肾癌中FHL1表达水平、肿瘤学意义研究及MDM2、KLF6、AR基因多态性与泌尿系肿瘤关系研究

发布时间：2018-02-28 05:18

本文关键词： FHL1 hMOF E-钙粘蛋白上皮细胞-间质转化 MDM2 KLF6 AR 基因多态性泌尿系肿瘤　出处：《吉林大学》2016年博士论文　论文类型：学位论文

【摘要】：LIM结构域拥有一个高度保守的双锌指域,现有研究结果显示,LIM结构域正在逐渐成为一种象征与肌动蛋白细胞骨架和转录机制相关联的标志。FHL蛋白家族(FHL LIM-only protein family)是含有四个半LIM结构域的、归属于单纯LIM蛋白亚类的一个蛋白家族,在人类中由FHL1、FHL2、FHL3、FHL5四个成员构成。关于FHL1,现有研究主要集中于FHL1与肌肉疾病、心血管疾病、肿瘤间的关系。FHL1与肾癌的相关研究非常少,仅有一个研究团队在较少的肾癌组织样本中通过免疫组化方法检测了FHL1的表达情况。这里,我们通过q PCR、WB、免疫组化、质粒转染实验方法,发现FHL1在肾癌中表达显著降低,与肾癌的主要临床特征和生存率无关联,在肾癌中h MOF能够上调FHL1表达,FHL1在肾癌中影响E-cadherin表达。同时,我们通过系统回顾和meta分析,评估研究了MDM2 SNP309与包含阴部肿瘤的皮肤癌易感性的关系、KLF6 IVS 1-27 GA与前列腺癌易感性的关系、AR基因多态性与睾丸生殖细胞肿瘤(TGCT)易感性的关系。SNP309(rs2279744 TG)作为MDM2基因启动子区发生频率最高的SNP,能够增加转录因子Sp1与P2启动子的亲和力,进而提高MDM2的m RNA和蛋白水平,从而影响p53通路。KLF6 IVS 1-27 GA是KLF6的一个常见SNP位点,位于KLF6第一个内含子,在其基因的3023位置上(即第二个外显子上游-27的位置)。KLF6IVS 1-27 GA属于异常选择性剪接,它废除了原有的SF2/ASF和SRp55结合位点,产生了一个新的有功能的SRp40结合位点,进而增加了选择性剪接体(SV1,SV2,SV3和产生于IVS 1-27 GA的新剪接体IVS?A)的量,但同时野生型KLF6的量并未减少。这些多产生的选择性剪接体在上调p21CIP1/WAF1和抑制增殖方面的能力要弱于野生型KLF6,进而对抗了野生型KLF6的正常功能。CAG三核苷酸重复序列(CAG)nCAA位于AR的多聚谷氨酰胺带,合适的多聚谷氨酰胺带长度对于保证N端和C端的相互作用是必要的,而N端和C端的相互作用情况会影响AR功能。CAG重复的增加还会降低AR的m RNA和蛋白水平。GGN三核苷酸重复序列(GGT)3GGG(GGT)2(GGC)n也位于多聚谷氨酰胺带,但功能尚不明确。这里,我们发现MDM2 SNP309与皮肤黑色素瘤易感性无关,但目前没有充分的数据来确定MDM2 SNP309与非黑色素瘤皮肤癌(NMSC:主要为BCC和SCC)易感性的关系。KLF6 IVS 1-27 GA与未经选择的前列腺癌整体易感性无关,但目前没有充分的数据来确定KLF6 IVS 1-27 GA分别与家族性前列腺癌、散发性前列腺癌易感性的关系。GGN重复23与TGCT易感性无关,但目前没有充分的数据来确定GGN重复23、CAG重复数、SNP rs6152、rs1204038、rs2361634与TGCT易感性的关系。需要具有精心设计、更大样本量、更多亚组的研究来完善当前meta分析的结果。
[Abstract]:The LIM domain has a highly conserved double zinc finger domain. The results show that the Lim domain is gradually becoming a marker associated with actin cytoskeleton and transcription mechanism. The FHL LIM-only protein family contains four semi-#en2# domains. A family of proteins belonging to a simple subclass of LIM, composed of four members of FHL1 / FHL2FHL3FHL5 in humans. Concerning FHL1, the current studies have focused on the relationship between FHL1 and muscle disease, cardiovascular disease, tumor, and renal cell carcinoma, and there are very few studies on the relationship between FHL1 and renal cell carcinoma. Only one team detected the expression of FHL1 in a small sample of RCC tissues by immunohistochemistry. Here, we found that the expression of FHL1 was significantly decreased in RCC by using Q PCR WB, immunohistochemistry, plasmid transfection assay. H MOF upregulated the expression of FHL1 in renal cell carcinoma, which was not associated with the main clinical features and survival rate of RCC. At the same time, we analyzed the expression of E-cadherin by systematic review and meta analysis. To evaluate the relationship between MDM2 SNP309 and skin cancer susceptibility including pudendal neoplasms. The relationship between KLF6 IVS 1-27 GA and prostate cancer susceptibility: relationship between AR gene polymorphism and TGCTs susceptibility to testicular germ cell tumor SNP309 rs2279744 TG. SNPs with the highest frequency of subregion occurrence can increase the affinity of transcription factor Sp1 to P2 promoter. Thus, the p53 pathway. KLF6 IVS 1-27 GA is a common SNP site of KLF6, which is located in the first intron of KLF6. KLF6IVS1-27 GA belongs to abnormal selective splicing at the 3023 position of its gene (the second exon upstream -27). It abolished the existing SF2/ASF and SRp55 binding sites and produced a new functional SRp40 binding site. Furthermore, the selective splicing body SV1 / SV2 / SV3 and the new splicing body produced by IVS 1-27 GA are added. A), But at the same time, the amount of wild-type KLF6 was not reduced. The ability of these multiple selective splicing to up-regulate p21CIP1 / WAF1 and inhibit proliferation was weaker than that of wild-type KLF6, which counteracted the normal function of wild-type KLF6. CAG trinucleotide repeats. The CAGN CAA is located in the poly-glutamine zone of AR. The appropriate length of the polyglutamine band is necessary to ensure the interaction between N-terminal and C-terminal. The interaction between N-terminal and C-terminal may affect AR function. The increase of CAG repeats will also decrease the m RNA and protein level of AR. GGGN trinucleotide repeats are also located in the polyglutamine band, but the function is not clear. We found that MDM2 SNP309 was not associated with skin melanoma susceptibility. But there is not enough data available to determine the relationship between MDM2 SNP309 and non-melanoma skin cancer NMSC.KLF6 IVS 1-27 GA has nothing to do with the overall risk of unselected prostate cancer. However, there is insufficient data to determine whether KLF6 IVS 1-27 GA is associated with familial prostate cancer and sporadic prostate cancer susceptibility. GGN repeat 23 is not associated with TGCT susceptibility. However, there is not enough data to determine the relationship between GGN repeat 23G repeat number and susceptibility to TGCT. It needs to be carefully designed, larger sample size and more subgroup studies to improve the results of current meta analysis.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R737.11

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