Association of Klotho Gene Polymorphism and Serum Level of α Klotho Protein with Different Tumor Grades, Overall Survival and Cytokine Profile in Glioma Patients
Jazyk angličtina Země Švýcarsko Médium electronic
Typ dokumentu časopisecké články
Grantová podpora
Z/2018/1079/VIII/LF/017
Slovak non-profit organization League against Cancer
UK/299/2019
Comenius University grants
UK/1127/2024
Comenius University grants
VEGA 1/0090/22
Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences
APVV-22-0231
Slovak Research and Development Agency
PubMed
39796185
PubMed Central
PMC11719750
DOI
10.3390/ijms26010330
PII: ijms26010330
Knihovny.cz E-zdroje
- Klíčová slova
- Klotho gene, cytokines, glioma, inflammation, overall survival, α klotho,
- MeSH
- cytokiny * krev genetika MeSH
- dospělí MeSH
- genotyp MeSH
- gliom * genetika krev mortalita patologie MeSH
- glukuronidasa * krev genetika MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery krev genetika MeSH
- nádory mozku * genetika krev mortalita patologie MeSH
- proteiny Klotho * MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- stupeň nádoru * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cytokiny * MeSH
- glukuronidasa * MeSH
- nádorové biomarkery MeSH
- proteiny Klotho * MeSH
Gliomas are the most common and lethal forms of malignant brain tumors. We attempted to identify the role of the aging-suppressor Klotho gene and Klotho protein in the immunopathogenesis of gliomas. We examined Klotho genetic variants by PCR-RFLP and measured serum Klotho levels using the ELISA method. We found a statistically significantly increased frequency of rs1207568A allele and rs1207568 GA genotypes in co-dominant, dominant and over-dominant models in grade IV as compared to grade II and III glioma patients. The levels of soluble α Klotho (sαKL) were significantly lower in grade III and IV glioma patients than in healthy controls (p = 0.034; 0.0083). Patients with sαKL levels above 2500 pg/mL survived significantly longer than patients with sαKL below 2500 pg/mL (p = 0.038). We also found a positive correlation of the serum levels of sαKL with seven biomarkers, like angiogenic vascular endothelial growth factor (p = 0.0008), chemokine fractalkine (p = 0.0009), interferon γ (p = 0.003), glial derived neurotrophic factor (p = 0.0268), pro-inflammatory and pro-Th1 cytokine IL-6 (p = 0.0347), anti-inflammatory, pro-Th2 cytokines IL-4 (p = 0.0037) and IL-13 (p = 0.0004). Our results suggest the impact of Klotho genetic variants and Klotho levels on advanced-grade glioma.
Clinic for Children and Adolescents Faculty Hospital Nitra 950 01 Nitra Slovakia
Zobrazit více v PubMed
Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Genetic and molecular epidemiology of adult diffuse glioma. Nat. Rev. Neurol. 2019;15:405–417. doi: 10.1038/s41582-019-0220-2. PubMed DOI PMC
Ostrom Q.T., Price M., Neff C., Cioffi G., Waite K.A., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2015–2019. Neuro-Oncology. 2022;24:v1–v95. doi: 10.1093/neuonc/noac202. PubMed DOI PMC
Cantrell J.N., Waddle M.R., Rotman M., Peterson J.L., Ruiz-Garcia H., Heckman M.G., Quiñones-Hinojosa A., Rosenfeld S.S., Brown P.D., Trifiletti D.M. Progress Toward Long-Term Survivors of Glioblastoma. Mayo Clin. Proc. 2019;94:1278–1286. doi: 10.1016/j.mayocp.2018.11.031. PubMed DOI
Tykocki T., Eltayeb M. Ten-year survival in glioblastoma. A systematic review. J. Clin. Neurosci. 2018;54:7–13. doi: 10.1016/j.jocn.2018.05.002. PubMed DOI
Gusyatiner O., Hegi M.E. Glioma epigenetics: From subclassification to novel treatment options. Semin. Cancer Biol. 2018;51:50–58. doi: 10.1016/j.semcancer.2017.11.010. PubMed DOI
Louis D.N., Perry A., Wesseling P., Brat D.J., Cree I.A., Figarella-Branger D., Hawkins C., Ng H.K., Pfister S.M., Reifenberger G., et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro-Oncology. 2021;23:1231–1251. doi: 10.1093/neuonc/noab106. PubMed DOI PMC
Thomas D.L. 2021 updates to the World Health Organization classification of adult-type and pediatric-type diffuse gliomas: A clinical practice review. Chin. Clin. Oncol. 2023;12:7. doi: 10.21037/cco-22-120. PubMed DOI
Hayashi H., Iwashita H., Tateishi K. Circumscribed Astrocytic Gliomas. No Shinkei Geka. 2023;51:884–891. PubMed
Kuro-o M., Matsumura Y., Aizawa H., Kawaguchi H., Suga T., Utsugi T., Ohyama Y., Kurabayashi M., Kaname T., Kume E., et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51. doi: 10.1038/36285. PubMed DOI
Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol. Chem. 2008;389:233–241. doi: 10.1515/BC.2008.028. PubMed DOI
Matsumura Y., Aizawa H., Shiraki-Iida T., Nagai R., Kuro-o M., Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem. Biophys. Res. Commun. 1998;242:626–630. doi: 10.1006/bbrc.1997.8019. PubMed DOI
Ito S., Fujimori T., Furuya A., Satoh J., Nabeshima Y., Nabeshima Y. Impaired negative feedback suppression of bile acid synthesis in mice lacking betaKlotho. J. Clin. Investig. 2005;115:2202–2208. doi: 10.1172/JCI23076. PubMed DOI PMC
Hayashi Y., Okino N., Kakuta Y., Shikanai T., Tani M., Narimatsu H., Ito M. Klotho-related protein is a novel cytosolic neutral beta-glycosylceramidase. J. Biol. Chem. 2007;282:30889–30900. doi: 10.1074/jbc.M700832200. PubMed DOI
Xu Y., Sun Z. Molecular basis of Klotho: From gene to function in aging. Endocr Rev. 2015;36:174–193. doi: 10.1210/er.2013-1079. PubMed DOI PMC
Wang Y., Sun Z. Current understanding of klotho. Ageing Res. Rev. 2009;8:43–51. doi: 10.1016/j.arr.2008.10.002. PubMed DOI PMC
Kuro-o M. Klotho. Pflugers Arch. 2010;459:333–343. doi: 10.1007/s00424-009-0722-7. PubMed DOI
Urakawa I., Yamazaki Y., Shimada T., Iijima K., Hasegawa H., Okawa K., Fujita T., Fukumoto S., Yamashita T. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444:770–774. doi: 10.1038/nature05315. PubMed DOI
Imai M., Ishikawa K., Matsukawa N., Kida I., Ohta J., Ikushima M., Chihara Y., Rui X., Rakugi H., Ogihara T. Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression. Endocrine. 2004;25:229–234. doi: 10.1385/ENDO:25:3:229. PubMed DOI
Kuro-o M. Klotho and aging. Biochim. Biophys. Acta (BBA)-Gen. Subj. 2009;1790:1049–1058. doi: 10.1016/j.bbagen.2009.02.005. PubMed DOI PMC
Yamamoto M., Clark J.D., Pastor J.V., Gurnani P., Nandi A., Kurosu H., Miyoshi M., Ogawa Y., Castrillon D.H., Rosenblatt K.P., et al. Regulation of oxidative stress by the anti-aging hormone klotho. J. Biol. Chem. 2005;280:38029–38034. doi: 10.1074/jbc.M509039200. PubMed DOI PMC
Yamazaki Y., Imura A., Urakawa I., Shimada T., Murakami J., Aono Y., Hasegawa H., Yamashita T., Nakatani K., Saito Y., et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem. Biophys. Res. Commun. 2010;398:513–518. doi: 10.1016/j.bbrc.2010.06.110. PubMed DOI PMC
Kurosu H., Yamamoto M., Clark J.D., Pastor J.V., Nandi A., Gurnani P., McGuinness O.P., Chikuda H., Yamaguchi M., Kawaguchi H., et al. Suppression of aging in mice by the hormone Klotho. Science. 2005;309:1829–1833. doi: 10.1126/science.1112766. PubMed DOI PMC
Nagai T., Yamada K., Kim H.C., Kim Y.S., Noda Y., Imura A., Nabeshima Y., Nabeshima T. Cognition impairment in the genetic model of aging klotho gene mutant mice: A role of oxidative stress. Faseb J. 2003;17:50–52. doi: 10.1096/fj.02-0448fje. PubMed DOI
Mytych J. Actions of Klotho on hippocampal neuronal cells. Vitam. Horm. 2022;118:223–246. PubMed
Cheng M.F., Chen L.J., Niu H.S., Yang T.T., Lin K.C., Cheng J.T. Signals mediating Klotho-induced neuroprotection in hippocampal neuronal cells. Acta Neurobiol. Exp. (Wars) 2015;75:60–71. doi: 10.55782/ane-2015-2016. PubMed DOI
Chen B., Wang X., Zhao W., Wu J. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J. Exp. Clin. Cancer. Res. 2010;29:99. doi: 10.1186/1756-9966-29-99. PubMed DOI PMC
Xie B., Zhou J., Yuan L., Ren F., Liu D.C., Li Q., Shu G. Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Hum. Pathol. 2013;44:795–801. doi: 10.1016/j.humpath.2012.07.023. PubMed DOI
Rubinek T., Wolf I. The Role of Alpha-Klotho as a Universal Tumor Suppressor. Vitam. Horm. 2016;101:197–214. PubMed
Abboud M., Merenbakh-Lamin K., Volkov H., Ben-Neriah S., Ligumsky H., Bronfeld S., Keren-Khadmy N., Giladi M., Shomron N., Wolf I., et al. Revealing the tumor suppressive sequence within KL1 domain of the hormone Klotho. Oncogene. 2024;43:354–362. doi: 10.1038/s41388-023-02904-2. PubMed DOI
Doi S., Zou Y., Togao O., Pastor J.V., John G.B., Wang L., Shiizaki K., Gotschall R., Schiavi S., Yorioka N., et al. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J. Biol. Chem. 2011;286:8655–8665. doi: 10.1074/jbc.M110.174037. PubMed DOI PMC
Mota J., Lima A.M.M., Gomes J.I.S., Souza de Andrade M., Brito H.O., Silva M., Faustino-Rocha A.I., Oliveira P.A., Lopes F.F., Gil da Costa R.M. Klotho in Cancer: Potential Diagnostic and Prognostic Applications. Diagnostics. 2023;13:3357. doi: 10.3390/diagnostics13213357. PubMed DOI PMC
Hanahan D., Weinberg R.A. Hallmarks of cancer: The next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. PubMed DOI
Peshes-Yeloz N., Ungar L., Wohl A., Jacoby E., Fisher T., Leitner M., Nass D., Rubinek T., Wolf I., Cohen Z.R. Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma. World Neurosurg. 2019;130:e324–e332. doi: 10.1016/j.wneu.2019.06.082. PubMed DOI
Su J., Ma Q., Long W., Tang H., Wu C., Luo M., Wang X., Xiao K., Li Y., Xiao Q., et al. LCTL Is a Prognostic Biomarker and Correlates With Stromal and Immune Infiltration in Gliomas. Front. Oncol. 2019;9:1083. doi: 10.3389/fonc.2019.01083. PubMed DOI PMC
National Library of Medicine (US) Genetics Home Reference. The Library; Bethesda, MD, USA: 2013. [(accessed on 27 May 2024)]. September 16. Available online: https://www.ncbi.nlm.nih.gov/snp/rs1207568.
National Library of Medicine (US) Genetics Home Reference. The Library; Bethesda, MD, USA: 2013. [(accessed on 31 May 2024)]. September 16. Available online: https://www.ncbi.nlm.nih.gov/snp/rs564481.
Liu C., Cui W., Wang L., Yan L., Ruan X., Liu Y., Jia X., Zhang X. Klotho gene polymorphisms are related to colorectal cancer susceptibility. Int. J. Clin. Exp. Pathol. 2015;8:7446–7449. PubMed PMC
Kamal A., Salama M., Kamal A., Mohsen A., Siam I. Klotho (rs1207568 and rs564481) gene variants and colorectal cancer risk. Turk. J. Gastroenterol. 2020;31:497–502. doi: 10.5152/tjg.2020.19235. PubMed DOI PMC
Kuro-o M. Klotho and the aging process. Korean J. Intern. Med. 2011;26:113–122. doi: 10.3904/kjim.2011.26.2.113. PubMed DOI PMC
Shimoyama Y., Taki K., Mitsuda Y., Tsuruta Y., Hamajima N., Niwa T. KLOTHO gene polymorphisms G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in Japanese hemodialysis patients. Am. J. Nephrol. 2009;30:383–388. doi: 10.1159/000235686. PubMed DOI
Chang B., Kim J., Jeong D., Jeong Y., Jeon S., Jung S.I., Yang Y., Kim K.I., Lim J.S., Kim C., et al. Klotho inhibits the capacity of cell migration and invasion in cervical cancer. Oncol. Rep. 2012;28:1022–1028. doi: 10.3892/or.2012.1865. PubMed DOI
Chen B., Ma X., Liu S., Zhao W., Wu J. Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner. Cancer Biol. Ther. 2012;13:1221–1228. doi: 10.4161/cbt.21420. PubMed DOI PMC
Xie B., Chen J., Liu B., Zhan J. Klotho acts as a tumor suppressor in cancers. Pathol. Oncol. Res. 2013;19:611–617. doi: 10.1007/s12253-013-9663-8. PubMed DOI
Zhou X., Wang X. Klotho: A novel biomarker for cancer. J. Cancer Res. Clin. Oncol. 2015;141:961–969. doi: 10.1007/s00432-014-1788-y. PubMed DOI PMC
Wolf I., Levanon-Cohen S., Bose S., Ligumsky H., Sredni B., Kanety H., Kuro-o M., Karlan B., Kaufman B., Koeffler H.P., et al. Klotho: A tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene. 2008;27:7094–7105. doi: 10.1038/onc.2008.292. PubMed DOI
Sachdeva A., Gouge J., Kontovounisios C., Nikolaou S., Ashworth A., Lim K., Chong I. Klotho and the Treatment of Human Malignancies. Cancers. 2020;12:1665. doi: 10.3390/cancers12061665. PubMed DOI PMC
Ligumsky H., Merenbakh-Lamin K., Keren-Khadmy N., Wolf I., Rubinek T. The role of αKlotho in human cancer: Molecular and clinical aspects. Oncogene. 2022;41:4487–4497. doi: 10.1038/s41388-022-02440-5. PubMed DOI
Gigante M., Lucarelli G., Divella C., Netti G.S., Pontrelli P., Cafiero C., Grandaliano G., Castellano G., Rutigliano M., Stallone G., et al. Soluble Serum αKlotho Is a Potential Predictive Marker of Disease Progression in Clear Cell Renal Cell Carcinoma. Medicine. 2015;94:e1917. doi: 10.1097/MD.0000000000001917. PubMed DOI PMC
Tang X., Wang Y., Fan Z., Ji G., Wang M., Lin J., Huang S., Meltzer S.J. Klotho: A tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma. Lab. Investig. 2016;96:197–205. doi: 10.1038/labinvest.2015.86. PubMed DOI PMC
Tang X., Fan Z., Wang Y., Ji G., Wang M., Lin J., Huang S. Expression of klotho and β-catenin in esophageal squamous cell carcinoma, and their clinicopathological and prognostic significance. Dis. Esophagus. 2016;29:207–214. doi: 10.1111/dote.12289. PubMed DOI
Pako J., Bikov A., Barta I., Matsueda H., Puskas R., Galffy G., Kerpel-Fronius A., Antus B., Horvath I. Assessment of the circulating klotho protein in lung cancer patients. Pathol. Oncol. Res. 2020;26:233–238. doi: 10.1007/s12253-018-0441-5. PubMed DOI
Ashkan K., Baig Mirza A., Soumpasis C., Syrris C., Kalaitzoglou D., Sharma C., James Z.J., Khoja A.K., Ahmed R., Vastani A., et al. MGMT Promoter Methylation: Prognostication beyond Treatment Response. J. Pers. Med. 2023;13:999. doi: 10.3390/jpm13060999. PubMed DOI PMC
Bucova M., Kluckova K., Kozak J., Rychly B., Suchankova M., Svajdler M., Matejcik V., Steno J., Zsemlye E., Durmanova V. HLA-G 14bp Ins/Del Polymorphism, Plasma Level of Soluble HLA-G, and Association with IL-6/IL-10 Ratio and Survival of Glioma Patients. Diagnostics. 2022;12:1099. doi: 10.3390/diagnostics12051099. PubMed DOI PMC
Saaid A., Monticelli M., Ricci A.A., Orlando G., Botta C., Zeppa P., Bianconi A., Osella-Abate S., Bruno F., Pellerino A., et al. Prognostic Analysis of the IDH1 G105G (rs11554137) SNP in IDH-Wildtype Glioblastoma. Genes. 2022;13:1439. doi: 10.3390/genes13081439. PubMed DOI PMC
Qiao Y., Liu F., Peng Y., Wang P., Ma B., Li L., Si C., Wang X., Zhang M., Song F. Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey. Cancer Med. 2023;12:1922–1934. doi: 10.1002/cam4.5027. PubMed DOI PMC
Villa C., Miquel C., Mosses D., Bernier M., Di Stefano A.L. The 2016 World Health Organization classification of tumours of the central nervous system. Presse Med. 2018;47:e187–e200. doi: 10.1016/j.lpm.2018.04.015. PubMed DOI
Miller S.A., Dykes D.D., Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215. doi: 10.1093/nar/16.3.1215. PubMed DOI PMC
Solé X., Guinó E., Valls J., Iniesta R., Moreno V. SNPStats: A web tool for the analysis of association studies. Bioinformatics. 2006;22:1928–1929. doi: 10.1093/bioinformatics/btl268. PubMed DOI