High expression of VAT1 is a prognostic biomarker and predicts malignancy in glioblastoma

  • Authors:
    • Xia Shan
    • Kuanyu Wang
    • Xuezhi Tong
    • Zhiliang Wang
    • Fan Wu
    • Xing Liu
    • Pei Yang
    • Jiangfei Wang
  • View Affiliations

  • Published online on: August 12, 2019     https://doi.org/10.3892/or.2019.7276
  • Pages: 1422-1430
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Vesicle amine transport protein 1 (VAT1) has been reported as a pathogenic factor in a variety of tumors. VAT1 has been revealed to be upregulated in glioblastoma (GBM) and promotes cell migration. However, the possible mechanism of VAT1 in promoting malignant development in GBM is unclear. The present study applied transcriptome data and functional experiments to explore the exact role of VAT1. Kaplan‑Meier survival analysis, univariate and multivariate Cox analyses were used to perform survival analysis. Furthermore, Gene Ontology analysis was used to analyze the biological implication of VAT1 expression. The in vitro experiment was performed to verify the hypothesis. The expression of VAT1 was detected in gliomas and control tissues. A functional experiment was performed and the sensitivity to TMZ was assessed after knocking down the expression of VAT1. In total, 120 patients with GBM were enrolled in the present study. The results of multivariate analysis revealed that VAT1 was an independent prognostic factor for survival. Patients with high VAT1 expression levels had shorter overall survival (P=0.009) and progression‑free survival (P=0.055) than those with low expression levels. Gene Ontology analysis revealed that the genes which were positively associated with VAT1 were functionally involved in proteolysis, oxidation‑reduction processes and immune response. The results of functional experiments demonstrated that VAT1 exhibited high expression levels in GBM, which could be inhibited by microRNA‑218. Upon VAT1 knockdown, cell proliferation and migration were markedly suppressed, while the sensitivity toward temozolomide chemotherapy was enhanced. Thus, VAT1 expression was revealed to be a prognostic factor for GBM. High expression of VAT1 may promote cell proliferation, migration and temozolomide chemotherapy‑resistance, which may be a potential therapeutic target for GBM.

References

1 

Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY and Olson JJ: Exciting new advances in neuro-oncology: The avenue to a cure for malignant glioma. CA Cancer J Clin. 60:166–193. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Claes A, Idema AJ and Wesseling P: Diffuse glioma growth: A guerilla war. Acta Neuropathol. 114:443–458. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, : National Cancer Institute of Canada Clinical Trials Group: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Smith TM, Lee MK, Szabo CI, Jerome N, McEuen M, Taylor M, Hood L and King MC: Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. Genome Res. 6:1029–1049. 1996. View Article : Google Scholar : PubMed/NCBI

7 

Wang Y and Jiang T: Understanding high grade glioma: Molecular mechanism, therapy and comprehensive management. Cancer Lett. 331:139–146. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Eiden LE, Schäfer MK, Weihe E and Schütz B: The vesicular amine transporter family (SLC18): Amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Pflugers Arch. 447:636–640. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Linial M and Levius O: VAT-1 from Torpedo is a membranous homologue of zeta crystallin. FEBS Lett. 315:91–94. 1993. View Article : Google Scholar : PubMed/NCBI

10 

Linial M, Miller K and Scheller RH: VAT-1: An abundant membrane protein from Torpedo cholinergic synaptic vesicles. Neuron. 2:1265–1273. 1989. View Article : Google Scholar : PubMed/NCBI

11 

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 266:66–71. 1994. View Article : Google Scholar : PubMed/NCBI

12 

Koch J, Foekens J, Timmermans M, Fink W, Wirzbach A, Kramer MD and Schaefer BM: Human VAT-1: A calcium-regulated activation marker of human epithelial cells. Arch Dermatol Res. 295:203–210. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Vicanová J, Boelsma E, Mommaas AM, Kempenaar JA, Forslind B, Pallon J, Egelrud T, Koerten HK and Ponec M: Normalization of epidermal calcium distribution profile in reconstructed human epidermis is related to improvement of terminal differentiation and stratum corneum barrier formation. J Invest Dermatol. 111:97–106. 1998. View Article : Google Scholar : PubMed/NCBI

14 

Owens DW, Brunton VG, Parkinson EK and Frame MC: E-cadherin at the cell periphery is a determinant of keratinocyte differentiation in vitro. Biochem Biophys Res Commun. 269:369–376. 2000. View Article : Google Scholar : PubMed/NCBI

15 

Mori F, Tanigawa K, Endo K, Minamiguchi K, Abe M, Yamada S and Miyoshi K: VAT-1 is a novel pathogenic factor of progressive benign prostatic hyperplasia. Prostate. 71:1579–1586. 2011.PubMed/NCBI

16 

Mottaghi-Dastjerdi N, Soltany-Rezaee-Rad M, Sepehrizadeh Z, Roshandel G, Ebrahimifard F and Setayesh N: Gene expression profiling revealed overexpression of vesicle amine transport protein-1 (VAT-1) as a potential oncogene in gastric cancer. Indian J Biotechnol. 15:161–165. 2016.

17 

Mertsch S, Becker M, Lichota A, Paulus W and Senner V: Vesicle amine transport protein-1 (VAT-1) is upregulated in glioblastomas and promotes migration. Neuropathol Appl Neurobiol. 35:342–352. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Novakova J, Slaby O, Vyzula R and Michalek J: MicroRNA involvement in glioblastoma pathogenesis. Biochem Biophys Res Commun. 386:1–5. 2009. View Article : Google Scholar : PubMed/NCBI

19 

Palumbo S, Miracco C, Pirtoli L and Comincini S: Emerging roles of microRNA in modulating cell-death processes in malignant glioma. J Cell Physiol. 229:277–286. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Gao X and Jin W: The emerging role of tumor-suppressive microRNA-218 in targeting glioblastoma stemness. Cancer Lett. 353:25–31. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Yang Y, Ding L, Hu Q, Xia J, Sun J, Wang X, Xiong H, Gurbani D, Li L, Liu Y, et al: MicroRNA-218 functions as a tumor suppressor in lung cancer by targeting IL-6/STAT3 and negatively correlates with poor prognosis. Mol Cancer. 16:1412017. View Article : Google Scholar : PubMed/NCBI

22 

Winter J, Jung S, Keller S, Gregory RI and Diederichs S: Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 11:228–234. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Hwang HW and Mendell JT: MicroRNAs in cell proliferation, cell death, and tumorigenesis. Br J Cancer. 94:776–780. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Yu J, Wang Y, Dong R, Huang X, Ding S and Qiu H: Circulating microRNA-218 was reduced in cervical cancer and correlated with tumor invasion. J Cancer Res Clin Oncol. 138:671–674. 2012. View Article : Google Scholar : PubMed/NCBI

25 

Nishikawa R, Goto Y, Sakamoto S, Chiyomaru T, Enokida H, Kojima S, Kinoshita T, Yamamoto N, Nakagawa M, Naya Y, et al: Tumor-suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting of LASP1 in prostate cancer. Cancer Sci. 105:802–811. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Gu J, Xu R, Li Y, Zhang J and Wang S: MicroRNA-218 modulates activities of glioma cells by targeting HMGB1. Am J Transl Res. 8:3780–3790. 2016.PubMed/NCBI

27 

Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, Cummings T, Allison JP, Bigner DD and Sampson JH: Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 13:2158–2167. 2007. View Article : Google Scholar : PubMed/NCBI

29 

See AP, Parker JJ and Waziri A: The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression. J Neurooncol. 123:405–412. 2015. View Article : Google Scholar : PubMed/NCBI

30 

Shukla SA, Rooney MS, Rajasagi M, Tiao G, Dixon PM, Lawrence MS, Stevens J, Lane WJ, Dellagatta JL, Steelman S, et al: Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat Biotechnol. 33:1152–1158. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, Dziurzynski K, Gilbert M and Heimberger AB: Immune heterogeneity of glioblastoma subtypes: Extrapolation from the cancer genome atlas. Cancer Immunol Res. 1:112–122. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Supper V, Hartl I, Boulègue C, Ohradanova-Repic A and Stockinger H: Dynamic interaction- and phospho-proteomics reveal Lck as a major signaling hub of CD147 in T cells. J Immunol. 198:2468–2478. 2017. View Article : Google Scholar : PubMed/NCBI

33 

Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, Becerril-Villanueva E, Cruz-Fuentes C, Flores-Gutierrez EO, Garcés-Alvarez ME, de la Cruz-Aguilera DL, Medina-Rivero E, Hurtado-Alvarado G, et al: Immunomodulatory effects mediated by dopamine. J Immunol Res. 2016:31604862016. View Article : Google Scholar : PubMed/NCBI

34 

Essand M, Vikman S, Grawé J, Gedda L, Hellberg C, Oberg K, Totterman TH and Giandomenico V: Identification and characterization of a novel splicing variant of vesicular monoamine transporter 1. J Mol Endocrinol. 35:489–501. 2005. View Article : Google Scholar : PubMed/NCBI

35 

Wimalasena K: Vesicular monoamine transporters: Structure- function, pharmacology, and medicinal chemistry. Med Res Rev. 31:483–519. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Cosentino M, Fietta AM, Ferrari M, Rasini E, Bombelli R, Carcano E, Saporiti F, Meloni F, Marino F and Lecchini S: Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood. 109:632–642. 2007. View Article : Google Scholar : PubMed/NCBI

37 

Amenta F, El-Assouad D, Mignini F, Ricci A and Tayebati SK: Neurotransmitter receptor expression by peripheral mononuclear cells: Possible marker of neuronal damage by exposure to radiations. Cell Mol Biol (Noisy-le-grand). 48:415–421. 2002.PubMed/NCBI

38 

Musso NR, Brenci S, Setti M, Indiveri F and Lotti G: Catecholamine content and in vitro catecholamine synthesis in peripheral human lymphocytes. J Clin Endocrinol Metab. 81:3553–3557. 1996. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2019
Volume 42 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Shan, X., Wang, K., Tong, X., Wang, Z., Wu, F., Liu, X. ... Wang, J. (2019). High expression of VAT1 is a prognostic biomarker and predicts malignancy in glioblastoma. Oncology Reports, 42, 1422-1430. https://doi.org/10.3892/or.2019.7276
MLA
Shan, X., Wang, K., Tong, X., Wang, Z., Wu, F., Liu, X., Yang, P., Wang, J."High expression of VAT1 is a prognostic biomarker and predicts malignancy in glioblastoma". Oncology Reports 42.4 (2019): 1422-1430.
Chicago
Shan, X., Wang, K., Tong, X., Wang, Z., Wu, F., Liu, X., Yang, P., Wang, J."High expression of VAT1 is a prognostic biomarker and predicts malignancy in glioblastoma". Oncology Reports 42, no. 4 (2019): 1422-1430. https://doi.org/10.3892/or.2019.7276