【作者】 宋薇；

【导师】 陈爱荣；

【作者基本信息】 兰州大学 ， 内科学·内分泌与代谢病（专业学位）， 2016， 硕士

【摘要】 目的:研究膀胱尿路上皮癌患者血清脂联素、瘦素水平与肿瘤大小、临床病理分级、分期、转移的相关关系,探索脂联素、瘦素应用于膀胱癌预测、诊断的效率,并尝试分析在膀胱癌的发生发展中这两种脂肪细胞因子可能的作用机制。脂联素、瘦素是由白色脂肪组织分泌的多肽类激素,具有调节糖脂代谢、炎症和免疫、细胞生长增殖和凋亡及血管生成等作用,而膀胱癌是泌尿系的常见恶性肿瘤,具有复发率高的特点,目前尚无膀胱癌与血清脂联素、瘦素水平相关关系的研究。方法:选取2015年3月至2015年10月兰州大学第二医院泌尿外科33例经膀胱镜病理活检新诊断为膀胱尿路上皮癌的初发患者作为病例组,术前未经任何内外科治疗,于同期在兰州大学第二医院体检中心选取20名健康体检者,两组均已排除糖尿病、高血压、严重肝脏、肾脏、心脏疾病患者,排除近期有严重感染病史、手术病史者,排除其他肿瘤病史。研究过程中,我们共收集了106例就诊于兰州大学第二医院泌尿外科并经膀胱镜病理活检确诊膀胱癌的患者及70例来自体检中心的正常对照者的信息,经排除复发、初发但已行内科或外科治疗、高血压、糖尿病、严重感染、严重的心肝肾疾病、3例腺癌患者和1例小细胞癌患者、临床资料不完整及中途退出的患者后,最终进入研究的包括33名膀胱尿路上皮癌患者,20名正常对照者。应用双抗体夹心酶联免疫法(ELISA)检测循环脂联素、瘦素水平,对病例组和正常对照组间、病例和对照中的吸烟和非吸烟亚组间、病例和对照中的性别亚组间、病例组不同临床病理特征的亚组间两个脂肪细胞因子的血清水平进行比较,分析血清脂联素水平、血清瘦素水平、瘦素/脂联素比值与膀胱尿路上皮癌临床病理特征之间的关系,评估血清脂联素、血清瘦素与人体一般参数及血清生化指标间的相关性,分析脂联素、瘦素与膀胱尿路上皮癌患病风险的相关性,进一步评价脂联素和瘦素作为膀胱尿路上皮癌诊断试验的生物标志物的优劣性。结果:1.膀胱尿路上皮癌组(病例组)和正常对照组(对照组)间的年龄、身高、体重、体重指数(BMI)、腰围、收缩压、舒张压、空腹血糖、血肌酐、血脂水平无统计学差异,病例组和正常对照组的吸烟率(吸烟者占组内总人数的百分比)及男女比例无统计学差异;2.病例组血清脂联素水平为4.88±0.88μg/ml,正常对照组血清脂联素水平为5.85±0.99μg/ml,病例组血清脂联素水平低于正常对照组,有统计学差异(p=0.001),病例组血清瘦素水平与正常对照组比较无统计学差异(p=0.413),病例组瘦素/脂联素比值与正常对照组比较无统计学差异(p=0.804);3.病例组内的男性对象中,吸烟和非吸烟亚组间血清脂联素水平、血清瘦素水平、瘦素/脂联素比值比较均无统计学差异(分别为p=0.281、p=0.528、p=0.545),正常对照组内的男性对象中,吸烟与非吸烟亚组间血清脂联素水平无统计学差异(p=0.569),吸烟亚组血清瘦素水平、瘦素/脂联素比值高于非吸烟亚组,有统计学差异(分别为p=0.042、p=0.032);4.包含吸烟者的病例组内,男性与女性2亚组间的血清脂联素水平、血清瘦素水平、瘦素/脂联素比值比较均无统计学差异(分别为p=0.136、p=0.705、p=0.546);包含吸烟者的对照组内,男性bmi高于女性,有统计学差异(p=0.039),血清脂联素水平2亚组间比较,女性高于男性,有统计学差异(p=0.028);2亚组间血清瘦素水平、瘦素/脂联素比值比较无统计学差异(分别为p=0.213、p=0.101);不包含吸烟者的病例组内,男性与女性2亚组间的血清脂联素水平、血清瘦素水平、瘦素/脂联素比值比较均无统计学差异(分别为p=0.345、p=0.91、p=0.741);不包含吸烟者的对照组内,男性bmi高于女性,有统计学差异(p=0.009),血清脂联素水平2亚组间比较,女性高于男性,有统计学差异(p=0.015);2亚组间血清瘦素水平、瘦素/脂联素比值比较无统计学差异(分别为p=0.632、p=0.407);5.病例组内,肿瘤低级别亚组血清脂联素水平高于高级别亚组,有统计学差异(p=0.003),tnm分期i期(非肌层浸润型)亚组血清脂联素水平高于ii/iii/iv期(肌层浸润型)亚组,有统计学差异(p<0.001),肿瘤直径<3cm亚组血清脂联素水平高于肿瘤直径≥3cm亚组,有统计学差异(p=0.013),病例组内,肿瘤高级别与低级别亚组间、tnm分期i期(非肌层浸润型)与ii/iii/iv期(肌层浸润型)亚组间、肿瘤直径<3cm与≥3cm亚组间,血清瘦素水平均无统计学差异(分别为p=0.800、p=0.419、p=0.591);6.病例组内,血清脂联素水平与bmi负相关(r=-0.347,p=0.048即p<0.05),血清脂联素水平与腰围负相关(r=-0.55,p=0.001即p<0.01),血清脂联素水平与高密度脂蛋白正相关(r=0.374,p=0.032即p<0.05),血清脂联素水平与肿瘤分期(i/ii/iii/iv期)负相关(r=-0.734,p<0.001),血清脂联素水平与收缩压、舒张压、空腹血糖、血脂(胆固醇、甘油三脂、低密度脂蛋白)及血清瘦素水平之间无相关性,正常对照组内,血清脂联素水平与bmi负相关(r=-0.764,p<0.001),血清脂联素水平与甘油三酯水平负相关(r=-0.525,p=0.017即p<0.05),血清脂联素水平与腰围、收缩压、舒张压、空腹血糖、血脂(胆固醇、高密度脂蛋白、低密度脂蛋白)及血清瘦素水平之间无相关性,无论在病例组还是对照组内,血清瘦素水平与bmi、腰围、收缩压、舒张压、空腹血糖、血脂及血清脂联素水平均无相关性;7.应用二元逻辑(logistic)回归分析膀胱尿路上皮癌患病的危险因素,校正可能的混杂因素后,结果证实低血清脂联素水平与膀胱尿路上皮癌的患病风险增高有关(脂联素分三段时,最低段血清脂联素水平的OR=53.259,95%可信区间为1.661-1707.994,P=0.025即P<0.05,脂联素分四段时,最低段血清脂联素水平的OR=75.507,95%可信区间为2.002-2848.190,P=0.02即P<0.05),血清瘦素水平则与膀胱尿路上皮癌患病风险无关;8.做血清脂联素的受试者工作特征曲线(ROC),在血清脂联素浓度为5.63μg/ml时,灵敏度为81.8%,特异度为60%,血清脂联素浓度为5.83μg/ml时,灵敏度为90.9%,特异度为55%;做血清瘦素的ROC曲线,在血清瘦素浓度为2.2297ng/ml时,灵敏度为90.9%,特异度为25%。结论:1.膀胱尿路上皮癌患者血清脂联素水平降低,并与BMI呈负相关;2.在膀胱尿路上皮癌患者中,低级别、非肌层浸润型(I期)和肿瘤直径<3cm的患者血清脂联素水平高于高级别、肌层浸润型(II/III/IV型)和肿瘤直径≥3cm的患者,显示血清脂联素水平降低与膀胱尿路上皮癌的侵袭性增高有关;3.低血清脂联素水平是膀胱尿路上皮癌患病的危险因素;瘦素在预测和诊断膀胱尿路上皮癌中结果不满意,而脂联素未来有可能成为预测、诊断膀胱尿路上皮癌甚至膀胱癌的生物标志物。更多还原

【Abstract】 Objectives: This study aims to examine a possible relationship between the serum levels of adiponectin and leptin and the various clinicopathological parameters, notably the tumor size, clinicopathological grade, stage and metastases in bladder urothelial carcinoma patients, to explore the efficiency of adiponectin and leptin for the prediction and diagnosis of bladder urothelial carcinoma, and try to analyze the mechanisms of the two adipocytokines involved in the development of bladder cancer. Adiponectin and leptin belong to a polypeptide hormone secreted by white adipose tissue, playing roles in the glucolipid metabolism, inflammation, immu nity, cell growth, cell proliferation, apoptosis and angiogenesis. Urinary bladder cancer is the common malignant tumor which has two characteristics of high incidence and recurrence rate. Until now we haven’t find a research about the relationship of the serum levels of adiponectin and leptin and bladder cancer. Methods: We all collected 106 cases of diagnosis of bladder cancer patients from the second hospital of Lanzhou University and 70 cases as healthy control group from medical examination center of the second hospital of Lanzhou University, after some cases ruled out, finally the study included 33 bladder urothelial carcinoma patients, 20 healthy subjects, case group recruited the new diagnosed patients with bladder urothelial carcinoma, without any treatment before surgery, the two groups excluded diabetes, hypertension patients or the ones with severe liver, kidney, heart disease, and severe infection history, surgical history and any other history of malignancy. Serum adiponectin and leptin levels were determined with a specific ELISA assay. We compared serum adiponectin and leptin levels between case group and healthy control group, and between the subgroups with different clinicopathological characteristics in the case group, and between the subgroups of smokers and non-smokers in case group and healthy control group respectively, then analysed the relationships among the serum adiponectin, leptin, leptin/adiponectin ratio levels and clinicopathological features in bladder urothelial carcinoma.We evaluated the correlations between the serum levels of adiponectin and leptin and the risk of bladder urothelial carcinoma, and further analysed the possibility of the two adipocytokines as promising biomarkers for bladder urothelial carcinoma. Results: There were no statistical differences in age, height, weight, BMI, waist circumference, systolic pressure, diastolic blood pressure, fasting blood glucose, blood lipids between case group and healthy control group. Serum adiponectin levels in bladder urothelial carcinoma patients were 4.88±0.88μg/ml,while serum adiponectin levels in healthy control group were5.85±0.99μg/ml, serum adiponectin levels in case group were lower than the healthy control group( P=0.001), there was no statistical difference in leptin levels between case group and healthy control group( P=0.413), there was no statistical difference in leptin / adiponectin ratio between case group and healthy control group(P=0.804); In case group, there were no statistical differences in the levels of serum adiponectin, serum leptin and leptin / adiponectin ratio between subgroups of smokers and non-smokers(P=0.281, P=0.528, P=0.545, respectively), in healthy control group, there was no statistical difference in the serum adiponectin levels between subgroups of smokers and non-smokers(P=0.569), whereas the levels of serum leptin and leptin / adiponectin ratio in the subgroup of smokers was higher than the subgroup of non-smokers(P=0.042, P=0.032, respectively). In case group, serum adiponectin levels in subgroup of low-grade was higher than in subgroup of high-grade(P=0.003), serum adiponectin levels in subgroup of TNM stage I(non-muscular-invasion bladder cancer) was higher than in subgroup of TNM stage II/III/IV(muscular-invasion bladder cancer)(P<0.001), and serum adiponectin levels in subgroup of tumors with diameter < 3 cm was still higher than in subgroup of tumors with diameter≥3 cm((P=0.013), in case group, there were no statistical differences in serum leptin levels between subgroups with different clinicopathological characteristics including clinicopathological grade, stage and the tumor size(P=0.800, P=0.419, P=0.591, respectively);In case group, serum adiponectin levels was negatively correlated to BMI and waist circumference(r=-0.348, P<0.05 and r=-0.55,P <0.01, respectively), serum adiponectin levels was positively correlated to high-density lipoprotein(r=0.347,P <0.05), serum adiponectin levels was negatively correlated to tumor stage(TNM stage I/II/III/IV)( r=-0.734,P <0.001), there were no correlations between systolic pressure, diastolic blood pressure, fasting blood glucose and serum adiponectin levels, in healthy control group, serum adiponectin levels was negatively correlated to BMI(r=-0.764, P <0.001), serum adiponectin levels was negatively correlated to triglycerides(r=-0.525,P <0.05), there were no correlations between systolic pressure, diastolic blood pressure, fasting blood glucose, waist circumference and serum adiponectin levels, there were no associations between BMI, waist circumference, systolic pressure, dias tolic blood pressure, fasting blood glucose, blood lipids and serum leptin levels either in case group or in healthy control group. When binary logistic regression was performed, we found the lowest serum adiponectin levels were significantly associated with an increased risk of bladder cancer after adjustment for possible confounding factors(in three segment, OR=53.259, 95% CI: 1.661-1707.994, P<0.05, in four segment, OR=75.507,95% CI: 2.002-2848.190,P<0.05,), whereas serum leptin levels didn’t affect the risk of bladder cancer. Draw the receiver-operating characteristic curves(ROC) of serum adiponectin and leptin levels, when serum adiponectin concentration was 5.63 μg/ml, the sensitivity was 81.8%, the specificity was 60%, when serum adiponectin concentration was 5.83μg/ml, the sensitivity was 90.9%, the specificity was 55%, when serum leptin concentration was 2.2297 ng/ml, the sensitivity was 90.9%, the specificity was 25%. Conclusion: Serum adiponectin levels were reduced in the bladder urothelial carcinoma patients and negatively correlated with BMI, in bladder urothelial carcinoma patients, serum adiponectin levels were higher in low-grade, TNM stage I(non-muscular-invasion bladder cancer) tumor and tumors with diameter < 3 cm patients compared to high-grade, TNM stage II/III/IV(muscular-invasion bladder cancer) and tumors with diameter≥3 cm patients, suggested that lower serum adiponectin levels were associated with an increased risk for bladder urothelial carcinoma. We was unsatisfactory with the results of leptin, while adiponectin may predict and diagnose the disease as a biomarker of bladder cancer.更多还原