IGF-1相关通路在高脂饮食对前列腺癌发生及进展影响中的作用

发布时间：2018-04-24 23:09

本文选题：前列腺癌 + 手术去势　；参考：《复旦大学》2014年博士论文

【摘要】：第一部分高血糖及超重与前列腺癌预后关系目的：代谢异常,如高血糖和超重,与前列腺癌的发生和进展存在联系。本研究通过随访接受双侧睾丸切除术的前列腺癌患者,来探讨高血糖及超重与前列腺癌患者预后之间的关系。材料与方法：我们以复旦大学附属华山医院为病人来源,采用历史前瞻性研究方式,纳入了自2003年1月至2012年8月期间323例接受手术去势的前列腺癌患者,其年龄介于50-91岁之间。所有病人均有详尽的临床信息,如血清前列腺特异性抗原(Prostate Specific Antigen, PSA)水平、Gleason评分、超声数据、CT或MRI及骨扫描等。所有纳入研究者对象都是汉族中国人。每个纳入研究者对象都被告知了本研究有关的目标要求,并签署了知情同意书。纳入的研究对象根据其是否具有高血糖、超重进行分组,分为对照组、高血糖组、超重组及超重+高血糖组。高血糖是指空腹血糖水平升高(≥5.6mmol/L)或经确诊为2型糖尿病。根据世界卫生组织(WHO)的定义,超重是指体质指数(BMI)≥25kg/m2。病人随访从手术去势之日开始,直至死亡之日或最后一次随访的患者仍然存活的日期。我们以电话随访的方式,每三个月电话询问患者或患者家属有关患者的生存情况。患者死亡经过疾病防治中心确认,对于有上海市医保的患者,我们将再通过上海市城镇医保系统进行二次确认。我们利用Fisher精确或卡方检验评价四组之间的临床病理特征以及总体生存率。四组的生存分析采用Kaplan-Meier法。统计软件采用SPSS 17.0版本,P0.05认为具有显著的统计学差异。结果：在平均为期43个月的随访期间,共有23例患者失访,失访率为7.1%。最后纳入研究共300例患者,包括对照组共166人(55.33%),超重组58人(19.33%),高血糖组50人(16.67%),超重+高血糖组26人(8.67%)。在本研究中共有122例患者死亡,其中对照组62人(37.35%),超重组25人(43.10%),高血糖组22人(44%),超重+高血糖组13人(50%)。死因包括前列腺癌、心脏病发作、中风和呼吸衰竭等。300例患者1年总体生存率为97%,而5年生存率为65.33%。四组之间1年生存率无显著的统计学差异,超重+高血糖组的5年生存率为50%,显着低于对照组的生存率的70.48%(P=0.038)。对照组、超重组及高血糖组之间的生存曲线无显著性差异,而超重+高血糖组生存曲线与对照组相比,其生存时间显著较短,P=0.044。结论：通过对接受双侧睾丸切除术的前列腺癌患者的随访,我们发现同时超重又有高血糖者其预后较差,5年总体生存率显著较低,生存时间较短,代谢异常与前列腺癌的预后结局有着一定联系,代谢异常对前列腺癌的发生及进展有重要影响。第二部分 IGF-1相关通路在高脂饮食促进TRAMP小鼠前列腺癌进展中的作用目的：通过比较高脂饮食TRAMP小鼠与普通饮食TRAMP小鼠的成瘤率与死亡率,研究高脂饮食对前列腺癌发生及进展的影响,并检验IGF-1相关通路在高脂饮食对前列腺癌发生及进展影响中发挥的作用。材料与方法：采用TRAMP转基因前列腺癌小鼠模型,随机分为实验组——高脂饮食组(n=42),对照组——普通饮食组(n=42)。高脂饮食TRAMP小鼠喂以高脂饲料诱导肥胖及胰岛素抵抗。两组TRAMP小鼠均于20周龄、24周龄和28周龄处死取材,每组每次各14只。TRAMP小鼠处死前一晚断粮。处死抽血后测定TRAMP小鼠空腹血糖值,留取血清利用ELISA法检测胰岛素、IGF-1、IGF-2,留取前列腺组织进行HE染色及免疫组化染色,测定指标包括IGF-1Rα、IGF-1R β、IGFBP1、IGFBP2、IGFBP3、IGFBP5、IGFBP6和Akt。结果：在TRAMP小鼠饲养期间共观察到13例小鼠死亡,包括普通饮食组3只(7.14%)及高脂饮食组10只(23.81%),高脂饮食组TRAMP小鼠的死亡率显著高于普通饮食组(P=0.035)。在TRAMP小鼠20周龄时,高脂饮食组已有11只(78.57%)TRAMP、鼠具有典型的前列腺癌,而普通饮食TRAMP小鼠只有5只(35.71%)发生了典型的前列腺癌,高脂饮食组TRAMP小鼠的20周龄时的成瘤率显著高于普通饮食组(P=0.022)。普通饮食与高脂饮食TRAMP小鼠在20周、24周及28周时,其血糖、血清胰岛素及IGF-2水平并无显著性差异。而在24周及28周时,高脂饮食TRAMP、鼠的血清IGF-1水平显著高于普通饮食组,其中以28周时最为明显(P=0.011)。另外,高脂饮食TRAMP小鼠随着周龄的增加,血清IGF-1的浓度也呈上升趋势。TRAMP小鼠前列腺免疫组化染色提示IGF-1Rα、IGF-1Rβ、IGFBP3及Akt在高脂饮食TRAMP小鼠中的阳性染色率均显著高于普通饮食组,其他IGF结合蛋白(IGFBP1、IGFBP2、IGFBP5和IGFBP6)虽然在TRAMP小鼠前列腺中也有表达,但是在两组小鼠中没有显著性差异。结论：高脂饮食TRAMP小鼠成瘤率及死亡率均明显高于普通饮食TRAMP小鼠,高脂饮食能够促进前列腺癌的发生及进展。通过ELISA和免疫组化研究胰岛素、IGF-1通路相关蛋白发现,多个蛋白分子,包括IGF-1、IGF-1Rα、IGF-1Rβ、IGFBP3及Akt在高脂饮食TRAMP小鼠中的表达量均显著高于普通饮食组,提示IGF-1相关通路在高脂饮食促进前列腺癌发生及进展中发挥重要作用。
[Abstract]:Part 1 Relationship between hyperglycemia and overweight and prognosis of prostate cancer: metabolic abnormalities, such as hyperglycemia and overweight, are associated with the development and progression of prostate cancer. This study was conducted to investigate the relationship between hyperglycemia and overweight and the prognosis of prostate cancer patients. Methods: We used a historical prospective study in Huashan Hospital Affiliated to Fudan University for 323 patients with surgical castration between January 2003 and August 2012, whose age was between the age of 50-91. All patients had detailed bed information, such as serum prostate specific antigen (Prostate). Specific Antigen, PSA) level, Gleason score, ultrasound data, CT or MRI, and bone scan. All the participants were Han Chinese. Each participant was informed of the objectives of the study and signed an informed consent. The subjects included in the study were based on whether they had hyperglycemia and were overweight. Group, divided into control group, hyperglycemia group, super recombinant and overweight + hyperglycemia group. Hyperglycemia refers to higher level of fasting blood glucose (more than 5.6mmol/L) or type 2 diabetes. According to the definition of WHO (WHO), overweight refers to the body mass index (BMI) of patients with more than 25kg/m2. from the day of the surgical castration until the day of death or the last time The patients who were followed up were still alive. We call every three months by telephone to inquire about the survival of the patient or the patient's family. The patient's death is confirmed by the disease control center. For patients with medical insurance in Shanghai, we will make a two confirmation through the medical insurance system in the city of Shanghai city. We use Fishe R accurate or chi square test was used to evaluate the clinicopathological features and overall survival rate between the four groups. The four group's survival analysis adopted the Kaplan-Meier method. The statistical software adopted the SPSS 17 version, and the P0.05 thought there was a significant statistical difference. Results: during the average period of 43 months of follow-up, there were 23 patients who lost their visits and the loss rate was 7.1%. final. A total of 300 patients were included in the study, including 166 (55.33%) in the control group, 58 in the super recombinant (19.33%), 50 in the hyperglycemia group (16.67%), and 26 in the hyperglycemic group (8.67%). In this study, 122 patients were killed, including 62 (37.35%) in the control group, hyperglycemic 25 (43.10%), hyperglycemic group, overweight and hyperglycemic group. The total 1 year survival rate of.300 patients with prostate, heart attack, stroke, and respiratory failure was 97%, while the 5 year survival rate was no significant difference between the group 65.33%. four and the 1 year survival rate. The 5 year survival rate of the overweight + hyperglycemia group was 50%, significantly lower than that of the control group (70.48% (P=0.038). The control group, the super recombination and hyperglycemia group) There was no significant difference between the survival curve and the survival curve of the overweight + hyperglycemia group compared with the control group, and the survival time was significantly shorter than those in the control group. P=0.044. conclusion: by follow-up to the prostate cancer patients receiving bilateral testicle excision, we found that the prognosis of those with both overweight and hyperglycemia was poor, and the overall survival rate was significantly lower in 5 years. Short storage time and metabolic abnormalities have a certain relationship with the prognosis of prostate cancer. Metabolic abnormalities have important effects on the development and progression of prostate cancer. Second the role of the IGF-1 related pathway in promoting the progression of prostate cancer in TRAMP mice by high fat diet: by comparing the high fat diet TRAMP mice with the common diet TRAMP The effect of high fat diet on the occurrence and progression of prostate cancer and the role of IGF-1 related pathway in the development and progression of prostate cancer in high fat diet. Materials and methods: the model of TRAMP transgenic prostate cancer mice was divided into experimental group, high fat diet group (n=42), and the effect of high fat diet on the development and progression of prostate cancer was examined. Group (n=42). High fat diet TRAMP mice were fed with high fat diet induced obesity and insulin resistance. Two groups of TRAMP mice were sacrificed at 20 weeks of age, 24 weeks old and 28 weeks old, and 14.TRAMP mice in each group were sacrificed a night before death. The fasting blood glucose values of TRAMP mice were determined and ELISA method was used to determine the use of serum. Detection of insulin, IGF-1, IGF-2, and retained prostate tissue for HE staining and immunohistochemical staining. The indicators included IGF-1R alpha, IGF-1R beta, IGFBP1, IGFBP2, IGFBP3, IGFBP5, IGFBP6 and Akt.. During the feeding of mice, 13 mice were killed, including 3 (7.14%) and 10 (23.81%), high fat diet group, and high fat diet. The mortality of TRAMP mice in the diet group was significantly higher than that in the normal diet group (P=0.035). In the 20 week old TRAMP mice, there were 11 (78.57%) TRAMP in the high fat diet group, and the rat had typical prostate cancer, while only 5 (35.71%) of the normal diet TRAMP mice had a typical prostate cancer, and the high fat diet group TRAMP mice had a significant tumorigenesis rate at the age of 20 weeks. Higher than normal diet group (P=0.022). There was no significant difference in blood glucose, serum insulin and IGF-2 levels between normal diet and high fat diet TRAMP mice at 20 weeks, 24 weeks and 28 weeks. At 24 and 28 weeks, high fat diet TRAMP, the serum IGF-1 level of rats was significantly higher than that of ordinary drinking group, which was most obvious at 28 weeks (P=0.011). With the increase of age, the concentration of serum IGF-1 in the serum of TRAMP mice increased with the increase of the serum level in.TRAMP mice. The positive staining rates of IGF-1R alpha, IGF-1R beta, IGFBP3 and Akt in the high fat diet TRAMP mice were significantly higher than those in the normal diet group, while the other IGF nodal proteins (IGFBP1, IGFBP2, IGFBP5, and Akt) were in spite of There is also expression in the prostate of mice, but there is no significant difference in the two groups of mice. Conclusion: the rate of tumor formation and mortality in the high fat diet TRAMP mice is significantly higher than that of the normal diet TRAMP mice. The high fat diet can promote the development and progression of the prostate cancer. The study of insulin by ELISA and immunohistochemistry and the discovery of IGF-1 pathway related proteins are found. The expression of protein molecules, including IGF-1, IGF-1R a, IGF-1R beta, IGFBP3 and Akt in high fat diet TRAMP mice were significantly higher than those in the normal diet group, suggesting that the IGF-1 related pathway plays an important role in promoting the development and progression of prostate cancer in high fat diet.

【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.25

【参考文献】