (GLIPR1-ΔTM) protein therapy both showed antitumor activities and stimulated immune response in prostate cancers. Whether GLPIR1 can be used to treat other tumors is an important topic to be explored. Among which, whether GLPIR1 can be used to treat lung cancer by atomizing inhalation is the key topic we care about. If it does, this therapy has a wide application prospect and is a great progression in lung cancer treatment.

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Fig. 1
Fig. 2: Structure of sGLIPR1 adopted from Asojo et al. [36, 37].
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References

  1. Murphy EV, Zhang Y, Zhu W, Biggs J. The human glioma pathogenesis-related protein is structurally related to plant pathogenesis-related proteins and its gene is expressed specifically in brain tumors. Gene. 1995;159:131–5.

    Article  CAS  PubMed  Google Scholar 

  2. Rich T, Chen P, Furman F, Huynh N, Israel MA. RTVP-1, a novel human gene with sequence similarity to genes of diverse species, is expressed in tumor cell lines of glial but not neuronal origin. Gene. 1996;180:125–30.

    Article  CAS  PubMed  Google Scholar 

  3. Szyperski T, Fernandez C, Mumenthaler C, Wuthrich K. Structure comparison of human glioma pathogenesis-related protein GliPR and the plant pathogenesis-related protein P14a indicates a functional link between the human immune system and a plant defense system. Proc Natl Acad Sci USA. 1998;95:2262–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lincoln JE, Sanchez JP, Zumstein K, Gilchrist DG. Plant and animal PR1 family members inhibit programmed cell death and suppress bacterial pathogens in plant tissues. Mol Plant Pathol. 2018;19:2111–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Thompson TC. Glioma pathogenesis-related protein 1: tumor-suppressor activities and therapeutic potential. Yonsei Med J. 2010;51:479–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gibbs GM, Roelants K, O’Bryan MK. The CAP superfamily: cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins-roles in reproduction, cancer, and immune defense. Endocr Rev. 2008;29:865–97.

    Article  CAS  PubMed  Google Scholar 

  7. Ren C, Ren CH, Li L, Goltsov AA, Thompson TC. Identification and characterization of RTVP1/GLIPR1-like genes, a novel p53 target gene cluster. Genomics. 2006;88:163–72.

    Article  CAS  PubMed  Google Scholar 

  8. Scheuring UJ, Corbeil J, Mosier DE, Theofilopoulos AN. Early modification of host cell gene expression induced by HIV-1. AIDS. 1998;12:563–70.

    Article  CAS  PubMed  Google Scholar 

  9. Gingras MC, Margolin JF. Differential expression of multiple unexpected genes during U937 cell and macrophage differentiation detected by suppressive subtractive hybridization. Exp Hematol. 2000;28:65–76.

    Article  CAS  PubMed  Google Scholar 

  10. Rasmussen LM, Frederiksen KS, Din N, Galsgaard E, Christensen L, Berchtold MW, et al. Prolactin and oestrogen synergistically regulate gene expression and proliferation of breast cancer cells. Endocr Relat Cancer. 2010;17:809–22.

    Article  CAS  PubMed  Google Scholar 

  11. Awasthi A, Woolley AG, Lecomte FJ, Hung N, Baguley BC, Wilbanks SM, et al. Variable expression of GLIPR1 correlates with invasive potential in melanoma cells. Front Oncol. 2013;3:225.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chilukamarri L, Hancock AL, Malik S, Zabkiewicz J, Baker JA, Greenhough A, et al. Hypomethylation and aberrant expression of the glioma pathogenesis-related 1 gene in Wilms tumors. Neoplasia. 2007;9:970–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bier A, Giladi N, Kronfeld N, Lee HK, Cazacu S, Finniss S, et al. MicroRNA-137 is downregulated in glioblastoma and inhibits the stemness of glioma stem cells by targeting RTVP-1. Oncotarget 2013;4:665–76.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ziv-Av A, Giladi ND, Lee HK, Cazacu S, Finniss S, Xiang C, et al. RTVP-1 regulates glioma cell migration and invasion via interaction with N-WASP and hnRNPK. Oncotarget. 2015;6:19826–40.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Giladi ND, Ziv-Av A, Lee HK, Finniss S, Cazacu S, Xiang C, et al. RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop. Oncotarget. 2015;6:22680–97.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Li L, Abdel Fattah E, Cao G, Ren C, Yang G, Goltsov AA, et al. Glioma pathogenesis-related protein 1 exerts tumor suppressor activities through proapoptotic reactive oxygen species-c-Jun-NH2 kinase signaling. Cancer Res. 2008;68:434–43.

    Article  CAS  PubMed  Google Scholar 

  17. Li L, Ren C, Yang G, Fattah EA, Goltsov AA, Kim SM, et al. GLIPR1 suppresses prostate cancer development through targeted oncoprotein destruction. Cancer Res. 2011;71:7694–704.

    Article  CAS  PubMed  Google Scholar 

  18. Li L, Yang G, Ren C, Tanimoto R, Hirayama T, Wang J, et al. Glioma pathogenesis-related protein 1 induces prostate cancer cell death through Hsc70-mediated suppression of AURKA and TPX2. Mol Oncol. 2013;7:484–96.

    Article  CAS  PubMed  Google Scholar 

  19. Ren C, Li L, Goltsov AA, Timme TL, Tahir SA, Wang J, et al. mRTVP-1, a novel p53 target gene with proapoptotic activities. Mol Cell Biol. 2002;22:3345–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ren C, Li L, Yang G, Timme TL, Goltsov A, Ren C, et al. RTVP-1, a tumor suppressor inactivated by methylation in prostate cancer. Cancer Res. 2004;64:969–76.

    Article  CAS  PubMed  Google Scholar 

  21. Sheng X, Bowen N, Wang Z. GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer. Mol Cancer. 2016;15:25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhang LJ, Xiong Y, Nilubol N, He M, Bommareddi S, Zhu X, et al. Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity. Carcinogenesis. 2015;36:420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yan L, Li Q, Yang J, Qiao B. TPX2-p53-GLIPR1 regulatory circuitry in cell proliferation, invasion, and tumor growth of bladder cancer. J Cell Biochem. 2018;119:1791–803.

    Article  CAS  PubMed  Google Scholar 

  24. Dong J, Bi B, Zhang L, Gao K. GLIPR1 inhibits the proliferation and induces the differentiation of cancer-initiating cells by regulating miR-16 in osteosarcoma. Oncol Rep. 2016;36:1585–91.

    Article  CAS  PubMed  Google Scholar 

  25. Quinn MC, Filali-Mouhim A, Provencher DM, Mes-Masson AM, Tonin PN. Reprogramming of the transcriptome in a novel chromosome 3 transfer tumor suppressor ovarian cancer cell line model affected molecular networks that are characteristic of ovarian cancer. Mol Carcinog. 2009;48:648–61.

    Article  CAS  PubMed  Google Scholar 

  26. Tam M, Lin P, Hu P, Lennon PA. Examining Hedgehog pathway genes GLI3, SHH, and PTCH1 and the p53 target GLIPR1/GLIPR1L1/GLIPR1L2 gene cluster using fluorescence in situ hybridization uncovers GLIPR1/GLIPR1L1/GLIPR1L2 deletion in 9% of patients with multiple myeloma. J Assoc Genet Technol. 2010;36:111–4.

    PubMed  Google Scholar 

  27. Aytekin T, Ozaslan M, Cengiz B. Deletion mapping of chromosome region 12q13-24 in colorectal cancer. Cancer Genet Cytogenet. 2010;201:32–8.

    Article  CAS  PubMed  Google Scholar 

  28. Karantanos T, Tanimoto R, Edamura K, Hirayama T, Yang G, Golstov AA, et al. Systemic GLIPR1-DeltaTM protein as a novel therapeutic approach for prostate cancer. Int J Cancer. 2014;134:2003–13.

    Article  CAS  PubMed  Google Scholar 

  29. Naruishi K, Timme TL, Kusaka N, Fujita T, Yang G, Goltsov A, et al. Adenoviral vector-mediated RTVP-1 gene-modified tumor cell-based vaccine suppresses the development of experimental prostate cancer. Cancer Gene Ther. 2006;13:658–63.

    Article  CAS  PubMed  Google Scholar 

  30. Satoh T, Timme TL, Saika T, Ebara S, Yang G, Wang J, et al. Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer. Hum Gene Ther. 2003;14:91–101.

    Article  CAS  PubMed  Google Scholar 

  31. Sonpavde G, Thompson TC, Jain RK, Ayala GE, Kurosaka S, Edamura K, et al. GLIPR1 tumor suppressor gene expressed by adenoviral vector as neoadjuvant intraprostatic injection for localized intermediate or high-risk prostate cancer preceding radical prostatectomy. Clin Cancer Res. 2011;17:7174–82.

    Article  CAS  PubMed  Google Scholar 

  32. Tabata K, Kurosaka S, Watanabe M, Edamura K, Satoh T, Yang G, et al. Tumor growth and metastasis suppression by Glipr1 gene-modified macrophages in a metastatic prostate cancer model. Gene Ther. 2011;18:969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Capalbo G, Mueller-Kuller T, Koschmieder S, Klein HU, Ottmann OG, Hoelzer D, et al. Endoplasmic reticulum protein GliPR1 regulates G protein signaling and the cell cycle and is overexpressed in AML. Oncol Rep. 2013;30:2254–62.

    Article  CAS  PubMed  Google Scholar 

  34. de Vasconcellos JF, Laranjeira AB, Leal PC, Bhasin MK, Zenatti PP, Nunes RJ, et al. SB225002 induces cell death and cell cycle arrest in acute lymphoblastic leukemia cells through the activation of GLIPR1. PLoS One. 2015;10:e0134783.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Gong X, Liu J, Zhang D, Yang D, Min Z, Wen X, et al. GLIPR1 modulates the response of cisplatin-resistant human lung cancer cells to cisplatin. PLoS One. 2017;12:e0182410.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Asojo OA, Koski RA, Bonafe N. Structural studies of human glioma pathogenesis-related protein 1. Acta Crystallogr D Biol Crystallogr. 2011;67:847–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Madej T, Lanczycki CJ, Zhang D, Thiessen PA, Geer RS, Marchler-Bauer A. et al. MMDB and VAST+: tracking structural similarities between macromolecular complexes. Nucleic Acids Res. 2014;42:297–303. 2014 Jan.

    Article  CAS  Google Scholar 

  38. Gibbs GM, Lo JC, Nixon B, Jamsai D, O’Connor AE, Rijal S, et al. Glioma pathogenesis-related 1-like 1 is testis enriched, dynamically modified, and redistributed during male germ cell maturation and has a potential role in sperm-oocyte binding. Endocrinology. 2010;151:2331–42.

    Article  CAS  PubMed  Google Scholar 

  39. Xiang C, Sarid R, Cazacu S, Finniss S, Lee HK, Ziv-Av A, et al. Cloning and characterization of human RTVP-1b, a novel splice variant of RTVP-1 in glioma cells. Biochem Biophys Res Commun. 2007;362:612–8.

    Article  CAS  PubMed  Google Scholar 

  40. Capalbo G, Muller-Kuller T, Dietrich U, Hoelzer D, Ottmann OG, Scheuring UJ. Inhibition of HIV-1 replication by small interfering RNAs directed against glioma pathogenesis related protein (GliPR) expression. Retrovirology. 2010;7:26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Karanika S, Karantanos T, Kurosaka S, Wang J, Hirayama T, Yang G, et al. GLIPR1-DeltaTM synergizes with docetaxel in cell death and suppresses resistance to docetaxel in prostate cancer cells. Mol Cancer. 2015;14:122.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Rosenzweig T, Ziv-Av A, Xiang C, Lu W, Cazacu S, Taler D, et al. Related to testes-specific, vespid, and pathogenesis protein-1 (RTVP-1) is overexpressed in gliomas and regulates the growth, survival, and invasion of glioma cells. Cancer Res. 2006;66:4139–48.

    Article  CAS  PubMed  Google Scholar 

  43. Iyer D, Chang D, Marx J, Wei L, Olson EN, Parmacek MS, et al. Serum response factor MADS box serine-162 phosphorylation switches proliferation and myogenic gene programs. Proc Natl Acad Sci USA. 2006;103:4516–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Soh JW, Lee EH, Prywes R, Weinstein IB. Novel roles of specific isoforms of protein kinase C in activation of the c-fos serum response element. Mol Cell Biol. 1999;19:1313–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shore P, Sharrocks AD. The MADS-box family of transcription factors. Eur J Biochem. 1995;229:1–13.

    Article  CAS  PubMed  Google Scholar 

  46. Miano JM. Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol. 2003;35:577–93.

    Article  CAS  PubMed  Google Scholar 

  47. Park MY, Kim KR, Park HS, Park BH, Choi HN, Jang KY, et al. Expression of the serum response factor in hepatocellular carcinoma: implications for epithelial-mesenchymal transition. Int J Oncol. 2007;31:1309–15.

    CAS  PubMed  Google Scholar 

  48. Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science. 1995;269:403–7.

    Article  CAS  PubMed  Google Scholar 

  49. Ziv-Av A, Taller D, Attia M, Xiang C, Lee HK, Cazacu S, et al. RTVP-1 expression is regulated by SRF downstream of protein kinase C and contributes to the effect of SRF on glioma cell migration. Cell Signal. 2011;23:1936–43.

    Article  CAS  PubMed  Google Scholar 

  50. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Sun G, Ye P, Murai K, Lang MF, Li S, Zhang H, et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat Commun. 2011;2:529.

    Article  PubMed  CAS  Google Scholar 

  52. Zhang L, Yang B, Zhou K, Li H, Li D, Gao H, et al. Potential therapeutic mechanism of genistein in breast cancer involves inhibition of cell cycle regulation. Mol Med Rep. 2015;11:1820–6.

    Article  CAS  PubMed  Google Scholar 

  53. Liang T, Tan T, Xiao Y, Yi H, Li C, Peng F. et al.Methylation and expression of glioma pathogenesis-related protein 1 gene in acute myeloid leukemia.Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009;34:388–94.

    CAS  PubMed  Google Scholar 

  54. Xiao YH, Li XH, Tan T, Liang T, Yi H, Li MY, et al. Identification of GLIPR1 tumor suppressor as methylation-silenced gene in acute myeloid leukemia by microarray analysis. J Cancer Res Clin Oncol. 2011;137:1831–40.

    Article  CAS  PubMed  Google Scholar 

  55. Abdel-Rahman WM, Lotsari-Salomaa JE, Kaur S, Niskakoski A, Knuutila S, Jarvinen H, et al. The role of chromosomal instability and epigenetics in colorectal cancers lacking beta-Catenin/TCF regulated transcription. Gastroenterol Res Pract. 2016;2016:6089658.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sheng X, Wang Z. Protein arginine methyltransferase 5 regulates multiple signaling pathways to promote lung cancer cell proliferation. BMC Cancer. 2016;16:567.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Wang H, Thompson TC. Gene-modified bone marrow cell therapy for prostate cancer. Gene Ther. 2008;15:787–96.

    Article  CAS  PubMed  Google Scholar 

  58. Fujita T, Satoh T, Timme TL, Hirayama T, Zhu JX, Kusaka N, et al. Combined therapeutic effects of adenoviral vector-mediated GLIPR1 gene therapy and radiotherapy in prostate and bladder cancer models. Urol Oncol. 2014;32:92–100.

    Article  CAS  PubMed  Google Scholar 

  59. Robert X, Gouet P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014;42:W320–4. Web Server issue

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank George Osei-Adjei for checking the language. XS is supported by grants from Natural Science Foundation of Jiangsu Province (No. BK20191429) and Professional Research Foundation for Advanced Talents of Jiangsu University (No. 11JDG063).

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Authors and Affiliations

  1. Department of Pathophysiology, Jiangsu University School of Medicine, Zhenjiang, 212013, Jiangsu, China

    Junjie Wang

  2. Department of Biochemistry and Molecular Biology, Jiangsu University School of Medicine, Zhenjiang, 212013, Jiangsu, China

    Zeyu Li, Fenfen Yin, Rui Zhang, Ying Zhang & Xiumei Sheng

  3. The Center for Cancer Research and Therapeutic Development, Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, 30314, USA

    Zhengxin Wang

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Conceptualization: XS, ZW; Reference preparation: ZL, FY; Original draft preparation: JW, XS; Review and editing: RZ, YZ; Supervision: XS, ZW. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Zhengxin Wang or Xiumei Sheng.

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Wang, J., Li, Z., Yin, F. et al. Glioma pathogenesis-related protein 1 performs dual functions in tumor cells. Cancer Gene Ther 29, 253–263 (2022). https://doi.org/10.1038/s41417-021-00321-9

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