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研究生：	黃士宣 Huang, Shih-Hsuan
論文名稱：	在肺癌中microRNAs的失調促進ZNF322A表現及轉錄活性 Dysregulated microRNAs Enhance ZNF322A Expression and Transcriptional Activity in Lung Cancer
指導教授：	王憶卿 Wang, Yi-Ching
學位類別：	碩士 Master
系所名稱：	醫學院 - 藥理學研究所 Department of Pharmacology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	74
中文關鍵詞：	肺癌、ZNF322A鋅指蛋白、miR-326 、miR-484 、Cyclin D1 、Alpha-adducin 、生物標記
外文關鍵詞：	Lung cancer, ZNF322A, miR-326, miR-484, Cyclin D1, Alpha-adducin, Biomarker
相關次數：	點閱：82 下載：0
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研究背景: ZNF322A (zinc finger protein 322A) 是一個致癌性鋅指蛋白轉錄因子，它會使其下游基因例如Cyclin D1 (CCND1)、P53、Alpha-adducin (ADD1) 的表現失調進而促進癌細胞生長及移動能力。先前實驗室的研究指出約有70%的東西方族群肺癌病患其ZNF322A的mRNA及蛋白都有過度表達的情形。除此之外，實驗室也發現ZNF322A蛋白會受到CK1δ/GSK3/FBXW7 路徑調控而降解；然而我們對於ZNF322A mRNA的表現是透過什麼機制達成動態平衡仍是未知的。
研究目的: 本研究旨在以肺癌細胞及動物模式去探討微小核醣核酸 (microRNAs) 對於ZNF322A的轉錄調控；並以肺癌病人檢體闡明ZNF322A與其上游微小核醣核酸調控子的關聯性。
研究結果: 藉由預測軟體分析，在ZNF322A基因的3′端非轉譯區 (3′UTR) 上可能擁有miR-98-5p、miR-135a-5p、miR-326以及miR-484的結合位，為了驗證這些候選的微小核醣核酸是否會調控ZNF322A的mRNA表現，我們將這些候選的微小核醣核酸類似物 (mimics) 轉染 (transfect) 至多種肺癌細胞株中並進行後續的實驗分析。首先，我們針對這四種微小核醣核酸建構ZNF322A 3′端非轉譯區的冷光表現載體 (3′UTR luciferase reporter) 並去檢測候選的微小核醣核酸是否會抑制冷光表現。在這四個候選微小核醣核酸中，只有miR-326以及miR-484可以抑制野生型 (wild-type) 的3′端非轉譯區的冷光活性 (luciferase activity)，但是將miR-326與miR-484的預測結合位做突變 (mutation) 則冷光活性就不會受到miR-326與miR-484所抑制。再者，miR-326 mimics的大量表現會抑制ZNF322A的mRNA與蛋白表現；但是miR-484 mimics僅在mRNA層級去抑制ZNF322A表現而非蛋白層級。重要地，miR-326會透過減少ZNF322A下游標的CCND1及ADD1表現來抑制肺癌細胞的生長及爬行能力。在重建實驗 (reconstitution) 我們發現miR-326/ZNF322A/CCND1路徑對於細胞生長調控非常重要，而miR-326/ZNF322A/ADD1路徑則調控細胞移動能力。臨床檢體的檢測上，我們發現ZNF322A mRNA與miR-326的表現在肺癌病人上有著負相關的趨勢，此外，我們的分析結果也指出低表達ZNF322A/高表達miR-326 (ZNF322A-L/miR326-H) 的病人族群擁有較好的整體存活期(overall survival)。
結論：我們的結果顯示了miR-326/ZNF322A路徑藉由減少CCND1與ADD1來抑制腫瘤進程 (tumor progression)。除此之外，腫瘤組織中低ZNF322A/高miR-326 (ZNF322A-L/miR326-H) 的表達形式 (profile) 在未來臨床應用上可能可以作為一個有潛力的生物標記(biomarker)。

Background: ZNF322A is an oncogenic zinc-finger transcription factor, which dysregulates genes in control of cell growth and cell motility such as cyclin D1 (CCND1), p53 and alpha-adducin (ADD1). Our published reports show that overexpression of ZNF322A mRNA and protein is found in about 70% of Asian and Caucasian lung cancer patients. In addition, ZNF322A protein degradation is regulated in part by the CK1δ/GSK3/FBXW7 axis. However, the mechanism involved in homeostasis of ZNF322A mRNA remains unclear.
Purpose: This study aims to investigate the microRNAs regulation on ZNF322A transcription in lung cancer cell and xenograft models. In addition, we explore the relationship between ZNF322A and its upstream miRNA regulators using clinical studies.
Results: The 3′UTR of ZNF322A contained target sites for microRNAs miR-98-5p, miR-135a-5p, miR-326 and miR-484 according to three prediction software or database. To validate the reciprocal transcription regulation of microRNA candidates on ZNF322A mRNA expression, multiple lung cancer cells were transfected with these indicated miRNAs mimics. We constructed 3′UTR luciferase reporter assay for all four miRNA candidates. Among them, miR-326 and miR-484 inhibited the ZNF322A wild-type 3′UTR luciferase activity, but the 3′UTR luciferase activity with the mutated seed regions of the corresponding microRNAs had no response to miR-326 or miR-484. Furthermore, expression of both ZNF322A mRNA and protein was attenuated by overexpressing of miR-326 mimics, but miR-484 inhibited ZNF322A expression only at the mRNA level, not protein level. Importantly, miR-326 suppressed proliferation and migration ability through inhibition of expression of ZNF322A and its downstream target genes CCND1 and ADD1 in lung cancer cells. Reconstitution experiments indicated that miR-326/ZNF322A/CCND1 was important for cell growth regulation while miR-326/ZNF322A/ADD1 was important for cell motility. Clinically, a trend of inverse correlation between miR-326 and ZNF322A mRNA expression was observed in lung cancer patients. Moreover, low ZNF322A/ high miR-326 (ZNF322A-L/miR326-H) profile showed better overall survival.
Conclusions: Our results reveal that miR-326/ZNF322A axis inhibits lung cancer progression by reducing CCND1 and ADD1 expression. Furthermore, our clinical studies suggest that low ZNF322A/ high miR-326 (ZNF322A-L/miR326-H) profile may be a potential prognosis biomarker for clinical application in the future.

Introduction	1
I.	Lung cancer
(A).	Epidemiology of lung cancer	1
(B).	Genetic alteration in lung cancer	1
II.	MicroRNAs (miRNAs) in cancer
(A).	Overview of miRNAs	2
(B).	miRNAs in lung cancer	2
(C).	Biomarkers and therapeutic strategies of miRNAs in cancer	3
(D).	miR-326 in cancer	4
(E).	miR-484 in cancer	4
III.	Transcription regulation of ZNF322A in lung cancer cells
(A).	Structure and function of ZNF322A	5	
(B).	ZNF322A in lung cancer progression	5	
IV.	The roles of centrosomal protein 170 (CEP170) and    protein O-mannose kinase (SGK196)
(A).	The function of CEP170	6	
(B).	The function of SGK196	7	
Study basis and specific aims	8
Materials and methods	10
I.	Cell lines and culture conditions	10
II.	miRNA target prediction software programs	10
III.	Transfection of plasmids and miRNA mimics	10
IV.	3′UTR reporter construct and site-directed mutagenesis	10 
V.	3′UTR reporter assay	11 
VI.	Dual luciferase promoter activity assay	11
VII.	RNA extraction and quantitative reverse transcriptase-polymerase 
chain reaction (RT-qPCR) assay	12
VIII.	TaqMan miRNA RT-qPCR assay	12
IX.	Protein extraction	12
X.	Western blot	13
XI.	Cell proliferation assay	13
XII.	Foci formation assay	14
XIII.	Transwell migration assay	14
XIV.	Tail vein injection metastasis assay in vivo	14
XV.	Clinical samples of lung cancer patients	15
XVI.	Statistical analysis	15
Results	16
I.	Identification of candidate miRNAs that may target on ZNF322A 3′UTR
(A).	The schematic diagram of candidate miRNAs selected from 
miRNA target prediction software	16
(B).	miR-326 and miR-484 inhibited the ZNF322A wild-type 3′UTR luciferase activity, but the 3′UTR with the mutated seed regions was not responding to the corresponding miRNAs	16
II.	miR-326 inhibited ZNF322A expression and cancer cell  proliferation and migration ability in vitro
(A).	miR-326 downregulated expression of ZNF322A mRNA and protein 	18
(B).	miR-326 attenuated lung cancer cell proliferation and 
migration ability in vitro	18
III.	miR-326/ZNF322A/cyclin D1 axis regulated lung cancer cell   growth in vitro 
(A).	miR-326 attenuated cyclin D1 (CCND1) mRNA and protein expression	19
(B).	miR-326 decreased CCND1 expression through ZNF322A  
transcriptional regulation in vitro	19
(C).	miR-326 suppressed cancer cell proliferation through miR-326/ZNF322A/CCND1 axis in vitro	20
IV.	miR-326/ZNF322A/alpha-adducin axis regulated            tumor metastasis of lung cancer
(A).	miR-326 decreased alpha-adducin (ADD1) expression       through ZNF322A transcriptional regulation in vitro	20
(B).	miR-326 attenuated lung cancer cell migration ability through miR-326/ZNF322A/ADD1 axis in vitro	21
(C).	miR-326 inhibited lung tumor metastasis through miR-326/ZNF322A/ADD1 axis in vivo	21
V.	miR-326 expression negative correlated with ZNF322A        mRNA level in lung cancer patients
(A).	miR-326 expression negative correlated with ZNF322A        mRNA level in lung cancer patients	22
(B).	The patients with low ZNF322A/ high miR-326 (ZNF322A-L/miR-326-H) expression profile showed the better overall survival than other patients	23
VI.	miR-484 negatively regulated ZNF322A mRNA expression
(A).	miR-484 downregulated ZNF322A mRNA without changing     the protein expression of ZNF322A	24
(B).	miR-484 did not inhibit mRNA expression of FBXW7α, the E3-ligase of ZNF322A	25
VII.	ZNF322A activated promoter activity of CEP170 and SGK196  genes
(A).	ZNF322A activated promoter activity of CEP170 and SGK196	25
(B).	ZNF322A transcriptionally activated expression of CEP170 gene,  but not SGK196 gene	26
Discussion	27
I.	Dysregulated miR-326/ZNF322A/CCND1 axis and miR-326/ZNF322A/ADD1 axis contribute to lung tumorigenesis	27
II.	Low ZNF322A/ high miR-326 (ZNF322A-L/miR326-H) profile may be selected as a potential prognosis biomarker	28
III.	miR-484 may inhibit other ZNF322A protein ubiquitination pathways in lung cancer	29
IV.	ZNF322A promoted CEP170 promoter activity and mRNA  expression, while ZNF322A promoted SGK196 promoter activity  but not the SGK196 mRNA expression	30
V.	Conclusion and perspectives	31
References	32
Tables	39
Figures	48
Appendix Figures	68
Appendix Tables	71
 
TABLE CONTENTS
Table 1.	The plasmids and their characteristics used in the         current study	40
Table 2.	The primers used in the current study	42
Table 3.	Antibodies and their reaction conditions used in the        current study	44
Table 4.	Alteration of ZNF322A mRNA and miR-326 expression        in relation to clinicopathological parameters in 120 lung     cancer patients’ samples	45
Table 5.	Cox regression analysis of risk factors for          cancer-related death in lung cancer patients	46


 
FIGURE CONTENTS
Figure 1.	The schematic diagram of candidate miRNAs selected from miRNA target prediction software	49
Figure 2.	miR-326 and miR-484 inhibited the ZNF322A wild-type  3′UTR luciferase activity, but the 3′UTR with the      mutated seed regions was not responding to the   corresponding miRNAs	51
Figure 3.	miR-326 downregulated expression of ZNF322A mRNA    and protein	53
Figure 4.	miR-326 attenuated lung cancer cell proliferation and  migration ability in vitro	54
Figure 5.	miR-326 attenuated CCND1 mRNA and protein expression	56
Figure 6.	miR-326 decreased CCND1 expression through ZNF322A transcriptional regulation in vitro	57
Figure 7.	miR-326 suppressed cancer cell proliferation through miR-326/ZNF322A/CCND1 axis in vitro	58
Figure 8.	miR-326 decreased ADD1 expression through ZNF322A transcriptional regulation in vitro	59
Figure 9.	miR-326 attenuated lung cancer cell migration ability   through miR-326/ZNF322A/ADD1 axis in vitro	60
Figure 10.	miR-326 inhibited lung tumor metastasis through miR-326/ZNF322A/ADD1 axis in vivo	61
Figure 11.	miR-326 expression negative correlated with ZNF322A  mRNA level in lung cancer patients	62
Figure 12.	miR-484 downregulated ZNF322A mRNA without changing  the protein expression of ZNF322A	64
Figure 13.	miR-484 did not inhibit mRNA expression of FBXW7α, the E3-ligase of ZNF322A	65
Figure 14.	ZNF322A enhanced promoter activity of CEP170 gene     and SGK196 gene	66
Figure 15.	The schematic model of miR-326/ZNF322A/CCND1 axis       and miR-326/ZNF322A/ADD1 axis in regulation of           lung tumor growth and metastasis	67
 
APPENDIX CONTENTS
Appendix Figure 1.	The biogenesis and function of miRNA	69
Appendix Figure 2. The experimental procedure of 3′UTR reporter    assay used in this study	70
Appendix Table 1. The well-known suppressor-miRNAs and  onco-miRNAs in lung cancer	72
Appendix Table 2. The downstream targets of miR-326 or miR-484      in lung cancer	74


                                    

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