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.
Similar content being viewed by others
References
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 28:1022–1028
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 15:1777–1785
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 27:7094–7105
Rubinek T, Wolf I (2016) The role of alpha-klotho as a universal tumor supressor. Vitam Horm 101:197–214
Zhou X, Wang X (2015) Klotho: a novel biomarker for cancer. J Cancer Res Clin Oncol 141:961–969
Kuro-o M (2010) Klotho. Eur J Physiol 459:333–343
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 5742:1829–1833
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 317:803–806
Velcheti V, Ramaswamy G (2006) Insulin-like growth factor and lung cancer. J Thorac Oncol 1:607–610
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 7:54–60
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 4:51–60
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 20:999–1015
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 13:1221–1228
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 74:332–337
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 72:355–359
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 29:99
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 35:751–757
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:e57391
Tang X, Fan Z, Huang S (2013) Can soluble klotho protein be a potential tumor biomarker? Am J Clin Pathol 139:259–262
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:e1917
Pedersen L, Pedersen SM, Brasen CL, Rasmussen LM (2013) Soluble serum klotho levels in healthy subjects. Comparison of two different immunoassays. Clin Biochem 46:1079–1083
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 14:176–180
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 113:50–56
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 398:513–518
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 133:649–657
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 44:795–801
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 49:1118–1123
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 168:575–583
Sze L, Bernays RL, Zwimpfer C, Wiesli P, Brändle M, Schmid C (2012) Excessively high soluble Klotho in patients with acromegaly. J Intern Med 272:93–97
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 188:282–287
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 91:151–156
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 11:1413–1418
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 4:506–508
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 4:609–614
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 48:3716–3719
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 110:1148–1155
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 293:332–337
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
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 2:1091e1095
Acknowledgements
The authors are thankful to Timea Barna and Sandy Bartok for blood sample collection and Maria Mikoss for laboratory assistance.
Funding
This work was supported by the research grant provided by the Hungarian Respiratory Society to Judit Pako and by the Bolyai János Scholarship provided by the Hungarian Academy of Sciences to Andras Bikov.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Pako, J., Bikov, A., Barta, I. et al. Assessment of the circulating klotho protein in lung cancer patients. Pathol. Oncol. Res. 26, 233–238 (2020). https://doi.org/10.1007/s12253-018-0441-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12253-018-0441-5