上尿路移行上皮癌术后膀胱和对侧上尿路复发肿瘤的危险因素分析及肿瘤相关蛋白的基础研究

发布时间：2019-05-15 16:49

【摘要】：背景：上尿路移行上皮癌术后膀胱及对侧上尿路肿瘤的发生鲜有报道，就目前的研究看，对于此现象的文献因素尚未确定。此外，一些病例报道描述了复发肿瘤及对侧肿瘤的特点，以及两者之间的联系。方法：对大连医科大学附属二院近10年来882例移行上皮癌的原始文件进行整理，剔除原发膀胱肿瘤及远处转移，对112例的11个变量进行多因素分析，确定上尿路移行上皮癌的复发因素。结果：一侧上尿路移行上皮癌术后，膀胱和对侧上尿路肿瘤的再发率分别是31.2％和5.8％。上尿路多发肿瘤是其术后再发膀胱癌的危险因素，合并膀胱肿瘤及肾功不全是对侧上尿路移行上皮癌再发肿瘤的危险因素。再发的膀胱肿瘤和对侧上尿路肿瘤在复发的时间和肿瘤的分期上有明显的区别。结论：对原发性上尿路移行上皮癌的患者定期行膀胱镜检查是必要的，对具有复发对侧上尿路肿瘤高危因素的患者在行膀胱镜检查的同时，应施行静脉尿路造影（IVU）或CT尿路造影（CTU）。葡萄糖合酶激酶3β（Glycogen synthase kinase3β,GSK3β）是一个牵涉到多个生物进程，，特别是胰岛素通路及Wnt通路中的多功能丝/苏氨酸激酶，同样GSK3β可以被蛋白激酶B(protein kinase B,PKB)磷酸化。对于GSK3β的氮端Arg4和Arg6突变为丙氨酸会明显的削弱Ser9的自磷酸化。尽管这样的实验结果已经在前期报道过，在分子水平具体的自抑制机理并未完全清楚。在我们的研究中，Arg4和Arg6突变为丙氨酸会明显的削弱PKB和GSK3β之间的亲和力，与野生型相比，突变导致了在原子水平的损失是有意义的。我们从四个方面（构象、残基运动、氢键和结合自由能）分析了突变复合体的重要变化。突变体亲和力的降低会明显的削弱对GSK3β的磷酸化，同样也会削弱GSK3β的自抑制。这对解释GSK3β的自抑制机理具有相当大的意义，或许可以应用到2型糖尿病及肿瘤的机制研究及药物开发中。
[Abstract]:Background: the occurrence of bladder and contralateral upper urinary tract tumors after operation of transitional epithelial carcinoma of upper urinary tract is rarely reported. According to the current study, the literature factors of this phenomenon have not been determined. In addition, some case reports describe the characteristics of recurrent tumors and contralateral tumors, as well as the relationship between them. Methods: the original files of 882 cases of transitional epithelial carcinoma in the second affiliated Hospital of Dalian Medical University in recent 10 years were sorted out, the primary bladder tumor and distant metastasis were eliminated, and 11 variables of 112 cases were analyzed by multivariate analysis. To determine the recurrence factors of transitional epithelial carcinoma of upper urinary tract. Results: after operation, the recurrence rate of bladder and contralateral upper urinary tract tumors was 31.2% and 5.8%, respectively. Multiple tumors of upper urinary tract are the risk factors of recurrent bladder cancer after operation, and bladder tumors and renal insufficiency are the risk factors of recurrent tumors of contralateral transitional epithelial carcinoma of upper urinary tract. The recurrence time and stage of recurrent bladder tumor and contralateral upper urinary tract tumor were significantly different from those of contralateral upper urinary tract tumor. Conclusion: it is necessary to perform cystoscopy regularly in patients with primary transitional epithelial carcinoma of upper urinary tract. Patients with recurrent contralateral upper urinary tract tumors are examined by cystoscopy at the same time. Intravenous urography (IVU) or CT urography (CTU). Should be performed Glucokinase 3 尾 (Glycogen synthase kinase3 尾 (GSK3 尾) is a multifunctional serine / threonine kinase involved in many biological processes, especially insulin pathway and Wnt pathway. GSK3 尾 can also be phosphorylated by protein kinase B (protein kinase B. For the nitrogen terminal Arg4 and Arg6 mutation of GSK3 尾 to alanine, the autophosphorylation of Ser9 was significantly weakened. Although such experimental results have been reported earlier, the specific self-inhibition mechanism at the molecular level is not fully understood. In our study, the mutation of Arg4 and Arg6 into alanine significantly weakens the affinity between PKB and GSK3 尾. Compared with the wild type, it is meaningful that the mutation leads to the loss at the atomic level. We analyze the important changes of the mutant complex from four aspects (conformational, residue movement, hydrogen bond and binding free energy). The decrease of affinity of mutants significantly weakened the phosphorylation of GSK3 尾 and the self-inhibition of GSK3 尾. This is of great significance to explain the autoinhibition mechanism of GSK3 尾, and may be applied to the study of the mechanism of type 2 diabetes mellitus and tumor and the development of drugs.
【学位授予单位】：大连医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R737.1

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