Expression and significance of leptin receptor, p-STAT3 and p-AKT in diffuse large B-cell lymphoma
Introduction
Leptin is a 167-amino acid peptide with a molecular mass of 16 kDa that plays a central role in the control of satiety, food intake, energy expenditure, and various reproductive processes (Flier, 1997). It is secreted mainly by adipocytes, and expressed in normal mammary epithelial cells as well as in malignant tissues (Hoggard et al., 1997, Bado et al., 1998, Smith-Kirwin et al., 1998, Hardwick et al., 2001, Zabeau et al., 2003, Somasundar et al., 2004, Uddin et al., 2010). Leptin exerts its biological activity through a specific membrane receptor, the leptin receptor (OBR), which belongs to the class 1 cytokine receptor family (Zabeau et al., 2003). OBR is produced predominantly in the hypothalamus and choroid plexus, and expressed in many other tissues, such as the placenta, pancreas, adrenal gland, hematopoietic cells, liver, and heart (Cioffi et al., 1996, Emilsson et al., 1997, Glasow et al., 1998, Briscoe et al., 2001, Dall’Aglio et al., 2012). Several different OBR variants have been identified, but only the long intracellular domain isoform (OBRL) has the signaling potential (Tartaglia, 1997). According to current studies, binding of leptin to OBR results in autophosphorylation of OBR and then activates JAK/STAT (Janus kinase/signal transducer and activator of transcription), PI3K/AKT (phosphatidylinositol-3-kinase/protein kinase B) and MAPK/ERK (mitogen-activated protein kinase) signaling pathways (Saxena et al., 2007). Leptin/OBR-mediated signaling pathways may significantly influence the cancer proliferation, invasion, and metastasis (Uotani et al., 1999).
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma in adults, with significant heterogeneity and invasiveness. Despite the fact that patients with DLBCL are potentially curable with combination chemotherapy, the disease proves fatal in approximately 50% of patients (Muris et al., 2005). DLBCL can be divided into at least two molecular subgroups by the gene expression profiling analyses, germinal center B-cell-like (GBC) and activated B-cell-like (ABC)-DLBCL. These biological analyses have been able, not only to capture the molecular heterogeneity of tumor cells (Alizadeh et al., 2000), but also to prove the complex interaction between the tumor and its microenvironment involving multiple signaling pathways and regulatory mechanisms (Lenz et al., 2008). It has been shown that OBR is overexpressed in DLBCL and OBR overexpression may affect DLBCL carcinogenesis through the PI3K/AKT signaling pathway (Uddin et al., 2010). Several studies have indicated the role of Leptin/OBR-mediated JAK/STAT pathway in cancer development and progression (Somasundar et al., 2004, Pai et al., 2005, Saxena et al., 2007). However their roles in lymphoid malignancies have not been reported. In the present study, we examined the expression of OBR, p-STAT3 and p-AKT in patients with DLBCL through immunohistochemical analysis. Furthermore, we explored the possible relationships between OBR-mediated signal transduction pathways and the malignant properties of DLBCL.
Section snippets
Patient samples
80 cases of de novo DLBCL diagnosed between 2010 and 2011 were collected from the Department of Pathology at the Affiliated Hospital of Qingdao University Medical College. 20 cases of RLH (reactive lymphoid hyperplasia) were also included in this study as the control group. This study was conducted after approval of the local ethics committee.
Immunohistochemistry
All specimens were fixed in 10% neutral buffered formalin and embedded in paraffin blocks. 3 μm-thick tissue sections were used for immunohistochemical
Clinicopathological characteristics of the patients
Clinical and pathological details of the 80 patients with DLBCLs included in this study are shown in Table 1. Among 80 patients, 60 have complete clinical data.
Immunophenotyping of DLBCLs
According to Hans algorithm (Hans et al., 2004), 23 cases (28.75%) were evaluated as GCB type and 57 cases (71.25%) were evaluated as non-GCB type. Among 23 cases of GCB subtype, 15 cases expressed CD10 and 8 cases expressed Bcl-6 alone. Among 57 cases of non-GCB subtype, 46 cases expressed both Mum-1 and Bcl-6, while other 11 cases were
Discussion
Increasing research data have linked obesity with various malignant diseases and suggested a strong link between Leptin/OBR signaling pathway and cancer cell proliferation, apoptosis and invasion. However, the direct roles of Leptin/OBR and associated signaling pathways in DLBCL have never been deciphered. So, in the present study, the expressions of OBR, p-STAT3 and p-AKT in DLBCL were examined. Furthermore, the possible relationships between OBR-mediated signal transduction pathways and the
References (29)
- et al.
Leptin receptor long-form signalling in a human liver cell line
Cytokine
(2001) - et al.
Immunolocalization of leptin and its receptor in the placenta of cats
Acta Histochem
(2012) - et al.
Ras p2l expression in the progression of breast cancer
Hum Pathol
(1987) - et al.
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray
Blood
(2004) - et al.
Leptin is a growth factor for colonic epithelial cells
Gastroenterology
(2001) - et al.
Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma
Blood
(2008) - et al.
Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B cell lymphomas
Blood
(2005) - et al.
Leptin activates STAT and ERK2 pathways and induces gastric cancer cell proliferation
Biochem Biophys Res Commun
(2005) - et al.
Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma
Blood
(2006) - et al.
Leptin is a growth factor in cancer
J Surg Res
(2004)
The leptin receptor
J Biol Chem
The ins and outs of leptin receptor activation
FEBS Lett
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling
Nature
The stomach is a source of leptin
Nature
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