Otho-deficient mice developed multiple premature aging syndromes, whereas overexpression of Klotho extended the lifespan of mice. The Klotho gene is located in chromosome 13q12 in human with the size of 50 kb [6]. It encodes a single-pass transmembrane protein, which consists of an extracellular domain, a single transmembrane domain, and an intracellular domain. The intracellular domain is very short and has no clear functions. Membrane Klotho functions as an obligate co-receptor of fibroblast growth factor 23 (FGF23) to regulate phosphate homeostasis [8]. The extracellular domain (secreted Klotho) could be released into the serum and functions as a circulating?The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Zhou et al. Journal of Hematology Oncology (2017) 10:Page 2 ofhormone to regulate the activity of oxidative stress, multiple growth factor receptors, and ion channels [9, 10]. The tumor suppressive activity of Klotho was first identified in breast cancer in 2008 [11]. Recent investigations have implicated that Klotho is extensively downregulated in several solid tumors, including cervical cancer, pancreatic cancer, melanoma, and several digestive neoplasm [12]. In these malignancies, Klotho was elucidated to be a modulator of several signaling pathways, including the FGF signaling, insulin-like growth factor-1 receptor (IGF-1R), and Wnt pathways, which are also involved in the pathogenesis of hematological malignancies [10, 13?5]. However, the role of Klotho in hematological malignancies has not been reported. A large number of aberrant receptor tyrosine kinases (RTKs) have been found in hematological malignancies [16, 17], but they are still indefinite in DLBCL. IGF-1R is a RTK primarily activated by its EPZ004777MedChemExpress EPZ004777 cognate ligands, IGF-1, and IGF-2. It plays a crucial role in the establishment and progression of tumors by regulating proliferation, self-renewal, apoptosis, and drug resistance of cancer cells [18?0]. Activation of IGF-1R following IGF-1 treatment results in phosphorylation of downstream signaling cascades, including PI3K/AKT and MAPK/ERK [19]. Blockade of PI3K/AKT signaling could restrain cell survival and function of lymphocytes [21, 22]. Activation of MAPK/ERK signaling promotes cell proliferation and metastasis of cancer cells [23]. Strategies to block IGF-1R pathway in solid malignancies are being tested in clinical trials [24], whereas the function of IGF-1R signaling in DLBCL has been less studied [25]. In this present study, we aimed to assess the expression level and functional mechanism of Klotho in DLBCL. We identified reduced expression of Klotho in DLBCL for the first time. Noted inhibition of cell growth and induction of apoptosis were observed in DLBCL PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/25432023 with Klotho overexpression. Tumor growth was restrained by administration of Klotho protein in xenograft model of DLBCL. Our findings demonstrated that Klotho was a tumor suppressor and modulator of IGF-1R signaling.
