本文關鍵詞： FHL1 hMOF E-鈣粘蛋白 上皮細胞-間質轉化 MDM2 KLF6 AR 基因多態(tài)性 泌尿系腫瘤　出處：《吉林大學》2016年博士論文　論文類型：學位論文

【摘要】：LIM結構域擁有一個高度保守的雙鋅指域,現(xiàn)有研究結果顯示,LIM結構域正在逐漸成為一種象征與肌動蛋白細胞骨架和轉錄機制相關聯(lián)的標志。FHL蛋白家族(FHL LIM-only protein family)是含有四個半LIM結構域的、歸屬于單純LIM蛋白亞類的一個蛋白家族,在人類中由FHL1、FHL2、FHL3、FHL5四個成員構成。關于FHL1,現(xiàn)有研究主要集中于FHL1與肌肉疾病、心血管疾病、腫瘤間的關系。FHL1與腎癌的相關研究非常少,僅有一個研究團隊在較少的腎癌組織樣本中通過免疫組化方法檢測了FHL1的表達情況。這里,我們通過q PCR、WB、免疫組化、質粒轉染實驗方法,發(fā)現(xiàn)FHL1在腎癌中表達顯著降低,與腎癌的主要臨床特征和生存率無關聯(lián),在腎癌中h MOF能夠上調FHL1表達,FHL1在腎癌中影響E-cadherin表達。同時,我們通過系統(tǒng)回顧和meta分析,評估研究了MDM2 SNP309與包含陰部腫瘤的皮膚癌易感性的關系、KLF6 IVS 1-27 GA與前列腺癌易感性的關系、AR基因多態(tài)性與睪丸生殖細胞腫瘤(TGCT)易感性的關系。SNP309(rs2279744 TG)作為MDM2基因啟動子區(qū)發(fā)生頻率最高的SNP,能夠增加轉錄因子Sp1與P2啟動子的親和力,進而提高MDM2的m RNA和蛋白水平,從而影響p53通路。KLF6 IVS 1-27 GA是KLF6的一個常見SNP位點,位于KLF6第一個內含子,在其基因的3023位置上(即第二個外顯子上游-27的位置)。KLF6IVS 1-27 GA屬于異常選擇性剪接,它廢除了原有的SF2/ASF和SRp55結合位點,產生了一個新的有功能的SRp40結合位點,進而增加了選擇性剪接體(SV1,SV2,SV3和產生于IVS 1-27 GA的新剪接體IVS?A)的量,但同時野生型KLF6的量并未減少。這些多產生的選擇性剪接體在上調p21CIP1/WAF1和抑制增殖方面的能力要弱于野生型KLF6,進而對抗了野生型KLF6的正常功能。CAG三核苷酸重復序列(CAG)nCAA位于AR的多聚谷氨酰胺帶,合適的多聚谷氨酰胺帶長度對于保證N端和C端的相互作用是必要的,而N端和C端的相互作用情況會影響AR功能。CAG重復的增加還會降低AR的m RNA和蛋白水平。GGN三核苷酸重復序列(GGT)3GGG(GGT)2(GGC)n也位于多聚谷氨酰胺帶,但功能尚不明確。這里,我們發(fā)現(xiàn)MDM2 SNP309與皮膚黑色素瘤易感性無關,但目前沒有充分的數據來確定MDM2 SNP309與非黑色素瘤皮膚癌(NMSC:主要為BCC和SCC)易感性的關系。KLF6 IVS 1-27 GA與未經選擇的前列腺癌整體易感性無關,但目前沒有充分的數據來確定KLF6 IVS 1-27 GA分別與家族性前列腺癌、散發(fā)性前列腺癌易感性的關系。GGN重復23與TGCT易感性無關,但目前沒有充分的數據來確定GGN重復23、CAG重復數、SNP rs6152、rs1204038、rs2361634與TGCT易感性的關系。需要具有精心設計、更大樣本量、更多亞組的研究來完善當前meta分析的結果。
[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.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R737.11

【參考文獻】

相關期刊論文 前2條

1 王曉明;孫亮;張政;史曉紅;張耀光;魏東;萬奔;楊澤;王建業(yè);;雄激素受體CAG重復多態(tài)性與BPH和PCa相關性的meta分析[J];中華男科學雜志;2014年02期

2 王少平;亢黎莉;陳孝平;周鶴俊;;Frequent Down-regulation and Deletion of KLF6 in Primary Hepatocellular Carcinoma[J];Journal of Huazhong University of Science and Technology(Medical Sciences);2010年04期

，

本文編號：1545914