The Role Of Leptin And PI3K/mTOR/STAT3 Pathway In The Mechanisms Of Obesity Promoted Lung Cancer Development

Background: Lung cancer is the most common malignancy,accounting for the largest proportion of new cancer diagnoses and death in the world.It has also become the leading cause of morbidity and mortality among cancers in China.Obesity has now become a common risk factor for many cancers.However,because of the existence of various confounding factors such as smoking and cachexia,the relationship between obesity and lung cancer has not yet been clearly defined.Leptin is currently the most studied adipokine and is considered to be an intermediate of obesity-related cancers.It can promote cell proliferation and differentiation,affect body immunity,promote angiogenesis,and increase cell invasion.Related studies have found that the expression of leptin has increased in lung cancer,breast cancer,ovarian cancer,gastrointestinal cancer,and prostate cancer patients.However,the role of leptin in the development of lung cancer is not yet clear.Objective:(1)Meta analysis of the relationship between obesity and the risk of lung cancer,to explore the relevance of obesity and lung cancer.(2)Urethane-induced lung cancer model was used to detect theexpression of leptin and CD68 in lung tissues of mice with high-fat diet,and to explore the correlation between leptin expression and the occurrence and development of lung cancer.(3)Lung cancer cell lines A549 and H460 were used to investigate whether leptin promotes proliferation of lung cancer cells by activating PI3K/mTOR/STAT3 pathwayMethods: Relevant studies were identified by searching Pubmed,Web of Science,EBSCO,Ovid,CNKI,VIP and WANGFANG MED,and fixed or random effects model was used to calculate pooled RRs.The thresholds were determined by the authors of each original publication,based on either the distributions within their study population or predefined cut-offs.Immunohistochemistry was used to detect the expression of leptin and macrophage marker CD68 in lung tissues of mice fed with high-fat diet.Cell Counting Kit-8(CCK-8)assay was used to determine the effect of leptin on the activity of lung cancer cell lines A549/H460.Flow cytometry was used to detect the effect of leptin on the cell cycle and apoptosis of lung cancer cell line A549.Western Blot was used to detect the activation of PI3K/mTOR/STAT3 pathway and the expression of cell cycle and apoptosis-related target proteins in leptin-treated A549 cells.Results:(1)Twenty-seven prospective cohort studies were identified with 5,905,064 participants and 55,028 lung cancer cases included.BMI was negatively correlated with lung cancer risk(RR = 0.77,95% CI:0.72-0.82);Stratification by smoking status showed that the BMI of ex-smoker(RR = 0.75,95% CI: 0.69-0.82)and currents smokers(RR =0.70,95% CI: 0.63-0.77)were negatively correlated with lung cancer risk,but the BMI of never smokers was not associated with lung cancer risk(RR= 0.96,95% CI: 0.85-1.10);Further analysis considered the lag time and excluded the effects of preclinical cancer,there is no statistically significant inverse association between BMI and lung cancer risk,RR=0.89(95% CI:0.66-1.19).In contrast,WC was associated with increased lung cancer risk among never smoking RR=1.30(95% CI: 1.03-1.63),ex-smokers RR=1.20(95% CI: 1.06-1.37)and current smokers RR=1.34(95% CI: 1.15-1.56).(2)The expression of leptin in lung cancer tissues in the high-fat diet group of urethane-induced model was significantly higher than that in adjacent normal tissues,and the expression of leptin was related to the infiltration of macrophages in lung cancer tissues.(3)Leptin can significantly increase the activity of lung cancer cell lines A549/H460,and there is a dose-effect relationship.When treated with100ng/ml leptin,the percentage of G0/G1 phase cells was significantly lower than that of the control group,while the proportion of S+G2/M phase cells was significantly higher than that of the control group.The apoptotic rate of A549 treated with 100ng/ml leptin was significantly lower than that of the control group.(4)The expression of mTOR,STAT3,Cyclin D1,and Bcl-2 proteinin A549 cells treated with leptin was increased compared with the control group.The expression of mTOR,STAT3,CyclinD1,and Bcl-2 protein in A549 cells treated with PI3 K inhibitor LY294002 was lower than control group.The expression of mTOR,STAT3,Cyclin D1,and Bcl-2 in A549 cells treated with leptin and LY294002 was lower than leptin group.(5)The expression of STAT3,Bcl-2,and CyclinD1 in A549 cells treated with leptin was increased compared with the control group.The expression of STAT3 and CyclinD1 in A549 cells treated with mTOR inhibitor rapamycin was lower than that in the control group.The expression of STAT3,Bcl-2,and CyclinD1 in A549 cells treated with leptin and rapamycin was lower than that in the leptin group.Conclusions:(1)Obesity is related to the occurrence of lung cancer,especially central obesity may be associated with the etiology of lung cancer.(2)High-fat diet can increase the expression of leptin in lung cancer tissues of urethane-induced lung cancer model mice.The high expression of leptin may be related to the infiltration of macrophages in lung cancer tissues.(3)Leptin may promote the proliferation and inhibit the apoptosis of A549 by activating PI3K/mTOR/STAT3.