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研究生:陳俊孚
研究生(外文):Chun-fu Chen
論文名稱:微型核醣核酸及其調控之標的物在史托利細胞症候群之不孕男性表現之探討
論文名稱(外文):The identification of microRNAs and their putative targets in infertile men with Sertoli cell- only syndrome
指導教授:林永明林永明引用關係
指導教授(外文):Yung-ming Lin
學位類別:碩士
校院名稱:國立成功大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:59
中文關鍵詞:微型核醣核酸微陣列不孕症史托利細胞症候群
外文關鍵詞:Sertoli cell-only syndromemicroRNAsinfertilitymicroarray
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微型核醣核酸 (microRNA, miRNA)是新一類微小,非解碼的核糖核酸。根據研究其作用在於轉譯後控制基因之表現。 最近的研究顯示微型核醣核酸參與了哺乳動物的精子發育過程。本研究的主要目的即為探討正常生育男性與患有史托利細胞症候群(Sertoli cell-only syndrome,SCOS)男性不孕症患者睪丸組織內微型核醣核酸表現的差異。
我們採集了正常造精功能和史托利細胞症候群病患的睪丸組織為研究檢體。自睪丸組織我們採集了所有的核糖核酸進行微型核醣核酸微陣列(miRNA microarray,Agilent microRNA Human v2)和補體去氧核醣核酸微陣列(cDNA microarray, AgilentHuman 1 cDNA microarray)分析。所檢測之微型核醣核酸或基因在兩組患者所測得數值相差兩倍以上且統計上有顯著差異者視為基因量表現異常。在史托利細胞症候群的睪丸組織內微型核醣核酸過度表現及基因降低表現者為本研究之重點。利用現有之生物資訊庫(bioinformatics)預測出微型核醣核酸之可能標的核醣核酸。再從cDNA microarray 結果和所預測之微型核醣核酸標的核醣核酸進行交叉比對。最後確認在史托利細胞症候群患者表現量增高之微型核醣核酸及其標的核醣核酸,並進一步實驗確認其表現量差異之正確性。
在史托利細胞症候群這組實驗檢體我們發現總共三個微型核醣核酸的表現量異常升高,包含hsa-miR-136、hsa-miR-630 和 hsa-miR-663。這三個微型核糖核酸均可在人體內可找到相對應的標的基因。 另ㄧ方面,利用cDNA 微陣列分析我們在史托利細胞症候群這組的檢體內發現了共有218 個基因表現量降低。藉著交叉分析比對,我們發現miR-136 有8 個對應標的基因,miR-630 有9 個對應標的基因,而miR-663有11 個對應標的基因。我們利用即時反轉錄聚合酵素鏈鎖反應(real time RT-PCR)進一步作確認。證實miR-136 (P = 0.0039)和miR-630 (P = 0.0005)這兩組微型核醣核酸以及其標的基因ILF2 (P = 0.0023), TLE1 (P = 0.0008), FBXW5 (P = 0.0049), SNW1 (P = 0.0325) and GLG1 (P = 0.0201)在史托利細胞症候群和正常造精功能兩組患者間有顯著表現量之差異。接著我們將miR-136 及其標的基因(ILF2, TLE1, SNW1 and GLG1)的3'非轉譯區(3'-UTR)片段送入PC-3 細胞。利用冷光報導基因分析法(luciferase reporter assay) 實驗證實當miR-136 的濃度越高時,其抑制標的基因的作用越明顯。
我們的結果指出miR-136 和miR-630在史托利細胞症候群患者睪丸組織確實有表現量升高的情形,而其相對應的標的基因則表現量下降。這個結果表示微型核醣核酸在造精功能的基因調控上扮演著一個重要的關鍵角色,甚而導致史托利細胞症候群的發生。
MicroRNA (miRNA) is a new class of small, noncoding RNA known to post-transcriptionally control gene expression. Recent studies indicated that miRNAs are involved in the development of mammalian spermatogenesis. This study was conducted to identify the profiling of miRNAs and their putative targets differentially expressed in the testes of normal spermatogenesis and Sertoli cell-only syndrome (SCOS).
Testicular samples with normal spermatogenesis and SCOS were used for study. Total RNA was isolated from the testicular tissue for miRNA array (Agilent microRNA Human v2) and cDNA microarray (Agilent Human 1 cDNA microarray) analysis. miRNA or genes with significant differential expressions were identified by t-test analysis and more than 2-fold changes. Up-expression of miRNAs and down-expression of genes in SCOS group were evaluated. By using bioinformatics tool, the putative mRNA targets of individual miRNAs were predicted. After crossmatch comparison analysis between the predicted mRNA targets from miRNAs and mRNAs from cDNA microarray, specific target genes for up-regulated miRNAs in SCOS testes were determined. Validation analysis of miRNA and their putative targets were carried out.
A total of three miRNAs were found to be up-expressed in SCOS specimen including hsa-miR-136, hsa-miR-630 and hsa-miR-663. All these 3 miRNAs have been shown to have putative target genes in humans. On the other hand, a total of 218 genes were found to be down-expressed in SCOS specimen by cDNA microarray analysis. A cross-matching analysis of miRNA targets and genes from microarray showed that hsa-miR-136 has 8 putative targets, hsa-miR-630 has 9 putative targets and hsa-miR-663 has 11 putative targets. Validation was done by real time RT-PCR, and significant differences were found between the fertile and SCOS group in miR-136 (P = 0.0039), miR-630 (P = 0.0005) and their target genes ILF2 (P = 0.0023), TLE1 (P = 0.0008), FBXW5 (P = 0.0049), SNW1 (P = 0.0325) and GLG1 (P = 0.0201). Then we co-transfected the miR-136 mimic and 3′-UTR fragments of the target genes (ILF2, TLE1, SNW1 and GLG1) into PC-3 cells, followed by luciferase reporter assay. The results showed that higher concentration of miR-136 mimic would attenuate the target gene expressions.
Our results indicate that miRNA-136 and -630 are up-regulated and their targets genes are down-expressed in SCOS testis, suggesting a crucial role of miRNAs in regulating human spermatogenesis that may ultimately lead to SCOS.
Table of Contents
List of Figures……………………………………… 3
List of Tables ……………………………………… 3
Abstract in Chinese………………………………… 4
Abstract in English………………………………… 6
Acknowledgement……………………………………… 8
Introduction ………………………………………… 10
Sertoli cell-only syndrome …………………… 10
MicroRNAs (miRNAs) ……………………………… 10
Microarray for detection of miRNAs ………… 12
MiRNAs and infertility ………………………… 12
Materials and Methods……………………………… 15
Subjects and testicular specimen collection 15
Total RNA and miRNA isolation………………… 16
miRNA microarray analysis……………………… 16
cDNA microarray analysis ……………………… 17
Crossmatch comparison analysis between miRNA
putative targets and down-regulated genes
from cDNA microarray …………………………… 17
Real-time quantitative reverse transcription
polymerase chain reaction (real time qRT-PCR)
analysis of miRNA expression ………………… 18
Real time qRT-PCR analysis of target mRNA
expression…………………………………………… 19
Luciferase reporter constructs and luciferase
assay………………………………………………… 21
Statistical analysis…………………………… 21
Results………………………………………………… 22
Differential expression of miRNAs and mRNAs
between normal and SCOS testes………………… 22
Validation of miRNA expression………………… 22
Determination of miRNA putative targets by
crossmatch comparison analysis………………… 23
Validation of putative target mRNA expression 24
miR-136 attenuates target mRNA expressions … 24
Discussion ……………………………………………… 25
References ……………………………………………… 30
Appendix ………………………………………………… 52

List of Figures
Figure 1. miRNA microarray analysis…………… 42
Figure 2. qRT-PCR analysis of miR-136 and 630
expressions…………………………………………… 43
Figure 3. qRT-PCR analysis of miR-136 and 630
target genes expressions………………………… 44
Figure 4. miR-136 putative binding sites on
3'UTR of the target genes……………………… 45
Figure 5. pGL3-p reporter vector map………… 46
Figure 6. Effects of miR-136 on putative
target genes expression in vivo………………… 47



List of Tables
Table 1. Crossmatch comparison analysis between
miRNA target genes and genes from cDNA microarray
assay………………………………………………… 48
Table 2. Primer sequences for real time RT-PCR
analysis of target genes………………………… 50
Table 3. Primer sequences for luciferase reporter
constructs…………………………………………… 51
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