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研究生：	吳莉婷 Wu, Li-Ting
論文名稱：	肺癌細胞中過量表達的ZNF322A促使腫瘤血管新生 Overexpression of ZNF322A in lung cancer cells promotes neo-angiogenesis
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：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	67
中文關鍵詞：	肺癌、ZNF322A 、音蝟因子(Sonic hedgehog) 、腫瘤血管新生
外文關鍵詞：	Lung cancer, ZNF322A, sonic hedgehog, angiogenesis.
相關次數：	點閱：86 下載：2
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研究背景: 文獻研究指出癌症細胞與周圍細胞會相互溝通進一步促進癌症進程。本研究室過去發現致癌性鋅指蛋白 (zinc finger protein) ZNF322A會藉由轉錄層次調控癌症相關基因導致肺癌惡化；而先前本研究室以ZNF322A為主的基因體染色質免疫沉澱測序 (chromatin immunoprecipitation-sequencing) 及全核糖核酸測序 (RNA-seqencing) 資料庫的細胞路徑分析 (pathway analyses)，發現許多ZNF322A下游基因參與血管新生 (angiogenesis) 路徑，暗示著ZNF322A也許會參與腫瘤血管生成，進而促使肺癌進程。
研究目的: 本研究旨在探討以肺癌細胞及動物模式中過度表現的致癌蛋白ZNF322A參與調控腫瘤血管新生之機制及其轉錄目標基因，並以肺癌病人檢體研究闡明肺癌細胞與內皮細胞在腫瘤微環境的交互作用。
研究結果: 大量表達ZNF322A於肺癌細胞，會促使共同培養之人類臍帶血管內皮細胞 (human umblical vein endothelail cell, HUVEC) 遷移 (migration) 及管狀形成 (tube formation)。我們利用冷光啟動子分析 (luciferase promoter activity)、染色質免疫沉澱-即時聚合酶連鎖反應 (ChIP-qPCR)、即時逆轉錄聚合酶連鎖反應 (qRT-PCR) 及西方墨點法 (Western blot)，發現ZNF322A透過正向調控音蝟因子 (Sonic hedgehog, Shh) 基因啟動子區域進而促進Shh表現；然而，若降低Shh表現則可抑制由ZNF322A促進的HUVEC遷移及管狀形成的現象。在動物實驗中，我們利用Matrigel plug angiogenesis assay發現若抑制肺癌細胞中Shh表現會減少由ZNF322A所促使之in vivo 血管新生現象，證明ZNF322A-Shh路徑確實有促腫瘤血管新生的作用。在臨床檢體研究，我們透過免疫組織染色化學法發現ZNF322A、Shh及代表血管新生的標記 CD31的表現在肺癌病人中具有正相關，其中ZNF322A與CD31同時高表現的病人有明顯較差的預後 (prognosis)。
結論: 我們的細胞及動物研究提出了ZNF322A參與在肺癌形成中促腫瘤血管新生的角色，其機制是因ZNF322A透過正向調控Shh啟動子區域進而促進其表現以導致腫瘤血管新生，肺癌病人癌組織中ZNF322A與CD31同時高表現可作為獨立預後危險預測因子。

Background: Accumulating evidence indicates that the crosstalks between cancer cells and surrounding cells (tumor associated cells) contribute to tumor progression. Our lab previously identified a novel oncogenic zinc finger transcription factor ZNF322A, which promotes lung tumorigenesis through transcriptionally dysregulating expression of cancer-related genes. Notably, pathway analysis of ZNF322A downstream genes identified by our genome-wide chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing datasets showed a significant enrichment in angiogenesis, implicating that ZNF322A may participate in neo-angiogenesis to promote lung cancer progression.
Purpose: This study aims to investigate whether ZNF322A involves in angiogenesis and to reveal the underlying mechanism of angiogenesis promotion mediated by ZNF322A overexpression in lung cancer cells and animal models. In addition, the interplay between lung cancer cells and endothelial cells will be elucidated in clinical study.
Results: Our conditioned medium culture data showed that overexpression of ZNF322A in lung cancer cells promoted HUVEC (human umbilical vein endothelial cell) migration and tube formation abilities. Among the ZNF322A potential transcriptional targets in angiogenesis pathway, we validated that ZNF322A upregulated the expression of sonic hedgehog (Shh) through targeting to its promoter region by luciferase promoter assay, ChIP-qPCR, quantitative reverse transcriptase-PCR and Western blot assays. Reconstitution experiments by knocking down of Shh in ZNF322A expressing cancer cells indeed decreased ZNF322A-promoted HUVEC migration and tube formation abilities. Furthermore, knockdown of Shh in lung cancer cells attenuated ZNF322A-promoted in vivo angiogenesis by Matrigel plug angiogenesis assay. These cell and xenograft data confirmed the ZNF322A-Shh signaling axis in angiogenesis. Clinically, ZNF322A protein expression positively correlated with Shh and CD31, an endothelial cell marker, in 133 lung cancer patients using immunohistochemistry analysis. Notably, patients with concordantly high expression of ZNF322A and CD31 correlated with poor prognosis.
Conclusions: Our study provides cell, animal and clinical evidences of pro-angiogeneic role of ZNF322A in lung cancer. ZNF322A transcriptionally upregulates Shh expression through targeting to its promoter region and thus induces angiogenesis. ZNF322Ahigh/CD31high expression profile is a prognostic biomarker for lung cancer.

Introduction	1
I.	Lung cancer
(A).	Epidemiology of lung cancer	1
(B).	Genetic alteration in lung cancer	1
II.	Neo-angiogenesis
(A).	Angiogenesis	2
(B).	Angiogenesis signaling in cancer	3
III.	Sonic hedgehog (Shh) in cancers 
(A).	Biogenesis and regulation of hedgehog genes	3
(B).	The role of Shh in cancer progression	4
(C).	The transcriptional regulation of Shh signal components 
in cancer	5
IV.	Transcription regulation of ZNF322A in lung cancer cells
(A).	Discovery of ZNF322A (Zinc finger protein 322A)	6
(B).	ZNF322A in lung cancer progression	6	
Study basis and specific aims	8
Materials and methods	10
I.	Cell lines and culture conditions	10 
II.	Transfection of plasmids and RNAi	10 
III.	RNA extraction and quantitative reverse transcriptase-            polymerase chain reaction (qRT-PCR) assays	10
IV.	Protein extraction and Western blot	11
V.	Conditioned medium preparation	11
VI.	Tube formation assay	12
VII.	Transwell migration assay	12
VIII.	Chromatin immunoprecipitation (ChIP) assay	13
IX.	Dual luciferase promoter activity assay	13
X.	Site-directed mutagenesis	13
XI.	Immunohistochemistry (IHC)	14
XII.	Clinical samples of lung cancer patients	15
XIII.	In vivo Matrigel plug angiogenesis assay	15
XIV.	Statistical analysis	15
Results	17
I.	ZNF322A promoted angiogenesis
(A).	ZNF322A regulated angiogenic genes expression	17
(B).	Overexpression of ZNF322A in lung cancer cells induced 
migration of human umbilical vein endothelial cells (HUVEC)	18
(C).	Overexpression of ZNF322A in lung cancer cells promoted 
tube formation ability	18
(D).	Tumor xenograft of ZNF322A overexpressing lung cancer 
cells showed an increase of CD31 staining	19
II.	ZNF322A upregulated angiogenic genes expression
(A).	ZNF322A promoted Shh expression	19
(B).	ZNF322A upregulated the expression of Shh through binding 
onto Shh promoter to enhance its promoter activity	20
III.	Reconstitution experiments revealed that Shh acted as a downstream effector of ZNF322A to promote angiogenesis
(A)	Reconstitution experiments showed that Shh is downstream of ZNF322A-mediated gene expression	20
(B)	Reconstitution experiments showed that inhibition of Shh 
decreased HUVEC migration and tube formation mediated by 
ZNF322A	21
(C)	In vivo Matrigel plug experiments revealed that inhibition of     Shh decreased in vivo angiogenesis promoted by ZNF322A 	------21
IV.	Positive correlations of ZNF322A, Shh and CD31 in lung cancer 
patients whose prognosis was poor
(A).	Positive correlations of ZNF322A, Shh, CD31 expression
in lung cancer patients	22
(B).	ZNF322Ahigh/Shhhigh/CD31high in lung cancer patients were 
associated with patient poor overall survival and    progression-free survival	23
Discussion	25
References	30
Tables	39
Figures	45
Appendix Figures and Table	62
 
TABLE CONTENTS
Table 1.	The plasmids and their characteristics used in the         current study -----------------	40
Table 2.	The primers used in the current study ---------	41
Table 3.	Antibodies and their reaction conditions used in the         current study	42
Table 4.	ZNF322A protein expression levels in relation to         clinicopathological parameters in 133 lung cancer patients	43
Table 5.	Cox regression analysis of risk factors for cancer-related 
death in lung ancer patients	44
 
FIGURE CONTENTS
Figure 1.	Gene ontology analysis of ZNF322A-mediated transcriptome 
revealed the novel role of ZNF322A angiogenesis-----------------	46
Figure 2.	Overexpression of ZNF322A in lung cancer cells promoted 
	HUVEC migration------------------------------------------------------	47
Figure 3.	Overexpression of ZNF322A in lung cancer cells promoted 
		HUVEC tube formation	49
Figure 4.	CD31 angiogenesis marker and Shh staining by IHC in tumor xenograft of H460 lung cancer cells	51
Figure 5.	ZNF322A overexpression in lung cancer cells enhanced       the expression of angiogenesis factor Shh at RNA and      protein level	52
Figure 6.	ZNF322A transcriptional activation of Shh promoter 	53
Figure 7.	Reconstitution experiments showed that angiogenesis factor    Shh acted as the downstream factor of ZNF322A in          lung cancer cells	54
Figure 8.	Knockdown of Shh in lung cancer cells inhibited ZNF322A-promoted HUVECs migration ability	55
Figure 9.	Knockdown of Shh in lung cancer cells inhibited ZNF322A-promoted HUVECs tube formation ability	57


Figure 10.	Knockdown of Shh in lung cancer cells inhibited angiogenesis   by ZNF322A promotion using in vivo Matigel plug   angiogenesis assay	58
Figure 11.	Expression of ZNF322A, Shh, and CD31 showed positive correlations in lung cancer patients	59
Figure 12.	Lung cancer patients with ZNF322Ahigh/Shhhigh/CD31high expression profile were associated with poor overall survival   and progression-free survival 	60
Figure 13.	Model of ZNF322A-mediated neo-angiogenesis promotion via transcriptional upregulation of Shh expression	61
 
APPENDIX CONTENTS
Appendix Figure 1. Production and secretion of Shh--------------------------63
Appendix Figure 2. Canonical and non-canonical Shh signaling
pathways interaction in different cell types	------------65
Appendix Figure 3.	The putatively binding sequences of ZNF322A 
in Shh promoter region------------------------------------66
Appendix Table 1.	The inhibitors of targeting the sonic hedgehog  signaling pathway------------------------------------------67
                                    

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