| Background:? lung cancer is one of the most prevalent malignancies in the whole world, and now it has been on the top of deaths caused by cancer. There are about 600 thousand people died of cancer, and the number was increasing every year. The incidence rate of female patients especially got an increasingly trend. China is also a country which has a high incidence of lung cancer. Therefore, the reacerch of correlation of lung cancer has been taken to attention. According to pathohistology, lung cancer is devided into two category. One is small cell lung cancer (SCLC), another is non-small cell lung cancer(NSCLC). 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. In the tumor process, abnormality of the cell signal transduction and loss of balance of cell proliferation and apoptosis have been proven to be the two key elements. These two aspects are inseparable with lung cancer occurrence and development of mechanisms.Leptin is a N terminal signal peptide with 21 amino acid peptide which is coded by obese gene (OB) and mainly secreted by adipose tissue. Its main function is to regulate the body's energy metabolism and fat synthesis. Serum leptin levels were directly correlated with patient's body weight, suggesting that leptin is closely related with the feeding. Leptin also has many important physiological functions, including amplification of inflammation and immune function. However, further studies have shown that leptin can stimulate the proliferation of tumor cells, inhibit tumor cell apoptosis,,And can increase the invasiveness of tumor cells and to promote the formation of new blood vessels within the tumor, Therefore, in tumor occurrence and development of leptin plays a role can not be ignored.The current study confirmed that leptin over expressed in various tumor tissues and cells, ?and was closely linked with tumor occurrence and development. Leptin can only perform its biological function through combining with its receptor (Ob-R) on different target organs. The long leptin receptor (Ob-Rb) of its receptors is the only complete intracellular domain and has intracellular tyrosine residues of the Ob-R forms, which have a signal transduction function. Many clinical trials confirm that functional leptin and leptin receptor (OB-Rb) have high expressions in endometrial cancer, stomach cancer, breast cancer, prostate cancer and a variety of tumor tissue and tumor cell lines. Meanwhile, we found expression of OB-Rb in human lung tissues, which indicated that the lung is the target organ of leptin. As a cytokine, leptin have functions both in physiological process and pathological process of lung. For example, it is involved in fetal lung maturity and play a role in physiological function in the maintenance of adult normal lung epithelial cells. It also found that leptin can promote the proliferationof SQ-5 lung squamous cell carcinoma cell line. Therefore, leptin is closely related to the development of the occurrence of lung cancer. Currently, however, it is still unclear the concrete mechanism of leptin in the development of lung cancer.Another study showed that leptin signal transduction pathways have relationships with the activity of JAKs / STATs family. Animal tests also suggested that the hypothalamus of leptin signal transduction mainly involves JAK2/STAT3. Ob-R ligand binds to Ob-Rb and phosphorylate tyrosine residue in cells, and then activates JAK2 by transphosphorylation. A connection site with single STAT3 is formed through phosphorylation of Ob-Rb. STATs are a group of cytoplasmic proteins. Its role as a signal transductor and transcription factor involved in the reaction to cytokines and growth factors in normal cells. STAT3 is a potential cytoplasmic transcription factor in STATs family. Once STAT3 attachs its receptors, in the No. 705 carboxy-terminal tyrosine phosphorylation site (Y705) has been phosphorylated by JAK2, and the STAT3 transforms into p-STAT3. Through the role of SH2 region STAT3 forms the homodimer or heterodimer, and transfers into the nucleus. nteracted with a specific gene promoter region of the DNA components or other transcription factors or ancillary proteins, the homodimer or heterodimer regulate the downstream target genes, Such as: bcl-2 transcription, which can cause growth disorders, promote cell malignant transformation and tumorigenesis.Objective: (1) To detect the expressions of leptin, STAT3, p-STAT3, Bcl-2 in the human non-small cell lung cancer(NSCLC), and to approach the function of the leptin in the development of NSCLC. The relationship between the proteins and the malignant proceeding of NSCLC were also investigated.(2)To study the mechanism of leptin in stimulating the proliferation of human lung adenocarcinoma cells, and to approach its function in the development of hunman lung cancer.Methods:The immunohistochemical SP method was used to examine the protein expressions of leptin, STAT3, p-STAT3, Bcl-2 in 52 cases of non-small cell lung cancer and 34 cases of paracancerous normal lung tissues. Their correlations with clinical stage, and lymph node metastasis of lung cancer were statistically analyzed. MTT assay was used to determine the effect of leptin on the cell proliferation. Flow cytometry was used to detect the growth rate of A549 cells treated by different concentration of leptin. Immunocytochemistry staining were used to evaluate the protein expression of STAT3, p-STAT3 and Bcl-2 in human lung adenocarcinoma A549 cells.Results:The positive staining rates of leptin, STAT3, p-STAT3 and Bcl-2 protein in NSCLC tissues were significantly higher than Para cancerous normal lung tissues. The expression of STAT3 and p-STAT3 had close relationships with TNM stage of lung cancer and Lymph node metastasis (P<0.05). The expression of STAT3 was positively correlated with the expression of p-STAT3(P<0.05), and the expression of p-STAT3 was positively correlated with the expression of Bcl-2 (P<0.05).The expressions of STAT3, p-STAT3 and Bcl-2 were detected in the human lung adenocarcinoma A549 cells, which were gradually increased accompaning time and concentration increasing. And The expressions of STAT3, p-STAT3 and Bcl-2 were significantly increased in 100ng/ml leptin treated group. Leptin can stimulate the proliferation of A549 cells, especially when leptin was 100 ng/ml after 24-hour treatment. Moreover, the ratio of cells in G2/M cell cycle in those treated with 100 ng/ml leptin was significant higher than in 0ng/ml,10ng/ml leptin treated group.Conclusions:(1) The high expression of leptin, STAT3, p-STAT3 may play an important role in the progression and development of human NSCLC which may be useful in the assessment of the malignant processing and biological behavior of the malignant tumor. (2) The activation of STAT3 is possibly mediated by over-expression of anti-apoptosis gene bcl-2 in the lung cancer cells which make continued proliferation of lung cancer cells. It plays an important role in malignant transformation and evolution of lung cancer cells. (3) Leptin may promote the proliferation of A549 cells by activating STAT3 signaling pathway and inducing the over expression of bcl-2. |
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