Abstract
Gliomas are the most common primary tumors of the Central Nervous System. Despite advances in the elucidation of molecular pathogenesis, gliomas still remain incurable. In the study, it was aimed to investigate the possible connection between ACE and AGTR1 polymorphisms with glioma pathogenesis and also the relationship of some angiogenic markers with gliomagenesis. In this respect, 96 glioma patients and 104 healthy controls were included in the study. To determine the effect of genetic polymorphisms on the predisposition of diffuse infiltrative glial tumors in the Turkish population, angiotensin-converting enzyme gene (ACE) insertion/deletion, angiotensin II receptor type 1 gene (AGTR1) ‒168A/G, ‒535C/T, ‒825T/A, and Vascular Endothelial Growth Factor gene (VEGF) +936C/T, ‒2578C/A polymorphisms were investigated by PCR-RFLP. Allele/genotype frequencies between patients and controls were determined. Besides, relative gene expressions of ACE, AGTR1, and VEGF were detected by real time-PCR, while ACE, VEGF, ET-1, eNOS, and NO levels were measured in both serum and tissue by ELISA. In AGTR1 ‒168A/G polymorphism, the risk of glioma in the AA genotype decreased, while increased by 2.27 times in the G allele. Allele frequency and genotype distributions of other polymorphisms were found similar between two groups. Serum levels of ACE, VEGF, eNOS, NO, and tissue levels of ACE, ET-1, eNOS, NO were also different between the patients and controls. ACE, AGTR1, and VEGF expressions in patient group were found significantly higher than in control one. These results provide the first evidence linking ‒168A/G polymorphism in AGTR1 gene with glioma risk in the Turkish population.
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DATA AVAILABILITY
The datasets generated during and analyzed during the current study will be available from the corresponding author upon reasonable request.
REFERENCES
Louis D.N., Perry A., Reifenberger G., von Deim-ling A., Figarella-Branger D., Cavenee W.K., Ohgaki H., Wiestler O.D., Kleihues P., Ellison D.W. 2016. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 131 (6), 803–820. https://doi.org/10.1007/s00401-016-1545-1
Studdy P.R., Lapworth R., Bird R. 1983. Angiotensin-converting enzyme and its clinical significance—a review. J. Clin. Pathol. 36 (8), 938‒947. https://doi.org/10.1136/jcp.36.8.938
Rigat B., Hubert C., Alhenc-Gelas F., Cambien F., Corvol P., Soubrier F. 1990. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86 (4), 1343–1346. https://doi.org/10.1172/JCI114844
Duncan J.A., Scholey J.W., Miller J.A. 2001. Angiotensin II type 1 receptor gene polymorphisms in humans: Physiology and pathophysiology of the genotypes. Curr. Opin. Nephrol. Hypertens. 10 (1), 111–116. https://doi.org/10.1097/00041552-200101000-00017
Munzenmaier D.H., Greene A.S. 1996. Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. Hypertension. 27 (3Pt2), 760–765. https://doi.org/10.1161/01.hyp.27.3.760
Uemura H., Ishiguro H., Nakaigawa N., Nagashima Y., Miyoshi Y., Fujinami K., Sakaguchi A., Kubota Y. 2003. Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: A possibility of tyrosine kinase inhibitor of growth factor. Mol. Cancer Ther. 2 (11), 1139–1147.
Watson C.J., Webb N.J., Bottomley M.J., Brenchley P.E. 2000. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: Correlation with variation in VEGF protein production. Cytokine. 12 (8), 1232–1235. https://doi.org/10.1006/cyto.2000.0692
Salani D., Taraboletti G., Rosanò L., Di Cast-ro V., Borsotti P., Giavazzi R., Bagnato A. 2000. Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Am. J. Pathol. 157 (5), 1703–1711. https://doi.org/10.1016/S0002-9440(10)64807-9
Kaur B., Khwaja F.W., Severson E.A., Matheny S.L., Brat D.J., Van Meir E.G. 2005. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol. 7 (2), 134–153. https://doi.org/10.1215/S1152851704001115
Fukumura D., Gohongi T., Kadambi A., Izumi Y., Ang J., Yun C.O., Buerk D.G., Huang P.L., Jain R.K. 2001. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc. Natl. Acad. Sci. U. S. A. 98 (5), 2604–2609. https://doi.org/10.1073/pnas.041359198
Brooks S.E., Gu X., Samuel S., Marcus D.M., Bartoli M., Huang P.L., Caldwell R.B. 2001. Reduced severity of oxygen-induced retinopathy in eNOS-deficient mice. Invest. Ophthalmol. Vis. Sci. 42 (1), 222–228.
Asgharzadeh F., Hassanian S., Ferns G., Khazaei M., Hasanzadeh M. 2018. The therapeutic potential of angiotensin-converting enzyme and angiotensin receptor inhibitors in the treatment of colorectal cancer: Rational strategies and recent progress. Curr. Pharm. Des. 24 (39), 4652–4658. https://doi.org/10.2174/1381612825666190111145140
Lian M., Jiang H., Wang H., Guo S. 2015. Angiotensin-converting enzyme insertion/deletion gene polymorphisms is associated with risk of glioma in a Chinese population. J. Renin. Angiotensin. Aldosterone Syst. 16 (2), 443–447. https://doi.org/10.1177/1470320313495910
Pandith A.A., Qasim I., Zahoor W., Shah P., Bhat A.R. 2018. ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients. Gene. 639, 62–68. https://doi.org/10.1016/j.gene.2017.10.013
Benenemissi I., Sifi K., Sahli L., Semmam O., Abadi N., Satta D. 2019. Angiotensin-converting enzyme insertion/deletion gene polymorphisms and the risk of glioma in an Algerian population. Pan. Afr. Med. J. 32, 1–7. https://doi.org/10.11604/pamj.2019.32.197.15129
Li J., Sima X., Zhao N. 2013. Studies on association between ACE I/D polymorphism and glioma. Chin. J. Neurosurg. Dis. Res. 12, 106–108.
Sun M., Fang Y., Ma S., Gao X., Sun Y. 2020. The genetic polymorphisms of angiotensin converting enzyme insertion / deletion and glioma susceptibility: A meta-analysis. J. Renin Angiotensin Aldosterone Syst. 21 (4), 1470320320963939. https://doi.org/10.1177/1470320320963939
Arrieta O., Guevara P., Escobar E., García-Navarrete R., Pineda B., Sotelo J. 2005. Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. Br. J. Cancer. 92 (7), 1247–1252. https://doi.org/10.1038/sj.bjc.6602483
Koh W.P., Yuan J.M., Van Den Berg D., Lee H.P., Yu M.C. 2005. Polymorphisms in angiotensin II type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore. Carcinogenesis. 26 (2), 459–464. https://doi.org/10.1093/carcin/bgh309
Li R., Zhao Y., Fan W., Chen H., Chen Y., Liu Y., Chen G., Zhou K., Huang F., Mao Y., Zhou L., Lu D., Shugart Y.Y. 2011. Possible association between polymorphisms of human vascular endothelial growth factor A gene and susceptibility to glioma in a Chinese population. Int. J. Cancer. 128 (1), 166–175. https://doi.org/10.1002/ijc.25306
Jiang H., Lian M., Xie J., Li J., Wang M. 2013. Three single nucleotide polymorphisms of the vascular endothelial growth factor (VEGF) gene and glioma risk in a Chinese population. J. Int. Med. Res. 41 (5), 1484–1494. https://doi.org/10.1177/0300060513498667
Zhang J., Yang J., Chen Y., Mao Q., Li S., Xiong W., Lin Y., Chen J., Ge J. 2016. Genetic Variants of VEGF (rs201963 and rs3025039) and KDR (rs7667298, rs2305948, and rs1870377) are associated with glioma risk in a Han Chinese population: A case-control study. Mol. Neurobiol. 53 (4), 2610–2618. https://doi.org/10.1007/s12035-015-9240-0
Linhares P., Viana-Pereira M., Ferreira M., Amorim J., Nabiço R., Pinto F., Costa S., Vaz R., Reis R.M. 2018. Genetic variants of vascular endothelial growth factor predict risk and survival of gliomas. Tumour Biol. 40 (3), 1010428318766273. https://doi.org/10.1177/1010428318766273
Juillerat-Jeanneret L., Celerier J., Bernasconi C.C., Nguyen G., Wostl W., Maerki H.P., Janzer R.C., Corvol P., Gasc J.M. 2004. Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br. J. Cancer. 90 (5), 1059–1068. https://doi.org/10.1038/sj.bjc.6601646
Bradshaw A.R., Wickremesekera A.C., Brasch H.D., Chibnall A.M., Davis P.F., Tan S.T., Itinteang T. 2016. Glioblastoma multiforme cancer stem cells express components of the renin–angiotensin system. Front. Surg. 3, 51. https://doi.org/10.3389/fsurg.2016.00051
Han C.D., Ge W.S. 2016. Up-regulation of angiotensin-converting enzyme (ACE) enhances cell proliferation and predicts poor prognosis in laryngeal cancer. Med. Sci. Monit. 22, 4132–4138. https://doi.org/10.12659/msm.896933
Zhang K., Mao T., He Z., Wu X., Peng Y., Chen Y., Dong Y., Ruan Z., Wang Z. 2019. Angiotensin I-converting enzyme gene plays a crucial role in the pathology of carcinomas in colorectal cancer. Artif. Cells Nanomed. Biotechnol. 47 (1), 2500–2506. https://doi.org/10.1080/21691401.2019.1626402
Mehranfard D., Perez G., Rodriguez A., Ladna J.M., Neagra C.T., Goldstein B., Carroll T., Tran A., Trivedi M., Speth R.C. 2021. Alterations in gene expression of renin-angiotensin system components and related proteins in colorectal cancer. J. Renin Angiotensin Aldosterone Syst. 2021, 9987115. https://doi.org/10.1155/2021/9987115
Ibiş M., Yüksel O., Yilmaz G., Köklü S., Yilmaz F.M., Ertuğrul I., Uçar E., Altiparmak M.E. 2008. Serum angiotensin converting enzyme levels in pancreatic diseases. Hepatogastroenterology. 55 (86–87), 1814–1817.
Beyazit F., Ayhan S., Celik H.T., Gungor T. 2015. Assessment of serum angiotensin-converting enzyme in patients with epithelial ovarian cancer. Arch. Gynecol. Obstet. 292 (2), 415–420. https://doi.org/10.1007/s00404-015-3661-x
Kardum D., Huskic J., Fabijanic D., Banic M., Buljevac M., Kjundzic M., Loncar B. 1999. Activity of serum angiotensin-converting enzyme as a tumor marker of hepatocellular carcinoma. Eur. J. Gastroenterol. Hepatol. 11 (11), 1209–1213. https://doi.org/10.1097/00042737-199911000-00004
Ohta T., Amaya K., Yi S., Kitagawa H., Kayahara M., Ninomiya I., Fushida S., Fujimura T., Nishimura G., Shimizu K., Miwa K. 2003. Angiotensin converting enzyme-independent, local angiotensin II-generation in human pancreatic ductal cancer tissues. Int. J. Oncol. 23 (3), 593–598
Procházka J., Krepela E., Sedo A., Viklický J., Fiala P. 1991. Aminopeptidases and angiotensin I-converting enzyme activities in primary human lung tumors and lung parenchyma. Neoplasma. 38 (5), 501–508.
Danilov S.M., Kadrev A.V., Kurilova O.V., Tikhomirova V.E., Kryukova O.V., Mamedov V.N., Kama-lov D.M., Danilova N.V., Okhobotov D.A., Gayful-lin N.M., Evdokimov V.V., Alekseev B.J., Kost O.A., Samokhodskaya L.M., Kamalov A.A. 2019. Tissue ACE phenotyping in prostate cancer. Oncotarget. 10 (59), 6349–6361. https://doi.org/10.18632/oncotarget.27276
Ganong W.F. 1984. The brain renin−angiotensin system. Annu. Rev. Physiol. 46, 17–31. https://doi.org/10.1146/annurev.ph.46.030184.000313
Arrieta O., Pineda-Olvera B., Guevara-Salazar P., Hernández-Pedro N., Morales-Espinosa D., Cerón-Lizarraga T.L., González-De la Rosa C.H., Rembao D., Segura-Pacheco B., Sotelo J. 2008. Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br. J. Cancer. 99 (1), 160–166. https://doi.org/10.1038/sj.bjc.6604431
Arrieta O., Villarreal-Garza C., Vizcaíno G., Pineda B., Hernández-Pedro N., Guevara-Salazar P., Wegman-Ostrosky T., Villanueva-Rodríguez G., Gamboa-Domínguez A. 2015. Association between AT1 and AT2 angiotensin II receptor expression with cell proliferation and angiogenesis in operable breast cancer. Tumour Biol. 36 (7), 5627–5634. https://doi.org/10.1007/s13277-015-3235-3
Plate K.H., Breier G., Weich H.A., Risau W. 1992. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 359 (6398), 845–848. https://doi.org/10.1038/359845a0
Pietsch T., Valter M.M., Wolf H.K., Von Deimling A., Huang H.J., Cavenee W.K., Wiestler O.D. 1997. Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropathol. 93 (2), 109–117. https://doi.org/10.1007/s004010050591
Samoto K., Ikezaki K., Ono M., Shono T., Kohno K., Kuwano M., Fukui M. 1995. Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res. 55 (5), 1189–1193.
Li J.T., Yan Q., Yu H.L. 2009. Expression of VEGF and NGF in gliomas of human. Sichuan Da Xue Xue Bao Yi Xue Ban. 40 (3), 408–411.
Nowacka A., Smuczyński W., Rość D., Woźniak-Dąbrowska K., Śniegocki M. 2018. Serum VEGF-A concentrations in patients with central nervous system (CNS) tumors. PLoS One. 13 (3), e0192395. https://doi.org/10.1371/journal.pone.0192395
Chiorean R., Berindan-Neagoe I., Braicu C., Florian I.S., Leucuta D., Crisan D., Cernea V. 2014. Quantitative expression of serum biomarkers involved in angiogenesis and inflammation, in patients with glioblastoma multiforme: Correlations with clinical data. Cancer Biomark. 14 (2–3), 185–194. https://doi.org/10.3233/CBM-130310
Rafat N., Beck G.C., Schulte J., Tuettenberg J., Vajkoczy P. 2010. Circulating endothelial progenitor cells in malignant gliomas. J. Neurosurg. 112 (1), 43–49. https://doi.org/10.3171/2009.5.JNS081074
Takano S., Yoshii Y., Kondo S., Suzuki H., Maruno T., Shirai S., Nose T. 1996. Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 56 (9), 2185–2190.
Schmidt N.O., Westphal M., Hagel C., Ergün S., Stavrou D., Rosen E.M., Lamszus K. 1999. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer. 84 (1), 10–18. https://doi.org/10.1002/(sici)1097-0215(19990219)84:1<10::aid-ijc3>3.0.co;2-l
Stiles J.D., Ostrow P.T., Balos L.L., Greenberg S.J., Plunkett R., Grand W., Heffner R.R.Jr. 1997. Correlation of endothelin-1 and transforming growth factor β1 with malignancy and vascularity in human gliomas. J. Neuropathol. Exp. Neurol. 56 (4), 435–439. https://doi.org/10.1097/00005072-199704000-00012
Abdel-Gawad I.A., Hassanein H.M., Bahgat N.A., Abdel Sattar M.A., El-Sissy A.H., Altaweel M.A., Helal A.M. 2008. Study of endothelin-1 and vascular endothelial growth factor in patients with cancer colon. J. Egypt. Natl. Canc. Inst. 20 (3), 216–223.
Yildirim Y., Gunel N., Coskun U., Sancak B., Bukan N., Aslan S., Cetin A. 2008. Serum big endothelin-1 levels in female patients with breast cancer. Int. Immunopharmacol. 8 (8), 1119–1123. https://doi.org/10.1016/j.intimp.2008.03.023
Teng X.J., Liu R., Zhang Z.X., He J.F., Shen Z.X. 2008. Correlation of preoperative plasma levels of big endothelin-1 to prognosis of gastric carcinoma. Ai Zheng. 27 (1), 88–91.
Pfab T., Stoltenburg-Didinger G., Trautner C., Godes M., Hocher B. 2004. The endothelin system in Morris hepatoma-7777: An endothelin receptor antagonist inhibits growth in vitro and in vivo. Br. J. Pharmacol. 141 (2), 215–222. https://doi.org/10.1038/sj.bjp.0705601
Alanen K., Deng D.X., Chakrabarti S. 2000. Augmented expression of endothelin-1, endothelin-3 and the endothelin-B receptor in breast carcinoma. Histopathology. 36 (2), 161–167. https://doi.org/10.1046/j.1365-2559.2000.00795.x
Zheng P.P., Hop W.C., Luider T.M., Sillevis Smitt P.A., Kros J.M. 2007. Increased levels of circulating endothelial progenitor cells and circulating endothelial nitric oxide synthase in patients with gliomas. Ann. Neurol. 62 (1), 40–48. https://doi.org/10.1002/ana.21151
Pan J.W., Zhan R.Y., Tong Y., Zhou Y.Q., Zhang M. 2005. Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in association with neovascularization in human primary astrocytoma. J. Zhejiang Univ. Sci. B. 6 (7), 693–698. https://doi.org/10.1631/jzus.2005.B0693
Mei K., Cai X.H., Du L., Chen Y.F., Huang S., Chen J., Yin X.D., Zhang Z.X., Zhao X., Zhou C.Y., Yu J.R. 2010. Basic Research Effect of nitric oxide derived from endothelial nitric oxide synthase (eNOS) on tumor angiogenesis. Chin. J. Cancer. 29 (1), 32–37. https://doi.org/10.5732/cjc.009.10246
Meena S.K., Kumar R., Sairoz. 2017. Serum nitric oxide and peroxynitrite in breast cancer patients. Int. J. Curr. Res. 9 (8), 55725–55727.
Ratajczak-Wrona W., Jablonska E., Marcinczyk M., Grabowska Z., Piotrowski L. 2022. Role of p38 MAPK pathway in induction of iNOS expression in neutrophils and peripheral blood mononuclear cells in patients with squamous cell carcinoma. J. Oral. Maxillofac. Surg. 67 (11), 2354–2363. https://doi.org/10.1016/j.joms.2009.04.030
Ghosh R., Castelino R.L., Babu S.G., Banerjee B. 2021. Estimation of salivary and tissue nitric oxide levels in oral squamous cell carcinoma: A biochemical study. Eur. J. Ther. 27, 26–31.
Sangle V.A., Chaware S.J., Kulkarni M.A., Ingle Y.C., Singh P., Pooja V.K. 2018. Elevated tissue nitric oxide in oral squamous cell carcinoma. J. Oral. Maxillofac. Pathol. 22 (1), 35–39. https://doi.org/10.4103/jomfp.JOMFP_27_16
ACKNOWLEDGMENTS
The authors would like to thank Prof. Ali Ergül and Umut Kibar for their contribution to primer design and selection of restriction enzymes and assistance in Real-Time PCR applications.
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This study was supported financially by the Scientific and Technological Research Council of Turkey (TÜBİTAK; project no. 216S995).
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TT: Conceptualization, Formal Analysis, Investigation, Roles/Writing—Original Draft.
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AG: Conceptualization, Formal analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Supervision, Writing—Review & Editing.
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The study was approved by the Clinical Research Ethics Committee of Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital with the decision number 189 dated December, 2015. All procedures involving people comply with the ethical standards of the institutional and/or national committee for research ethics and the 1964 Helsinki Declaration and its subsequent changes or comparable ethical standards. Informed written consent was achieved from all subjects included in the study according to the ethical standards of the Ethics Committee.
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Abbreviations: CNS, Central Nervous System; ACE, Angiotensin Converting Enzyme; I/D, Insertion/Deletion; AGTR1, Angiotensin II Type I Receptor; AGTR2, Angiotensin II Type II Receptor; VEGF, Vascular Endothelial Growth Factor; NO, Nitric Oxide; ET-1, Endothelin-1; eNOS, Endothelial Nitric Oxide Synthase; WHO, World Health Organization; PCR-RFLP, Polymerase Chain Reaction Restriction Fragment Length Polymorphism; Touch down-PCR, Touch Down Polymerase Chain Reaction; UV, Ultraviolet; RE, Restriction Enzyme; PBS, Phosphate Buffer; PASS, Power Analysis and Sample Size.
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Turan, T., Özaydın, B., Emmez, Ö.H. et al. Angiotensin II Type I Receptor—168A/G Polymorphism Is Associated with Increased the Risk of Glioma in Turkish Population. Mol Biol 58, 216–232 (2024). https://doi.org/10.1134/S0026893324020158
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DOI: https://doi.org/10.1134/S0026893324020158