Klotho plays a critical role in clear cell renal cell carcinoma progression and clinical outcome

Kim, Jihee; Hwang, Kyu Hee; Lkhagvadorj, Sayamaa; Jung, Jae Hung; Chung, Hyun Chul; Park, Kyu Sang; Kong, In Deok; Eom, Minseob; Kuy, Seung

doi:10.4196/kjpp.2016.20.3.297

Cited by 11 publications

(13 citation statements)

References 25 publications

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“…Alpha Klotho as a tumor suppressor factor is predominantly expressed in renal tubular cells, the origin of ccRCC, and altered expression or function of growth factor receptor has also been implicated in ccRCC development. Alpha Klotho suppresses tumor progression and acts as an upstream modulator of insulin-like growth factor-1 receptor signaling [13]. Its protein levels were significantly decreased in RCC tissues compared to normal tissues.…”

Section: Discussionmentioning

confidence: 98%

“…Within the framework of carcinogenesis, it is part of an alternative signaling VEGF pathway targeted by some modern drugs, including dovitinib, nintedanib and lenvatinib) [12]. Alpha Klotho acts as a co-receptor in the FGF 23 signaling pathway, and is known to weaken cell migration and invasiveness and can therefore have a protective effect in tumor suppression [13].…”

mentioning

confidence: 99%

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The importance of serum osteopontin and stanniocalcin-1 in renal cell carcinoma

Sobotka

Čapoun

Hanuš

et al. 2018

neo

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A total of 56 RCC patients with staging ≥ pT1b were enrolled in a prospective study to assess the prognostic importance of serum levels of osteopontin (OP), stanniocalcin-1 (SC), FGF-23, alpha Klotho and 25-OH-D at the time of diagnosis in renal cell carcinoma (RCC) patients. The relationship between the serum level of the analyzed parameters and recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) was examined, and our control group consisted of 20 patients without cancer. The levels of osteopontin, stanniocalcin-1, FGF-23 and alpha Klotho were determined by Enzyme-Linked Immunosorbent Assay (ELISA) and 25-OH-D by chemiluminiscence immunoanalysis (CLIA). The follow-up period median was 46 months. Renal cell carcinoma recurred in 9 patients and 20 patients died during follow-up; 12 of them from RCC. The level of osteopontin and stanniocalcin-1 varied between the control group and RCC patients (at p=0.02 and p=0.0003). Higher levels of stanniocalcin-1 were detected in the metastatic RCC group than in the localized RCC group (p=0.003). Only the stanniocalcin-1 level at the time of surgery was associated with RFS (p=0.0004). Both OS and CCS were associated with the osteopontin, stanniocalcin-1 and FGF preoperative level. Patients with stanniocalcin-1 level over 1,277 pg/ml and osteopontin level over 100 ng/ml had 17.8 times higher and 7.9 times higher risk of dying from RCC progression, respectively (p<0.001 and p=0.002). High levels of osteopontin, stanniocalcin-1 and FGF 23 at the time of surgery are important prognostic factors related to CSS and OS. Patients with high stanniocalcin-1 level were at risk of tumor recurrence.

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

The importance of serum osteopontin and stanniocalcin-1 in renal cell carcinoma

Sobotka

Čapoun

Hanuš

et al. 2018

neo

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“…In renal cell carcinoma (RCC) tissue and cell lines, KL protein and mRNA expression are reduced ( Zhu et al, 2013 ; Gigante et al, 2015 ; Kim et al, 2016 ; Dehghani et al, 2018 ). KL expression is negatively associated with TNM stage, tumor size, shorter overall and progression-free survival ( Zhu et al, 2013 ; Gigante et al, 2015 ).…”

Section: The Role Of αKlotho In Cancermentioning

confidence: 99%

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Ewendt

Feger

Föller

2021

Front. Cell Dev. Biol.

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Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.

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“…Com isso, por meio da inibição de uma ou múltiplas vias, sKL tem validado sua atuação sobre o processo carcinogênico, com impacto inclusive na sobrevida e na resposta à quimioterapia, confirmando assim, seu perfil antitumoral em diversos tipos de câncer, como pulmão, rim, cólon, próstata, ovário e colo uterino, além de ser protagonista em várias pesquisas contra a neoplasia mais prevalente entre as mulheres de todo o mundo, os tumores mamários (CHEN, T. et al, 2016;KIM, J. H. et al, 2016;LEE, J. et al, 2010;LI, X.-X. et al, 2014;RUBINEK, TAMI et al, 2012;SEO et al, 2017;USUDA et al, 2011;WANG, Y. et al, 2013;YAN et al, 2017).…”

Section: Figura 1 Diagrama Esquemático Do αKlotho De Membrana E Geraunclassified

“…Na análise que toma por base o estágio tumoral em inicial ou avançado, o grupo de pacientes que apresentavam tumores da mama em estágio inicial mostravam níveis maiores de αKlotho solúvel sérico em comparação com o grupo das pacientes com tumores avançados. Estes mesmos resultados foram encontrados em estudos de carcinoma hepatocelular e carcinoma renal de células claras, onde pacientes em estágios tumorais mais avançados apresentaram uma menor concentração de αKlotho em comparação com os estágios iniciais do tumor (KIM, J. H. et al, 2016;TANG, X. et al, 2016). No câncer de mama, o gene αKlotho tende a ser hipermetilado durante a transformação maligna, o que inibe sua expressão, fazendo com que esta proteína seja mais abundante em tecidos mamários normais (LIGUMSKY et al, 2015;RUBINEK, TAMI et al, 2012).…”

Section: Pacientes Com Tumores Er-negativos Apresentam Maior Risco Deunclassified

Proteína αKlotho: da associação in vitro com o ERβ ao perfil antitumoral no soro de pacientes com câncer de mama

Amaral¹

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αKlotho, a cellular anti-senescence protein, is related to antitumor actions, regulating the growth, proliferation and invasiveness in several types of tumors, including breast cancer. The diagnosis and prognosis of breast cancer are based on intrinsic characteristics of the tumor, such as the presence of estrogen receptors, especially ERα. In turn, ER despite demonstrating antitumor actions, remains with an uncertain role in breast carcinogenesis and its clinical use is limited. The aim of the study was to analyze the relationship between αKlotho and estrogen receptors, as well as to evaluate the serum levels of this protein in patients with breast cancer according to histopathological and immunohistochemical characteristics of the tumor. The luminal and triple-negative lineages of breast cancer, MCF-7 and MDA MB-231, were cultured and exposed to the agonists of ER, E2 and DPN, to determine the expression of αKlotho, then proliferation and EMT evaluation trials were performed on MCF-7 cells treated with the same agonists. For the soluble αKlotho assays, serum samples from 75 breast cancer patients and 63 healthy controls were randomized and serum levels were assessed by sandwich ELISA. Clinical and diagnostic data were obtained from hospital records and databases. In MCF-7 cells there was a considerable increase in αKlotho expression after stimulation of ER with PND (p<0.01). Activation of ER also led to decreased proliferation and cell cycle arrest, as well as inhibition of the epithelial-mesenchymal transition (EMT). In serum analyzes, healthy women had higher levels of soluble αKlotho than patients (p=0.04). Among the patients, those with initial tumor (p=0.02), ER positivity (p=0.03), and luminal subtype (p=0.04) had higher serum levels of soluble αKlotho. Furthermore, αKlotho production in low or high levels (p=0.04 and p=0.03) was associated with higher rates of proliferation by Ki67. Finally, patients with no lymph node metastasis also had higher levels of α Klotho (p=0.03). These data suggest that soluble αKlotho was related to factors of better prognosis in breast cancer and confirm the relationship between αKlotho and ER with the positive regulation of αKlotho expression by this receptor and its antitumor profile in breast lumen.

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Klotho plays a critical role in clear cell renal cell carcinoma progression and clinical outcome

Cited by 11 publications

References 25 publications

The importance of serum osteopontin and stanniocalcin-1 in renal cell carcinoma

The importance of serum osteopontin and stanniocalcin-1 in renal cell carcinoma

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Proteína αKlotho: da associação in vitro com o ERβ ao perfil antitumoral no soro de pacientes com câncer de mama

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