臺灣博碩士論文加值系統

極光激酶-A (Aurora-A)主要參與在細胞週期的進行，很多文獻報導指出Aurora-A在癌細胞中有異常大量表現，包括大腸直腸癌、乳癌、肝癌、及胃癌等，證明Aurora-A的異常表現與癌細胞生成有很大的關聯，因此，控制Aurora-A在細胞週期中的表現是很重要的，然而，Aurora-A在癌細胞大量表現的原因可能與mRNA表現量、轉錄能力及蛋白質穩定性增加有關。異源性核糖核蛋白Q1 (hnRNP Q1)是屬於RNA結合蛋白，並且參與mRNA代謝與轉譯的調控，但目前為止hnRNP Q1與癌症發生的相關性並不明確。根據RNA免疫沉澱及次世代定序結果，我們發現有一群與細胞週期相關的基因會受到hnRNP Q1調控，其中包含Aurora-A。在研究結果中，我們發現hnRNP Q1能增加Aurora-A蛋白質表現而非影響mRNA表現量，同時，也觀察到EGF增加hnRNP Q1與Aurora-A mRNA結合並增進Aurora-A mRNA的轉譯。 我們確認EGF是透過mTOR與ERK訊號傳遞路徑去調控hnRNP Q1對於Aurora-A mRNA相關的轉譯調控機制，同時，我們也發現hnRNP Q1可以促進一群紡錘絲監控蛋白(spindle assembly checkpoint)的轉譯。另一方面，在大腸直腸癌臨床檢體分析上，我們發現hnRNP Q1的表現與Aurora-A及紡錘絲監控蛋白表現呈現正相關。因此，我們認為hnRNP Q1是一個新的重要的細胞週期相關基因的調控因子，其在大腸直腸癌中與細胞週期相關基因過度表現而造成癌細胞生成或腫瘤發生有相關性。

Aurora-A, which is a serine/threonine kinase involved in regulating cell cycle progression, is frequently amplified and overexpressed in variety of cancers. Deregulation of Aurora-A has major roles in tumorigenesis. Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA binding protein, has been implicated in many post-transcriptional regulatory processes including mRNA splicing, RNA metabolism and translation. Using an RNA-immunoprecipitation (RIP)-seq analysis, a group of cell cycle-related genes targeted by hnRNP Q1 were identified, including Aurora-A kinase. Altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA. Stimulation with epidermal growth factor (EGF) is found to enhance both binding between hnRNP Q1 and the Aurora-A mRNA as well as the efficacy of the hnRNP Q1-induced translation of the Aurora-A mRNA. The EGF/hnRNP Q1-induced translation of Aurora-A mRNA is mediated by the mTOR and ERK pathways. We also show that hnRNP Q1 up-regulates the translation of a group of spindle assembly checkpoint (SAC) genes. hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and these SAC genes in human colorectal cancer tissues. Taken together, our data indicate that hnRNP Q1 plays an important role in regulating a group of cell cycle-related genes expression. hnRNP Q1 may therefore contribute to tumorigenesis by up-regulating the translation of these genes in colorectal cancer.

CHINESE ABSTRACT………… I
ABSTRACT………… II
ACKNOWLEDGEMENTS………… III
TABLE OF CONTENTS………… IV
CONTENTS OF TABLES………… VIII
CONTENTS OF FIGURES………… IX
CONTENTS OF APPENDICES………… XII
ABBREVIATION LIST………… XIII
A.INTRODUCTION………… 1
1. Colorectal cancer (CRC)………… 1
1-1. CRC and genomic instability………… 1
2. Aurora kinase………… 2
2-1. Aurora kinase A (Aurora-A)………… 3
2-2. Aurora-A and cancer………… 3
3. heterogeneous nuclear ribonucleoprotein (hnRNP) ………… 4
3-1. heterogeneous nuclear ribonucleoproteinQ (hnRNP Q)………… 5
3-2. The function of hnRNP Q………… 6
3-3. The function of hnRNP Q in translational regulation…………6
4. Research objectives………… 7
B.MATERIALS AND METHODS………… 9
1. Materials………… 9
2. Methods………… 16
2-1. Cell cultures………… 16
2-2. Constructs, siRNA and transfections………… 16
2-3. Quantitative real-time PCR (RT-qPCR)………… 16
2-4. Preparation of cell extracts and western blot analysis………… 17
2-5. Ribosomal protein S6 immunoprecipitation assay (S6-IP)………… 18
2-6. Ribosome profiling………… 18
2-7. RNA-immunoprecipitation assay (RIP)………… 19
2-8. In vivo translation assay………… 19
2-9. Biotin pull-down assay………… 20
2-10. Patient specimens………… 21
2-11. Immunohistochemistry (IHC)………… 21
2-12. ONCOMINE microarray datasets………… 21
2-13. The Cancer Genome Atlas (TCGA) dataset………… 21
2-14. Statistical analysis………… 22
C.RESULTS………… 23
1. EGF and hnRNP Q1 cooperatively enhance the translation of the Aurora-A mRNA………… 23
1-1. EGF combined with hnRNP Q1 results in a synergistic effect on Aurora-A protein but not mRNA expression………… 23
1-2. EGF enhances the hnRNP Q1-mediated increase in Aurora-A mRNA translation………… 24
1-3. EGF-enhanced Aurora-A expression is hnRNP Q1 dependent………… 24
2. EGF enhances the ability of hnRNP Q1 to bind to the Aurora-A mRNA 5’-UTR………… 25
2-1. EGF does not affect the expression or subcellular localization of hnRNP Q1………… 25
2-2. EGF enhances the binding ability of hnRNP Q1 to Aurora-A mRNA……… 25
3. EGF increases the hnRNP Q1-mediated translational up-regulation of the Aurora-A mRNA through the mTOR and ERK pathways………… 26
3-1. EGF enhances the hnRNP Q1-mediated translational up-regulation of Aurora-A by modulating the mTOR pathway………… 26
3-2. EGF increases the hnRNP Q1-mediated translational up-regulation of Aurora-A mRNA via the ERK pathway………… 27
4. hnRNP Q1 expression is positively correlated with Aurora-A levels in human colorectal cancer………… 28
4-1. hnRNP Q1 and Aurora-A mRNAs were significantly higher in colorectal cancer tissues than in normal tissues………… 28
4-2. High-level expression of both hnRNP Q1 and Aurora-A is positively correlated with a high-level expression of EGFR in colorectal cancer………… 29
5. hnRNP Q1 plays an important role in regulating the expression of a group of spindle assembly checkpoint genes………… 30
6. Co-expression of SAC proteins, EGFR and Aurora-A in human colorectal tissues………… 31
D.DISCUSSION………… 33
1. hnRNP Q1 expression is positively correlated with Aurora-A levels in human colorectal cancer………… 33
2. EGF may control the post-translational modification of hnRNP Q1 and regulate the function of hnRNP Q1………… 33
3. The role of PI3K/Akt/mTOR and ERK pathways in EGF-mediated hnRNP Q1-induced translation of Aurora-A mRNA………… 34
4. EGF signaling might be an important regulator of the expression of SAC genes………… 35
5. The role of hnRNP Q1 in tumorigenesis………… 36
6. Conclusion………… 37
E.REFERENCES………… 39
F.TABLES………… 49
G.FIGURES………… 54
H.APPENDICES………… 82
I.CURRICULUM VITAE………… 85

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