Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma

Xie, Biao; Zhou, Jianping; Yuan, Long; Ren, Feng; Liu, Dongcai; Li, Qinglong; Shu, Guoshun

doi:10.1016/j.humpath.2012.07.023

Cited by 65 publications

(69 citation statements)

References 18 publications

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“…Furthermore, α-Klotho has been revealed to have tumor suppressive properties during various malignant transformations by factor pathway (35), which is associated with cancer risk and tumor progression. Xie et al (36) measured mRNA and protein expression levels of α-Klotho in 64 HCC tumor tissues using real-time polymerase chain reaction and immunohistochemistry, respectively, demonstrating that a loss of α-Klotho expression in HCC cells was a predictive factor for the poor prognosis of the disease. Similarly, Shu et al (37) reported that exogenous expression of the Klotho gene significantly inhibited the proliferation of HCC cells, induced HCC cell apoptosis and decreased HCC cell migration, using a Matrigel invasion chamber assay.…”

Section: Discussionmentioning

confidence: 99%

Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis

Prystupa¹,

Dabrowska²,

Sak³

et al. 2016

Experimental and Therapeutic Medicine

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The aim of the present study was to evaluate the concentrations of fetuin-A, osteoprotegerin (OPG) and α-Klotho protein in patients with alcoholic cirrhosis at different stages of the disease, and to demonstrate that fetuin-A, osteoprotegin and α-Klotho may be used as markers of the severity of cirrhosis. A total of 54 patients with alcoholic liver cirrhosis treated in various hospitals in the Lublin region of Poland were randomly enrolled. The control group consisted of 18 healthy individuals without liver disease, who did not drink alcohol. Serum levels of fetuin-A, OPG and α-Klotho were measured by ELISA kits. Levels of fetuin-A were significantly reduced in patients with alcoholic liver cirrhosis compared with the control group. OPG levels were higher in patients with alcoholic liver cirrhosis than in the controls, whereas the levels of α-Klotho were comparable in the cirrhosis and control groups. No statistically significant differences in the concentrations of fetuin-A, OPG and α-Klotho protein were demonstrated according to type of liver cirrhosis. The findings of the present study revealed a significant negative correlation between the level of α-Klotho protein and C-reactive protein in the patients with alcoholic liver cirrhosis. Concentrations of fetuin-A were lower, whereas those of OPG were higher, in the alcoholic liver cirrhosis group compared with the control group. Fetuin-A, OPG and α-Klotho may not be good indicators of liver cirrhosis severity. In conclusion, fetuin-A and OPG may be used in the diagnosis of liver cirrhosis.

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Section: Discussionmentioning

confidence: 99%

Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis

Prystupa¹,

Dabrowska²,

Sak³

et al. 2016

Experimental and Therapeutic Medicine

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“…The hyperacetylation of histone in Klotho promoter was also proposed as a possible mechanism for Klotho silencing in many types of cancer cell lines [122, 123]. Furthermore, cytokines-induced elevation of histone acetylation is shown to be associated with downregulation of Klotho expression, because TNF and TNF-like weak inducer of apoptosis (TWEAK)-induced downregulation of Klotho expression in the kidney and kidney cell lines could be blunted by inhibition of histone deacetylase [46].…”

Section: Potential Treatment Strategy For Chronic Kidney Diseasementioning

confidence: 99%

Potential application of klotho in human chronic kidney disease

Neyra

2017

Bone

101

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The extracellular domain of transmembrane alpha-Klotho (αKlotho, hereinafter simply called Klotho) is cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho in the circulation starts to decline early in chronic kidney disease (CKD) stage 2 and urinary Klotho possibly even earlier in CKD stage 1. Therefore soluble Klotho could serve as an early and sensitive marker of kidney function decline. Moreover, preclinical animal data support Klotho deficiency is not just merely a biomarker, but a pathogenic factor for CKD progression and extrarenal CKD complications including cardiovascular disease and disturbed mineral metabolism. Prevention of Klotho decline, re-activation of endogenous Klotho production or supplementation of exogenous Klotho are all associated with attenuation of renal fibrosis, retardation of CKD progression, improvement of mineral metabolism, amelioration of cardiomyopathy, and alleviation of vascular calcification in CKD. Therefore Klotho is not only a diagnostic and/or prognostic marker for CKD, but the treatment of Klotho deficiency may be a promising strategy to prevent, retard, and decrease the burden of comorbidity in CKD.

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“…Calvisi et al (7) analyzed the global levels of DNA methylation and the methylation status of 105 putative tumor suppressor genes and identified that the extent of genome-wide hypomethylation and CpG hypermethylation correlated with the clinical outcome of HCC patients. The promoter DNA methylation of the Klotho gene was a predictive factor for poor HCC prognosis (62). Univariate and multivariate survival analysis revealed that HIST1H2AE methylation status is closely correlated with overall survival (10).…”

Section: Clinical Applicationsmentioning

confidence: 99%

Aberrant DNA methylation in hepatocellular carcinoma tumor suppression (Review)

Dong

Wang

2014

Oncology Letters

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Aberrant DNA methylation leads to altered gene expression, resulting in cancerous features. Numerous tumor suppressor genes are silenced by DNA methylation during hepatocarcinogenesis. Promoter CpG island hypermethylation is an important mechanism for inactivating tumor suppressor genes in hepatocellular carcinoma (HCC). Hypermethylation of CpG islands in the p16 (INK4a) and p15 (INK4b) promoters may increase the risk of developing HCC, particularly hepatitis B virus-related HCC. Environmental factors can lead to geographic variations in the methylation status of CpG islands. Aberrant DNA methylation of CpG islands is catalyzed by DNA methyltransferases (DNMTs). Thus, abnormal variations of DNMTs can contribute to hepatocarcinogenesis. In hepatitis-related HCC, microRNAs participate in hepatocarcinogenesis by directly targeting DNMTs, during which hepatitis B virus X acts as a regulator. DNA methylation may also contribute to HCC tumorigenesis by regulating the cell cycle. Based on the importance of DNA methylation in tumor suppression of HCC, certain DNA methylations may predict the risk of tumor development, tumor staging, patient survival and HCC recurrence.

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Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma

Cited by 65 publications

References 18 publications

Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis

Concentrations of fetuin-A, osteoprotegerin and α-Klotho in patients with alcoholic liver cirrhosis

Potential application of klotho in human chronic kidney disease

Aberrant DNA methylation in hepatocellular carcinoma tumor suppression (Review)

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