Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma

Our plain-English summary of Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma, by N. Peshes-Yeloz, L. Ungar, A. Wohl, et al (World Neurosurgery, 2019).

The study

• Authors: N. Peshes-Yeloz, L. Ungar, A. Wohl, E. Jacoby, T. Fisher, M. Leitner, D. Nass, T. Rubinek, I. Wolf, Z.R. Cohen
• Journal: World Neurosurgery
• Published: 2019;130:e324-e332
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Klotho, a single-pass transmembrane protein associated with premature aging, acts as a tumor suppressor gene by inhibiting insulin/insulin-like growth factor-1 and fibroblast growth factor pathways. Downregulated Klotho expression is reported in melanoma, mesothelioma, bladder, breast, gastric, cervix, lung, and kidney cancers and is associated with a poor prognosis. Klotho expression and Klotho promoter hypermethylation are predictive factors for patient prognosis.

Methods: To investigate the potential role of Klotho in glioblastoma-multiforme (GBM), 22 GBM samples were collected from the Sheba Tumor Bank and examined.

Results: We found that increased Klotho messenger ribonucleic acid (RNA) expression predicted longer survival (P = 0.03) of GBM patients. Methylation analysis was performed on bisulfite-treated deoxyribonucleic acid from the GBM patient samples using ionization time-of-flight mass spectrometry according to the Sequenom EpiTYPER protocols. Klotho promoter hypermethylation was detected in 65% of the GBM samples and correlated significantly with improved survival (P < 0.04). We found 3 major Klotho promotor hypermethylation sites located 585-579 bp, 540-533 bp, and 537-534 bp upstream of the transcription start site. Methylated deoxyribonucleic acid immunoprecipitation studies confirmed these results. Notably, the messenger RNA expression in these GBM samples revealed an unexpected linear correlation with methylation of these 3 hypermethylation sites identified in the Klotho promotor. Thus Klotho expression and methylation could predict prognosis in patients with GBM.

Conclusions: Epigenetic regulation in GBM appears to be complicated. Specific CpG islands affect genes or micro RNAs that interact to control Klotho expression. The diverse effects of these islands may be due to unique factors of GBM.

Copyright © 2019 Elsevier Inc. All rights reserved.

In plain English

This laboratory study, from Sheba Medical Center in Israel, examined the protein Klotho in glioblastoma multiforme (GBM), a brain cancer. It did not study asbestos. Mesothelioma is mentioned only as background from other studies. The authors compared Klotho messenger RNA (mRNA) levels in GBM tumor samples with patient survival. In 17 samples, higher Klotho mRNA levels correlated with longer survival (r = 0.596; P = 0.0005), and a survival-curve comparison gave P = 0.03. In a cancer database (TCGA), comparing 12 high- and 24 low-expression cases out of 154 showed a trend in the same direction that was not statistically significant (P = 0.36). In tumor samples, higher methylation at three sites in the Klotho promoter correlated with improved survival (P = 0.009, 0.015 and 0.04). In four GBM cell lines, soluble Klotho reduced cell viability, most effectively at 1.25 to 5 ng/mL. A demethylating drug increased Klotho expression in two cell lines. The authors concluded that Klotho expression and methylation could predict prognosis in GBM. They noted a relatively small sample size. Sample numbers differ between sections of the article.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human glioblastoma tumor samples and glioblastoma cell lines, with comparison of Klotho measurements against patient survival
• Who was studied: Glioblastoma multiforme tumor samples from the Sheba Tumor Bank, Chaim Sheba Medical Center, Israel (22 samples for methylation testing, 17 for the mRNA survival analysis). Also four GBM cell lines (T98G, LN229, U251, U87MG) and 154 cases from the TCGA 2013 database, of which 36 were compared. Dates of patient diagnosis are not given.
• Exposure: No asbestos or fiber exposure was studied. The factors examined were Klotho mRNA and protein levels, Klotho promoter methylation, and treatment of cell lines with soluble Klotho (0.5 to 100 ng/mL), 5-Aza and trichostatin A.
• Main results:
  • In 17 GBM samples, Klotho mRNA levels correlated with patient survival (r = 0.596; P = 0.0005).
  • A Kaplan-Meier survival analysis of the 17 GBM patients, grouped by Klotho mRNA level, was statistically significant (P = 0.03).
  • In the TCGA dataset of 154 cases, the survival comparison used 12 cases with high and 24 with low Klotho expression. The difference was not statistically significant (P = 0.36).
  • In GBM patient samples, hypermethylation at 3 sites of the Klotho promoter (585 to 579 bp, 540 to 533 bp, and 537 to 534 bp) correlated with improved survival (P = 0.009, P = 0.015 and P = 0.04, respectively).
  • Methylated DNA immunoprecipitation (MeDIP) in 3 patients gave results consistent with the main methylation method.
  • In the four GBM cell lines, soluble Klotho reduced cell viability, with 1.25 to 5 ng/mL most effective.
  • In LN229 and U251 cell lines, the demethylating drug 5-Aza increased Klotho expression.
  • In the samples listed in Table 1 (10 GBM samples), Klotho mRNA levels correlated with Klotho protein expression grade (r = 0.69; P = 0.0278).
• The authors' conclusion: The authors concluded that Klotho expression and methylation could predict prognosis in patients with GBM.
• Limitations the authors state:
  • The authors state that the study was limited by its relatively small sample size.
  • The authors state that cell-cycle analysis and animal experiments are still needed to clarify Klotho's role as a possible tumor suppressor.

Topics

Medical terms in this study, explained in our Lexicon: Prognosis, Tumor Suppressor Gene, Fibroblast, Mesothelioma.

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