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研究生:陳其欣
研究生(外文):Chen, Chi-Hsin
論文名稱:Oct4 轉錄調控網路參與肺癌進程之機制探討
論文名稱(外文):The Roles of Oct4 Mediated Transcription Network in Lung Tumorigenesis
指導教授:王憶卿
指導教授(外文):Wang, Yi-Ching
口試委員:孫孝芳洪建中陳炳焜
口試委員(外文):Hsiao-Fang SunJan-Jung HungBing-Kun Chen
口試日期:2013-07-16
學位類別:碩士
校院名稱:國立成功大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:英文
論文頁數:92
中文關鍵詞:Oct4癌幹細胞轉錄調控網路肺癌PTENDKK3TNCSp1
外文關鍵詞:Oct4cancer stem cellstranscription networklung cancerPTENDKK3TNCSp1
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研究背景: 轉錄因子 Oct4 已知在人類胚胎幹細胞的細胞多能性(pluripotency) 調控中扮演主要角色。目前癌症相關研究結果顯示 Oct4 可能參與癌症進展過程,但針對其在癌症中所調控的轉錄機制目前尚未有更進一步的探討。
研究目的: 本研究旨在透過辨識 Oct4 在肺癌中轉錄調控的基因群,並進一步觀察基因表現調控異常時所導致的肺癌惡化情形,以及鑑定協同 Oct4 進行轉錄調控的其他轉錄因子,來探討 Oct4 在肺癌中所扮演的角色。
研究結果: 利用免疫組織染色的實驗,我們在肺癌病人中檢測 Oct4 蛋白的表現程度,共有67.3% (66/98) 的病人有 Oct4 高表達的情形,且 Oct4 高度表達與病人不良預後有顯著相關性 (P=0.035)。穩定高度表現 Oct4 的肺癌細胞具有高度自我再生、增殖、轉移的能力,並對癌症化療藥物具有抗藥性。藉由全面性的基因chromatin-immunoprecipitation-sequencing (ChIP-seq) 檢測,我們辨識出 Oct4 結合位置以及可能為 Oct4 轉錄調控的基因。透過定量反轉錄 PCR (qRT-PCR) 實驗驗證 29個基因發現,Oct4 會透過轉錄調控使抑癌基因 (PTEN、DKK3) 表現量下降,致癌基因 (TNC) 表現量上升。進一步實驗結果顯示,Oct4 可能透過抑制DKK3,一個Wnt 訊息路徑傳遞 antagonist 的表現來促進細胞增生。穩定高度表現 Oct4 的肺癌細胞所具有的高轉移能力也被證實或許是透過 Oct4 使調控細胞附著力的 TNC 表現量上升所導致。先前研究已發現 PTEN 表現與抗藥性有關,而在我們的研究中也證實 Oct4 所抑制的 PTEN 表現會引發細胞對於 SAHA和cisplatin 的抗藥性;但 SAHA和cisplatin 與 PI3K 抑制劑LY294002 的合併用藥則可以有效降低抗藥性。我們另外也發現,臨床病人中 PTEN 蛋白表現與 Oct4 存在負相關性 (P=0.006),且高度表現 Oct4同時低表現 PTEN 的病人和其他病人相較之下會有較差的存活率 (P=0.049)。透過 PROMO 軟體預測,我們發現在 PTEN、DKK3 以及 TNC 的基因上游 promoter 位置皆具有Sp1 轉錄因子的 DNA 結合序列,並鄰近於Oct4的 DNA 結合序列。利用siRNA剔除Sp1表現後,PTEN、DKK3 以及 TNC mRNA的表現量皆有上升的現象,顯示 Sp1 會抑制此三個基因的表現。Imuunoprecipitation-Western 實驗結果顯示 Oct4 會和 Sp1 及 HDAC1/2 形成複合體,而 DNA affinity precipitation assay 結果則顯示Oct4 需透過 Sp1蛋白質結合到 PTEN 的 promoter 位置,而相反地Oct4可以獨立結合到TNC promoter。我們從以上結果推測,Oct4 會透過和其他轉錄因子的不同結合組態,進行下游基因的差異性轉錄調控 (differential transcription regulation)。
結論:我們的研究結果顯示,Oct4 是肺癌中重要的致癌轉錄因子,可以協同其他轉錄因子調控許多與肺癌進展相關的基因表現,包括細胞增生、轉移,與產生抗藥性的相關基因,來促使肺癌的惡化。
Background: Transcription factor Oct4 is critical in pluripotency regulation of human embryonic stem cells. Recent studies suggest Oct4 involvement in somatic cancer. However, the precise transcriptional control in tumorigenesis remains unclear.
Purpose: We aim to elucidate the roles of Oct4 in lung cancer by first identifying the interacting partners and transcriptional downstream targets of Oct4, then correlating Oct4 transcriptional regulation with tumorigenesis events involving Oct4 target genes.
Results: Clinical studies showed high Oct4 protein expression in 67.3% (66/98) lung cancer patients, which correlated with poor prognosis (P=0.035). Oct4 stably overexpressed lung cancer cells showed increased self-renewal properties, proliferation, migration, and drug-resistance to anticancer agents. Oct4 binding sites and putative transcriptional targets were identified via genome-wide chromatin- immunoprecipitation-sequencing (ChIP-seq) analysis of Oct4 stably overexpressed lung cancer cell lines. Validation of 29 putative target genes by quantitative reverse transcription-PCR showed that Oct4 downregulated tumor suppressor genes (PTEN, DKK3), and induced expression of oncogenes (TNC). Further investigations suggested that Oct4 may induce cell proliferation through downregulation of DKK3, a Wnt-signaling pathway antagonist. Increased cell invasiveness in Oct4 overexpressed cells partly resulted from Oct4-mediated upregulation of TNC, an adhesion-modulating extracellular matrix molecule. In addition to the previous studies associating PTEN and drug-resistance, we discovered a new mechanism that Oct4-mediated downregulation of PTEN resulted in drug resistance to SAHA and cisplatin, which could be diminished after co-treatment with LY294002, a PI3K inhibitor. Moreover, clinical PTEN protein expression had an inverse correlation with Oct4 (P=0.006), and patients with Oct4 overexpression and PTEN low expression had poor prognosis (P=0.049). Notably, we found the transcription factor Sp1 binding motifs are adjacent to the Oct4 binding sites in PTEN, DKK3 and TNC promoter regions, suggesting that Oct4 and Sp1 cooperatively regulate transcription of these promoters. Knockdown of Sp1 increased PTEN, DKK3 and TNC mRNA expressions, indicating a transcriptionally suppressive role for Sp1 in all three genes. In addition, immunoprecipitation-Western assay confirmed that Oct4, Sp1, HDAC1 and HDAC2 formed a complex in Oct4 stable cells. DNA affinity precipitation assay indicated that Oct4 bound to PTEN promoter in a Sp1-dependent manner, while Oct4 bound to TNC promoter independently of Sp1. These results suggested that distinct interactions between Oct4 and other transcription regulators may lead to differential transcription control on target genes.
Conclusion: Our results suggest Oct4 to be an important oncogenic transcription factor that cooperates with other transcription factors or cofactors in regulating expressions of critical genes promoting lung tumorigenesis events such as cell proliferation, invasion and drug-resistance.
Introduction 1
I. Lung cancer
(A). Lung cancer in Taiwan and worldwide 1
(B). Survival and recurrence of lung cancer patients 1
II. Cancer stem cells (CSCs)
(A). Overview of CSCs 1
(B). CSCs in lung cancer 2
III. Transcription factor Oct4 in cancer progression
(A). Oct4 maintains pluripotency in embryonic stem cells 2
(B). Transcription regulatory functions of Oct4 3
(C). Discovery of oncogenic roles for Oct4 3
(D). Oct4 in lung cancer 4
IV. PTEN (phosphatase and tensin homolog) and drug resistance
(A). Tumor suppressive roles of PTEN 4
(B). PTEN regulates signaling pathways involved in drug-resistance 5
V. DKK3 (Dickkopf-related protein 3) in regulation of cell proliferation
(A). DKK3 as a Wnt-signaling pathway antagonist 5
(B). Expression of DKK3 inhibits cell proliferation 6
VI. TNC (Tenascin C) involvements in cancer metastasis
(A). TNC is an adhesion-modulating extracellular matrix (ECM) protein 6
(B). TNC plays a crucial role during cancer metastasis initiation 6

Study basis and specific aims 8
I. Identification of Oct4 transcription network 8
II. Investigation of the role of Oct4 and its downstream target genes in lung cancer progression 9
III. Interrogation of the interplay between Oct4 and other transcriptional regulators contributes to differential transcriptional regulation of Oct4 target genes 9

Materials and Methods 10
I. Materials 10
(A). Clinical samples of lung cancer patients 10
(B). Cell lines 10
(C). Animal strains 10
(D). Plasmids and RNAi 11
(E). Chemotherapeutic compounds 11
II. Methods 11
(A). Immunohistochemistry (IHC) assay 11
(B). Cell culture 11
(C). Plasmid, RNAi transcription 12
(D). Sphere formation assay 12
(E). Anchorage-independent colony formation assay and
foci formation assay 12
(F). Transwell migration and invasion assay 13
(G). Cell cytotoxicity assay/MTT assay 13
(H). Chromatin-immunoprecipitation-sequencing (ChIP-seq) assay 14
(I). Quantitative ChIP-PCR assay 16
(J). RNA extraction and quantitative reverse-transcriptase PCR
(qRT-PCR) assays 16
(K). Western blot analysis 17
(L). Immunoprecipitation assay 17
(M). Luciferase Promoter assay 18
(N). Xenograft growth and inhibition assays 18
(O). Immunocytochemistry (ICC) assay 19
(P). DNA affinity precipitation assay (DAPA) 19
(Q). MEME and STAMP analysis 20
(R). Statistical analysis 20

Results 21
I. Oct4 expression in association with lung tumorigenesis
(A). Oct4 protein expression is high in lung cancer patients and correlates with poor prognosis 21
(B). Oct4 expression induces cancer stem cell-like properties in lung cancer cell 21
II. Oct4 regulated transcription network in lung cancer
(A). Putative Oct4 target genes are identified through a genome-wide study 23
(B). Putative Oct4 target genes are involved in tumorigenesis processes 24
(C). Oct4 downregulates tumor-suppressor (TSG)-like genes and upregulates oncogene-like genes 24
III. Oct4 deregulation of transcription network induces cancer stem cell-like properties in lung cancer cell line
(A). Oct4 induces drug-resistance by activating Akt signaling pathway through downregulation of PTEN 25
(B). PTEN protein expression inversely correlates with Oct4 protein expression in lung cancer patients 27
(C). Oct4 induces cell proliferation abilities by repression of DKK3 27
(D). Oct4 induces cell invasion abilities by activation of TNC 28
IV. Interplay between Oct4 and other transcriptional regulators contributes to differential transcriptional regulation of Oct4 target genes
(A). Sp1 binding sites are found in promoter of Oct4 target genes 29
(B). Oct4 forms protein complex with Sp1 and HDAC1/2 30
(C). Differential binding of Oct4 and Sp1 on the promoter of Oct4 target genes 30
(D). Oct4 negatively regulates PTEN promoter together with Sp1 and HDAC1/2 31
(E). Oct4 positively regulates TNC promoter activity 32

Discussion 33
I. Oct4-centered transcription network promotes lung tumorigenesis 34
II. Oct4-mediated transcriptional downregulation of PTEN results in drug-resistance in lung cancer cells 35
III. Oct4 transcriptional target genes are implicated in maintaining CSC-like properties 36
IV. Oct4 regulates downstream target genes in cooperation with Sp1 37
V. Conclusions and perspectives 39

References 40

Tables 51

Figures 69

TABLE CONTENTS
Table 1. siRNA sequences used in the current study 52
Table 2. The plasmids and their characteristics used in the current study 53
Table 3. The primers used in the current study 54
Table 4. The antibodies and their reaction condition used in the current study 60
Table 5. The DAPA probes used in the current study 62
Table 6. Alteration of Oct4 protein expression level in relation to clinicopathological parameters in 98 NSCLC patients 63
Table 7. The Oct4 target genes 65

FIGURE CONTENTS
Figure 1. Oct4 protein is upregulated in lung cancer patients and shows a significant correlation with poor survival 70
Figure 2. Overexpression of Oct4 induces CSCs properties of lung cancer cells 72
Figure 3. Knockdown of Oct4 reduces proliferation and cell motility of lung cancer cells 74
Figure 4. Genome-wide search for Oct4 binding regions 76
Figure 5. qChIP-PCR validation of ChIP-seq results 78
Figure 6. qRT-PCR validation of ChIP-seq results 79
Figure 7. Oct4 induces drug-resistance through downregulation of PTEN 81
Figure 8. Targeting Oct4-mediated PI3K/AKT signaling pathway reduces drug-resistance in animal model 83
Figure 9. Oct4 induces cell proliferation through DKK3 repression 85
Figure 10. Oct4 enhances cell invasiveness through upregulation of TNC 86
Figure 11. Prediction of binding sites for transcription factors on the promoter region of Oct4 target genes 88
Figure 12. Oct4 forms protein complex with Sp1 and HDAC1/2 89
Figure 13. Oct4 partners with Sp1 to regulate of Oct4 target genes 90
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