Klotho suppresses tumor progression via inhibiting IGF-1R signaling in T-cell lymphoma

Zhou, Xiangxiang; Zhang, Ya; Liu, Ying; Xu, Yangyang; Zhang, Lingyan; Wang, Xin

doi:10.3892/or.2017.5744

Cited by 10 publications

(8 citation statements)

References 30 publications

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“…3E). Prior studies have demonstrated that klotho suppresses the growth of various cancer cells by inhibiting several pathways implicated in the pathogenesis of PKD, including Wnt/␤-catenin and insulin-like growth factor 1 signals (34,45,49,50). Additionally, klotho has been demonstrated to increase intracellular Ca 2ϩ in tubular epithelial cells (6,23,44), an action that has been shown to suppress the mitogenic response to cAMP in cystic epithelial cells (46).…”

Section: Discussionmentioning

confidence: 99%

Dietary phosphate restriction attenuates polycystic kidney disease in mice

Omede

Zhang

Johnson

et al. 2020

American Journal of Physiology-Renal Physiology

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Studies in rodents with reduced nephron mass have suggested a strong positive correlation between dietary phosphate consumption and CKD progression. Prior work by our group demonstrated that dietary phosphate restriction can prevent tubular injury and microcyst formation in rodents with glomerulonephritis. Tubular injury and cystic dilation of tubules are key contributors to kidney function decline in polycystic kidney disease (PKD). Here, we determined whether dietary phosphate restriction slows renal cyst growth and fibrosis in a mouse model of PKD. Pcy/pcy mice received a normal phosphate (0.54%) or a phosphate-restricted (0.02%) diet ( n = 10/group) from 7 to 20 wk of age. All of the other major dietary constituents, including protein source and content, were comparable between the two diets. At 20 wk, body weight, kidney weight-to-body weight ratio (KW/BW), cystic area, cyst number, and kidney fibrosis were quantified. Pcy/pcy mice fed a phosphate-restricted diet had lower serum phosphate, fibroblast growth factor 23, and parathyroid hormone levels, along with elevated serum calcium levels and increased kidney Klotho gene expression compared with mice that consumed the control diet. Dietary phosphate restriction resulted in a 25% lower KW/BW ratio and reduced the cyst number, cystic index, and gene expression for the tubular injury markers neutrophil gelatinase-associated lipocalin and interleukin-18. Mice fed the phosphate-restricted diet exhibited lower kidney expression for pathways involved in collagen deposition and myofibroblast activation (collagen type I-α1, phosphorylated SMAD3, and α-smooth muscle actin); however, histological differences in kidney fibrosis were not appreciated. Dietary phosphate restriction slows cystogenesis and inhibits the activation of key pathways in the generation of kidney fibrosis in PKD mice.

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Section: Discussionmentioning

confidence: 99%

Dietary phosphate restriction attenuates polycystic kidney disease in mice

Omede

Zhang

Johnson

et al. 2020

American Journal of Physiology-Renal Physiology

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“…Immunohistochemical staining was scored by two independent observers who were blinded to the patients' clinical data. The scoring system for grading the level of YAP was reported previously [22]. The expression level was evaluated by immunohistochemistry (IHC) score calculated by multiplying a proportion score and intensity score.…”

Section: Immunohistochemistry and Hematoxylin-eosin Stainingmentioning

confidence: 99%

Regulation of Hippo-YAP signaling by insulin-like growth factor-1 receptor in the tumorigenesis of diffuse large B-cell lymphoma

Zhou

Chen

et al. 2020

J Hematol Oncol

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Background: Hippo-Yes-associated protein (YAP) signaling is a key regulator of organ size and tumorigenesis, yet the underlying molecular mechanism is still poorly understood. At present, the significance of the Hippo-YAP pathway in diffuse large B-cell lymphoma (DLBCL) is ill-defined. Methods: The expression of YAP in DLBCL was determined in public database and clinical specimens. The effects of YAP knockdown, CRISPR/Cas9-mediated YAP deletion, and YAP inhibitor treatment on cell proliferation and the cell cycle were evaluated both in vitro and in vivo. RNA sequencing was conducted to detect dysregulated RNAs in YAP-knockout DLBCL cells. The regulatory effects of insulin-like growth factor-1 receptor (IGF-1R) on Hippo-YAP signaling were explored by targeted inhibition and rescue experiments. Results: High expression of YAP was significantly correlated with disease progression and poor prognosis. Knockdown of YAP expression suppressed cell proliferation and induced cell cycle arrest in DLBCL cells. Verteporfin (VP), a benzoporphyrin derivative, exerted an anti-tumor effect by regulating the expression of YAP and the downstream target genes, CTGF and CYR61. In vitro and in vivo studies revealed that deletion of YAP expression with a CRISPR/Cas9 genome editing system significantly restrained tumor growth. Moreover, downregulation of IGF-1R expression led to a remarkable decrease in YAP expression. In contrast, exposure to IGF-1 promoted YAP expression and reversed the inhibition of YAP expression induced by IGF-1R inhibitors. Conclusions: Our study highlights the critical role of YAP in the pathogenesis of DLBCL and uncovers the regulatory effect of IGF-1R on Hippo-YAP signaling, suggesting a novel therapeutic strategy for DLBCL.

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“…The scores were independently evaluated by two observers. The criterion for determining the presence of klotho staining was 10%, as referenced in two studies [ 25 , 26 ]. The proportion score was determined as 0 (<10%), 1 (10–25%), 2 (26–50%), 3 (51–75%), or 4 (>75%) according to the percentages of positive staining areas in five representative high-power fields.…”

Section: Methodsmentioning

confidence: 99%

Down-expression of klotho in canine mammary gland tumors and its prognostic significance

2022

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Since the discovery of klotho as an anti-aging gene, its association with tumors has been studied. Several previous studies have reported the down-expression of klotho in various human cancers, and much of its mechanism has been revealed. Nonetheless, the significance of klotho in canine mammary gland tumors is not yet known. This study aimed to determine whether klotho is expressed within normal canine mammary glands and whether the expression changes in benign and malignant tumors. Using immunohistochemistry, the experiment was conducted on eight normal canine mammary gland tissues and 55 mammary gland tumor samples. Additionally, the correlation between the Ki-67 proliferation index and clinicopathological features, such as age, tumor size, tumor grade, histologic type, and metastasis, was evaluated. All eight normal mammary gland tissues showed immunohistochemistry expression of klotho, and the expression significantly decreased as malignancy increased. Among the samples, 11% (3/28) of benign tumors and 26% (7/27) of malignant tumors showed negative klotho expression. Furthermore, higher Ki-67 expression, higher grades, and metastasis were confirmed to be associated with the negative klotho expression. Analysis of the survival curve for dogs with malignant tumors revealed that negative klotho expression was significantly associated with poor overall survival and disease-free survival. These results indicate that klotho is expressed in normal canine mammary glands and that negative klotho expression in canine mammary gland tumors is positively correlated with poor prognosis.

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Klotho suppresses tumor progression via inhibiting IGF-1R signaling in T-cell lymphoma

Cited by 10 publications

References 30 publications

Dietary phosphate restriction attenuates polycystic kidney disease in mice

Dietary phosphate restriction attenuates polycystic kidney disease in mice

Regulation of Hippo-YAP signaling by insulin-like growth factor-1 receptor in the tumorigenesis of diffuse large B-cell lymphoma

Down-expression of klotho in canine mammary gland tumors and its prognostic significance

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