Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma

Tang, Xiaowei; Wang, Yun; Fan, Zhining; Ji, Guozhong; Wang, Min; Lin, Jie; Huang, Shu; Meltzer, Stephen J.

doi:10.1038/labinvest.2015.86

Cited by 92 publications

(92 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Pleiotropic actions of αKlotho include antioxidation and antiapoptosis, antifibrosis, enzymatic activity, growth factor regulation, ion transport, mineral metabolism, stem cell function, tumor suppression, autophagy activation, and cell maintenance . αKlotho inhibits Wnt signaling, and reciprocally interacts with erythropoietin receptor to enhance cytoprotection .…”

Section: Discussionmentioning

confidence: 99%

Alpha‐Klotho, a critical protein for lung health, is not expressed in normal lung

et al. 2019

View full text Add to dashboard Cite

Alpha‐Klotho (αKlotho), produced by the kidney and selected organs, is essential for tissue maintenance and protection. Homozygous αKlotho‐deficiency leads to premature multi‐organ degeneration and death; heterozygous insufficiency leads to apoptosis, oxidative stress, and increased injury susceptibility. There is inconsistent data in the literature regarding whether αKlotho is produced locally in the lung or derived from circulation. We probed murine and human lung by immunohistochemistry (IHC) and immunoblot (IB) using two monoclonal (anti‐αKlotho Kl1 and Kl2 domains) and three other common commercial antibodies. Monoclonal anti‐Kl1 and anti‐Kl2 yielded no labeling in lung on IHC or IB; specific labeling was observed in kidney (positive control) and also murine lungs following tracheal delivery of αKlotho cDNA, demonstrating specificity and ability to detect artificial pulmonary expression. Other commercial antibodies labeled numerous lung structures (IHC) and multiple bands (IB) incompatible with known αKlotho mobility; labeling was not abolished by blocking with purified αKlotho or using lungs from hypomorphic αKlotho‐deficient mice, indicating nonspecificity. Results highlight the need for rigorous validation of reagents. The lung lacks native αKlotho expression and derives full‐length αKlotho from circulation; findings could explain susceptibility to lung injury in extrapulmonary pathology associated with reduced circulating αKlotho levels, for example, renal failure. Conversely, αKlotho may be artificially expressed in the lung, suggesting therapeutic opportunities.

show abstract

Section: Discussionmentioning

confidence: 99%

Alpha‐Klotho, a critical protein for lung health, is not expressed in normal lung

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Klotho, a co-receptor for FGF23, may serve as a tumor suppressor, and also inhibit the WNT/β-catenin signaling pathway and reduce expression of c-Myc and cyclin D1 (80). Since Klotho is typically silenced in ovarian cancers (80), this gene is a potential key target for therapy.…”

Section: Serpin Family a Member 1 (Serpina1)mentioning

confidence: 99%

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

et al. 2018

View full text Add to dashboard Cite

Abstract. Cases of mucinous ovarian cancer are predominantly resistant to chemotherapies. The present review summarizes current knowledge of the therapeutic potential of targeting the Wingless (WNT) pathway, with particular emphasis on preclinical and clinical studies, for improving the chemoresistance and treatment of mucinous ovarian cancer. A review was conducted of English language literature published between January 2000 and October 2017 that concerned potential signaling pathways associated with the chemoresistance of mucinous ovarian cancer. The literature indicated that aberrant activation of growth factor and WNT signaling pathways is specifically observed in mucinous ovarian cancer. An evolutionarily conserved signaling cascade system including epidermal growth factor/RAS/RAF/mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase, phosphoinositide 3-kinase/Akt and WNT signaling regulates a variety of cellular functions; their crosstalk mutually enhances signaling activity and induces chemoresistance. Novel antagonists, modulators and inhibitors have been developed for targeting the components of the WNT signaling pathway, namely Frizzled, low-density lipoprotein receptor-related protein 5/6, Dishevelled, casein kinase 1, AXIN, glycogen synthase kinase 3β and β-catenin. Targeted inhibition of WNT signaling represents a rational and promising novel approach to overcome chemoresistance, and several WNT inhibitors are being evaluated in preclinical studies. In conclusion, the WNT receptors and their downstream components may serve as novel therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer.

show abstract

“…Klotho is a tumor suppressor, but its expression is aberrant in a variety of cancers (Tang et al, 2016). Restoration of Klotho expression has been proven to inhibit the proliferation and invasion of gastric cancer cells and hepatocellular carcinoma (HCC) cells (Shu et al, 2013; Xie et al, 2013a).…”

Section: Introductionmentioning

confidence: 99%

FLI‐1 mediates tumor suppressor function via Klotho signaling in regulating CRC

Xie

et al. 2020

Cell Biology International

View full text Add to dashboard Cite

Colorectal cancer (CRC) is an aggressive malignancy with a high incidence and mortality rate. Although a targeting therapy has been developed, the 5‐year survival rate is still very low in CRC patients with distant metastasis. Thus, the identification of new targets is still significant for improving CRC treatment. Klotho is a tumor suppressor, and its expression is aberrant in CRC. In this study, the roles of the FLI‐1 gene in regulating Klotho gene expression and Klotho‐associated signaling, as well as the effects of FLI‐1 on colony formation, invasion, and apoptosis were investigated in CRC cell lines. The methylation of the FLI‐1 gene was analyzed using a commercial methylation kit. Results showed that FLI‐1 messenger RNA and protein expression were downregulated in six CRC cell lines when compared with the normal colon mucosal epithelial cell line, which negatively correlated with the level of DNA methylation. Silencing of FLI‐1 gene expression decreased Klotho protein expression and phosphorylation of β‐catenin protein at Thr41/Ser45, but increased Wnt3a and β‐catenin protein expression and IGF‐1R phosphorylation in HT29 cells. In contrast to silencing FLI‐1, overexpressing FLI‐1 significantly increased Klotho protein expression and phosphorylation of β‐catenin protein at Thr41/Ser45, but decreased Wnt3a and β‐catenin protein expression and IGF‐1R phosphorylation in Caco‐2 cells. Silencing of FLI‐1 gene expression significantly increased colony formation and invasion, but decreased apoptosis in HT29 cells. In contrast, overexpressing the FLI‐1 gene significantly decreased colony formation and invasion, but increased apoptosis in Caco‐2 cells. These findings suggest that FLI‐1 functions as a tumor suppressor in CRC cells and positively regulates Klotho signaling. Hypermethylation may be one of the causes of the loss of FLI‐1 gene expression in CRC cells.

show abstract

Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma

Cited by 92 publications

References 36 publications

Alpha‐Klotho, a critical protein for lung health, is not expressed in normal lung

Alpha‐Klotho, a critical protein for lung health, is not expressed in normal lung

Potential signaling pathways as therapeutic targets for overcoming chemoresistance in mucinous ovarian cancer (Review)

FLI‐1 mediates tumor suppressor function via Klotho signaling in regulating CRC

Contact Info

Product

Resources

About