Leptin Activates STAT3 Pathways And Induces Human Lung Adenocarcinoma Cell Proliferation

Background : lung cancer is one of the most prevalent malignancies in china.Non-small cell lung cancer(NSCLC) comprises about 75-80% of all lung cancers and represents a heterogeneous group of cancers,consisting mainly of squamous cell carcinoma,adenocarcinoma,adenosqamous carcinoma and large cell carcinoma subtypes.most lung cancer patients are smokers,and tobacco consumption is a well-established risk factor.Chronic cigerette smoking retards mucociliary clearance of foreign particulates and secretions that favor a persistent inflammation,whereas the inhaled particles evoke vigorous lung and airway inflammatory responses.Initiation of the immunoinflammatory lung response is induced by exposure to inhaled antigenic particles and is followed by an expression pattern of chemokines and cytokines that may be influenced by the individual genetic background.Investigators have found that a functional polymorphism in the leptin gene(LEP-2548G/A) was associated with increased risk for developing non-small cell lung cancer and to earlier onset of disease,and that carriers of the risk genotyge simultaneously smokers had ever higher risk for developing cancer of the lung. And we also found that leptin can induces proliferation in tumor cell. Besides a possible leptin's up-regulatory role in the immunoinflammatory system, supporting its role as a prominent interplay between inflammation and lung cancer,most importantly, these is strong evidence of leptin's direct effect in tumor lung cells.Leptin-16kDa product of the obese gene is a peptide hormone secreted mainly by adipose tissues.and it is translated as a 167 amino acid protein with an amino-terminal secretory signal sequence of 21 amino acids. leptin is known to regulate body weight and peripheral energy expenditure.Increased serum leptin levels directly correlate with body mass,implicating involvement of this hormone in regulation of food intake,further exploration of leptin's link to cancer is of great importance. leptin treatment induces proliferation and apoptosis in tumor cells.and leptin also can stimulate invasiveness of tumor cells and angiogenesis in tumor. The expression levels of leptin and leptin receptor(OB-Rb)have been shown to be significantly elevated in variety of human cancers such as endometrium, gastric cancer,breast cancer,colon carcinoma,and supported its involvement in cancer development and progression.OB-Rb was identified in normal hunman lung tissue, suggenting that the lung is a peripheral site of action for leptin. Leptin is an adipocytokine that has been consistently implicated in lung physiology and pathophysiology.It is involved in fetal lung development and in adult normal lung cell's physiology or malignant proliferation(SQ-5).However,it remains unexplored the mechanism of leptin's action on lung cancer..Leptin exerts its actions through its specific receptor present in a variety of tissues localized to the cell membrane.leptin's receptor,OB-R,is a part of the cytokine receptor superfamily.At least six isoforms (OB-Ra--OB-Rf) have been identified so far. OB-Rb is the only OB-R isoform that is known to contain intracellular tyrosine residues. it is believed that leptin signaling is mediated mainly through the long-form(OB-Rb).Leptin is known to exert its actions via multiple signaling pathways that include Janus kinase/signal transducers and activatiors of transcription (JAK/STAT) pathways,mitogen-activated protein kinases (MAPK), phosphatidyliinositol 3-kinase (PI3-k), Protein kinase C (PKC), nitric oxide (NO), and cyclic AMP pathways. JAK/STAT pathway is of most importance,but whether activation of the above pathways by leptin occurs in lung cancer cells remains unknown.Objective:To investigate the protein expression of leptin and its receptor(OB-R)in adenocarcinoma of lung and tumor-free lung tissues , and analyse the relationship of leptin and its receptor(OB-R)with various clinicopathological such as TMN stage,lymph node metastasis . To explore the relationship between expression of leption and OB-Rb and oncogenesis development and clinical characteristic of lung cancer.To determine whether it is mediated by signal transducer and activator of transcription3 (STAT3). Methods: Immunohistochemical staining were used to evaluate the protein expression of leptin and OB-Rb in 35 tumor tissues and 35 samples of corresponding adjacent lung tissue.,and analyse the relation between the protein expression of them and clinic pathological parameters.MTT assay was used to determine the effect of leptin on the cell proliferation. Western blot was used to detect the expression of leptin receptor OB-Rb in A549 cells and to explore whether signal transducer and activator of transcription3 (STAT3) mediated the action of leptin.Results: The expression of leptin and OB-Rb detected in the adenocarcinoma of lung (68.6% and 48.6%) were significantly higher than that in the adjacent normal lung tissue (25.7% and 22.9%), P<0.05. Western blot showed the presence of OB-Rb in A549 cells. Leptin can stimulate the proliferation of A549 cells, which was markedly observed when leptin was 100 ng/ml after 24-hour treatment. Blocking STAT3 phosphorylation by AG490 significantly reduced the proliferation of A549 cells stimulated by leption.Conclusions: (1) The expression of leptin and OB-Rb was up-regulated indicating that they participate in the carciagenesis and development of adenocarcinoma of lung.(2) Leptin may promote the proliferation of A549 cells by activating STAT3 signaling pathway.