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Erschienen in: Pathology & Oncology Research 1/2020

12.06.2018 | Original Article

Assessment of the circulating klotho protein in lung cancer patients

verfasst von: Judit Pako, Andras Bikov, Imre Barta, Hideyo Matsueda, Rita Puskas, Gabriella Galffy, Anna Kerpel-Fronius, Balazs Antus, Ildiko Horvath

Erschienen in: Pathology & Oncology Research | Ausgabe 1/2020

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Abstract

The anti-aging factor, klotho has been identified as a tumor suppressor in various human cancers, including lung cancer. In vitro studies provided evidence that klotho expression influences the characteristics of lung cancer cells, however, in vivo results are lacking. The aim of our study was to evaluate whether circulating klotho protein might serve as a potential biomarker of lung cancer. Blood samples were taken from 45 newly diagnosed lung cancer patients (31 NSCLC, 14 SCLC) and 43 control subjects. Plasma klotho concentration was measured using ELISA. No difference in plasma klotho values was detected between patients and control subjects (366.3 (257.9–486.8) vs. 383.5 (304.6–489.7) pg/ml respectively (median (IQR)); p > 0.05). Plasma klotho levels in patients with distant metastasis did not differ from less advanced stage disease (354.2 (306.9–433.3 vs. 328.5 (242.5–419.7) pg/ml, p > 0.05). In contrast, analyzed with one-way ANOVA, significant difference (p = 0.04) was found between the examined histological types of lung cancer: adenocarcinoma (353 (329.4–438.5) pg/ml), squamous cell carcinoma (308 (209.6–348.1) pg/ml) and small cell lung cancer (388.8 (289.9–495.4) pg/ml). However, Tukey’s post hoc test did not reveal significant difference between any pairs of histological groups. There was no difference between any histological subtype and health either. Our results suggest that circulating klotho protein cannot be considered as a biomarker for lung cancer. Further studies are warranted in order to examine the relationship between klotho expression in lung tissue and circulating levels of the protein, and to explore its mechanism of action in lung cancer.
Literatur
1.
Zurück zum Zitat Chang B, Kim J, Jeong D, Jeong Y, Jeon S, Jung SI et al (2012) Klotho inhibits the capacity of cell migration and invasion in cervical cancer. Oncol Rep 28:1022–1028CrossRef Chang B, Kim J, Jeong D, Jeong Y, Jeon S, Jung SI et al (2012) Klotho inhibits the capacity of cell migration and invasion in cervical cancer. Oncol Rep 28:1022–1028CrossRef
2.
Zurück zum Zitat Yan Y, Wang Y, Xiong Y, Lin X, Zhou P, Chen Z (2017) Reduced Klotho expression contributes to poor survival rates in human patients with ovarian cancer, and overexpression of Klotho inhibits the progression of ovarian cancer partly via the inhibition of systemic inflammation nude mice. Mol Med Rep 15:1777–1785CrossRef Yan Y, Wang Y, Xiong Y, Lin X, Zhou P, Chen Z (2017) Reduced Klotho expression contributes to poor survival rates in human patients with ovarian cancer, and overexpression of Klotho inhibits the progression of ovarian cancer partly via the inhibition of systemic inflammation nude mice. Mol Med Rep 15:1777–1785CrossRef
3.
Zurück zum Zitat Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H et al (2008) Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27:7094–7105CrossRef Wolf I, Levanon-Cohen S, Bose S, Ligumsky H, Sredni B, Kanety H et al (2008) Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 27:7094–7105CrossRef
4.
Zurück zum Zitat Rubinek T, Wolf I (2016) The role of alpha-klotho as a universal tumor supressor. Vitam Horm 101:197–214CrossRef Rubinek T, Wolf I (2016) The role of alpha-klotho as a universal tumor supressor. Vitam Horm 101:197–214CrossRef
5.
Zurück zum Zitat Zhou X, Wang X (2015) Klotho: a novel biomarker for cancer. J Cancer Res Clin Oncol 141:961–969CrossRef Zhou X, Wang X (2015) Klotho: a novel biomarker for cancer. J Cancer Res Clin Oncol 141:961–969CrossRef
7.
Zurück zum Zitat Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P et al (2005) Suppression of aging in mice by the Hormone Klotho. Science 5742:1829–1833CrossRef Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P et al (2005) Suppression of aging in mice by the Hormone Klotho. Science 5742:1829–1833CrossRef
8.
Zurück zum Zitat Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J et al (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806CrossRef Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J et al (2007) Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317:803–806CrossRef
9.
Zurück zum Zitat Velcheti V, Ramaswamy G (2006) Insulin-like growth factor and lung cancer. J Thorac Oncol 1:607–610PubMed Velcheti V, Ramaswamy G (2006) Insulin-like growth factor and lung cancer. J Thorac Oncol 1:607–610PubMed
10.
Zurück zum Zitat He B, Barg RN, You L, Xu Z, Reguart N, Mikami I et al (2005) Wnt signaling in stem cells and non-small-cell lung cancer. Clin Lung Cancer 7:54–60CrossRef He B, Barg RN, You L, Xu Z, Reguart N, Mikami I et al (2005) Wnt signaling in stem cells and non-small-cell lung cancer. Clin Lung Cancer 7:54–60CrossRef
11.
Zurück zum Zitat Fidler MJ, Shersher DD, Borgia JA, Bonomi P (2012) Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls. Ther Adv Med Oncol 4:51–60CrossRef Fidler MJ, Shersher DD, Borgia JA, Bonomi P (2012) Targeting the insulin-like growth factor receptor pathway in lung cancer: problems and pitfalls. Ther Adv Med Oncol 4:51–60CrossRef
12.
Zurück zum Zitat Yang J, Chen J, He J, Li J, Shi J, Cho WC et al (2016) Wnt signaling as potential therapeutic target in lung cancer. Expert Opin Ther Targets 20:999–1015CrossRef Yang J, Chen J, He J, Li J, Shi J, Cho WC et al (2016) Wnt signaling as potential therapeutic target in lung cancer. Expert Opin Ther Targets 20:999–1015CrossRef
13.
Zurück zum Zitat Chen B, Ma X, Liu S, Zhao W, Wu J (2012) Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist in a dose-dependent manner. Cancer Biol Ther 13:1221–1228CrossRef Chen B, Ma X, Liu S, Zhao W, Wu J (2012) Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist in a dose-dependent manner. Cancer Biol Ther 13:1221–1228CrossRef
14.
Zurück zum Zitat Usuda J, Ichinose S, Ishizumi T, Ohtani K, Inoue T, Saji H et al (2011) Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery. Lung Cancer 74:332–337CrossRef Usuda J, Ichinose S, Ishizumi T, Ohtani K, Inoue T, Saji H et al (2011) Klotho predicts good clinical outcome in patients with limited-disease small cell lung cancer who received surgery. Lung Cancer 74:332–337CrossRef
15.
Zurück zum Zitat Usuda J, Ichinose S, Ishizumi T, Ohtani K, Inoue T, Saji H et al (2011) Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung. Lung Cancer 72:355–359CrossRef Usuda J, Ichinose S, Ishizumi T, Ohtani K, Inoue T, Saji H et al (2011) Klotho is a novel biomarker for good survival in resected large cell neuroendocrine carcinoma of the lung. Lung Cancer 72:355–359CrossRef
16.
Zurück zum Zitat Chen B, Wang X, Zhao W, Wu J (2010) Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res 29:99CrossRef Chen B, Wang X, Zhao W, Wu J (2010) Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res 29:99CrossRef
17.
Zurück zum Zitat Chen T, Ren H, Thakur A, Yang T, Li Y, Zhang S et al (2016) Decreased level of klotho contributes to drug resistance in lung cancer cells: involving in klotho-mediated cell autophagy. DNA Cell Biol 35:751–757CrossRef Chen T, Ren H, Thakur A, Yang T, Li Y, Zhang S et al (2016) Decreased level of klotho contributes to drug resistance in lung cancer cells: involving in klotho-mediated cell autophagy. DNA Cell Biol 35:751–757CrossRef
18.
Zurück zum Zitat Wang Y, Chen L, Huang G, He D, He J, Xu W et al (2013) Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. PLoS One 8:e57391CrossRef Wang Y, Chen L, Huang G, He D, He J, Xu W et al (2013) Klotho sensitizes human lung cancer cell line to cisplatin via PI3k/Akt pathway. PLoS One 8:e57391CrossRef
19.
Zurück zum Zitat Tang X, Fan Z, Huang S (2013) Can soluble klotho protein be a potential tumor biomarker? Am J Clin Pathol 139:259–262CrossRef Tang X, Fan Z, Huang S (2013) Can soluble klotho protein be a potential tumor biomarker? Am J Clin Pathol 139:259–262CrossRef
20.
Zurück zum Zitat Gigante M, Lucarelli G, Divella C, Netti GS, Pontrelli P, Cafiero C et al (2015) Soluble serum αklotho is a potential predictive marker of disease progression in clear cell renal cell carcinoma. Medicine 94:e1917CrossRef Gigante M, Lucarelli G, Divella C, Netti GS, Pontrelli P, Cafiero C et al (2015) Soluble serum αklotho is a potential predictive marker of disease progression in clear cell renal cell carcinoma. Medicine 94:e1917CrossRef
21.
Zurück zum Zitat Pedersen L, Pedersen SM, Brasen CL, Rasmussen LM (2013) Soluble serum klotho levels in healthy subjects. Comparison of two different immunoassays. Clin Biochem 46:1079–1083CrossRef Pedersen L, Pedersen SM, Brasen CL, Rasmussen LM (2013) Soluble serum klotho levels in healthy subjects. Comparison of two different immunoassays. Clin Biochem 46:1079–1083CrossRef
22.
Zurück zum Zitat Pako J, Barta I, Balogh Z, Kerti M, Drozdovszky O, Bikov A et al (2017) Assessment of the anti-aging klotho protein in patients with COPD undergoing pulmonary rehabilitation. COPD 14:176–180CrossRef Pako J, Barta I, Balogh Z, Kerti M, Drozdovszky O, Bikov A et al (2017) Assessment of the anti-aging klotho protein in patients with COPD undergoing pulmonary rehabilitation. COPD 14:176–180CrossRef
23.
Zurück zum Zitat Patel MS, Donaldson AV, Lewis A, Natanek SA, Lee JY, Andersson YM et al (2016) Klotho and smoking – An interplay influencing the skeletal muscle functions deficits that occur in COPD. Respir Med 113:50–56CrossRef Patel MS, Donaldson AV, Lewis A, Natanek SA, Lee JY, Andersson YM et al (2016) Klotho and smoking – An interplay influencing the skeletal muscle functions deficits that occur in COPD. Respir Med 113:50–56CrossRef
24.
Zurück zum Zitat Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y et al (2010) Establishment of sandwich ELISA for soluble alpha-klotho measurement: Age-dependent change of soluble alpha-klotho levels in healthy subjects. Biochem Biophys Res Commun 398:513–518CrossRef Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y et al (2010) Establishment of sandwich ELISA for soluble alpha-klotho measurement: Age-dependent change of soluble alpha-klotho levels in healthy subjects. Biochem Biophys Res Commun 398:513–518CrossRef
25.
Zurück zum Zitat Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A et al (2012) Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat 133:649–657CrossRef Rubinek T, Shulman M, Israeli S, Bose S, Avraham A, Zundelevich A et al (2012) Epigenetic silencing of the tumor suppressor klotho in human breast cancer. Breast Cancer Res Treat 133:649–657CrossRef
26.
Zurück zum Zitat Xie B, Zhou J, Yuan L, Ren F, Liu DC, Li Q et al (2013) Epigenetic silencing of klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Hum Pathol 44:795–801CrossRef Xie B, Zhou J, Yuan L, Ren F, Liu DC, Li Q et al (2013) Epigenetic silencing of klotho expression correlates with poor prognosis of human hepatocellular carcinoma. Hum Pathol 44:795–801CrossRef
27.
Zurück zum Zitat Usugi T, Ohno T, Ohyama Y, Uchiyama T, Saito Y, Matsumura Y et al (2000) Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging. Metabolism 49:1118–1123CrossRef Usugi T, Ohno T, Ohyama Y, Uchiyama T, Saito Y, Matsumura Y et al (2000) Decreased insulin production and increased insulin sensitivity in the klotho mutant mouse, a novel animal model for human aging. Metabolism 49:1118–1123CrossRef
28.
Zurück zum Zitat Neidert MC, Sze L, Zwimpfer C, Sarnthein J, Seifert B, Frei K et al (2013) Soluble α-klotho: a novel serum biomarker for the activity of GH-producing pituitary adenomas. Eur J Endocrinol 168:575–583CrossRef Neidert MC, Sze L, Zwimpfer C, Sarnthein J, Seifert B, Frei K et al (2013) Soluble α-klotho: a novel serum biomarker for the activity of GH-producing pituitary adenomas. Eur J Endocrinol 168:575–583CrossRef
29.
Zurück zum Zitat Sze L, Bernays RL, Zwimpfer C, Wiesli P, Brändle M, Schmid C (2012) Excessively high soluble Klotho in patients with acromegaly. J Intern Med 272:93–97CrossRef Sze L, Bernays RL, Zwimpfer C, Wiesli P, Brändle M, Schmid C (2012) Excessively high soluble Klotho in patients with acromegaly. J Intern Med 272:93–97CrossRef
30.
Zurück zum Zitat Kohler S, Tschopp O, Sze L, Neidert M, Bernays RL, Spanaus KS et al (2013) Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery. Gen Comp Endocrinol 188:282–287CrossRef Kohler S, Tschopp O, Sze L, Neidert M, Bernays RL, Spanaus KS et al (2013) Monitoring for potential residual disease activity by serum insulin-like growth factor 1 and soluble Klotho in patients with acromegaly after pituitary surgery. Gen Comp Endocrinol 188:282–287CrossRef
31.
Zurück zum Zitat Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X (1999) Plasma levels of insulin-like growth factor-1 and lung cancer risk: a case-control analysis. J Natl Cancer Inst 91:151–156CrossRef Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X (1999) Plasma levels of insulin-like growth factor-1 and lung cancer risk: a case-control analysis. J Natl Cancer Inst 91:151–156CrossRef
32.
Zurück zum Zitat Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M (2002) Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-carotene and retinol efficacy trial cohort. Cancer Epidemiol Biomarkers Prev 11:1413–1418PubMed Spitz MR, Barnett MJ, Goodman GE, Thornquist MD, Wu X, Pollak M (2002) Serum insulin-like growth factor (IGF) and IGF-binding protein levels and risk of lung cancer: a case-control study nested in the beta-carotene and retinol efficacy trial cohort. Cancer Epidemiol Biomarkers Prev 11:1413–1418PubMed
33.
Zurück zum Zitat Zhang M, Li X, Zhang X, Yang Y, Feng Z, Liu X (2014) Association of serum hemoglobin A1c, C-peptide and insulin-like growth factor-1 levels with the occurrence and development of lung cancer. Mol Clin Oncol 4:506–508CrossRef Zhang M, Li X, Zhang X, Yang Y, Feng Z, Liu X (2014) Association of serum hemoglobin A1c, C-peptide and insulin-like growth factor-1 levels with the occurrence and development of lung cancer. Mol Clin Oncol 4:506–508CrossRef
34.
Zurück zum Zitat Tas F, Bilgin E, Tastekin D, Erturk K, Duranyildiz D (2016) Serum IGF-1 and IGFBP-3 levels as clinical markers for patients with lung cancer. Biomed Rep 4:609–614CrossRef Tas F, Bilgin E, Tastekin D, Erturk K, Duranyildiz D (2016) Serum IGF-1 and IGFBP-3 levels as clinical markers for patients with lung cancer. Biomed Rep 4:609–614CrossRef
35.
Zurück zum Zitat Minuto F, Del Monte P, Barreca A, Alama A, Cariola G, Giordano G (1988) Evidence for autocrine mitogenic stimulation by somatomedin-C/insuline-like growth factor I on an established human lung cancer cell line. Cancer Res 48:3716–3719PubMed Minuto F, Del Monte P, Barreca A, Alama A, Cariola G, Giordano G (1988) Evidence for autocrine mitogenic stimulation by somatomedin-C/insuline-like growth factor I on an established human lung cancer cell line. Cancer Res 48:3716–3719PubMed
36.
Zurück zum Zitat Toshifumi S, Takeshita Y, Murohara T, Sasaki K, Egami K, Shintani S et al (2004) Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse. Circulation 110:1148–1155CrossRef Toshifumi S, Takeshita Y, Murohara T, Sasaki K, Egami K, Shintani S et al (2004) Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse. Circulation 110:1148–1155CrossRef
37.
Zurück zum Zitat Fukino K, Suzuki T, Saito Y, Shindo T, Amaki T, Kurabayashi M et al (2002) Regulation of angiogenesis by the aging suppressor gene klotho. Biochem Biophys Res Commun 293:332–337CrossRef Fukino K, Suzuki T, Saito Y, Shindo T, Amaki T, Kurabayashi M et al (2002) Regulation of angiogenesis by the aging suppressor gene klotho. Biochem Biophys Res Commun 293:332–337CrossRef
38.
Zurück zum Zitat Pan JY, Sun CC, Li SJ, Huang J, Li DJ (2015) Role of miR-10b in non-small cell lung cancer (NSCLC) cells by targeting klotho. Cancer Cell Microenviron 2:e936 Pan JY, Sun CC, Li SJ, Huang J, Li DJ (2015) Role of miR-10b in non-small cell lung cancer (NSCLC) cells by targeting klotho. Cancer Cell Microenviron 2:e936
39.
Zurück zum Zitat Qi HW, Shen Z, Fan LH (2011) Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line. Exp Ther Med 2:1091e1095CrossRef Qi HW, Shen Z, Fan LH (2011) Combined inhibition of insulin-like growth factor-1 receptor enhances the effects of gefitinib in a human non-small cell lung cancer resistant cell line. Exp Ther Med 2:1091e1095CrossRef
Metadaten
Titel
Assessment of the circulating klotho protein in lung cancer patients
verfasst von
Judit Pako
Andras Bikov
Imre Barta
Hideyo Matsueda
Rita Puskas
Gabriella Galffy
Anna Kerpel-Fronius
Balazs Antus
Ildiko Horvath
Publikationsdatum
12.06.2018
Verlag
Springer Netherlands
Erschienen in
Pathology & Oncology Research / Ausgabe 1/2020
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-018-0441-5

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