探討14-3-3ε調控第一型金屬硫蛋白Metallothionein-1 在肝癌腫瘤進展中所扮演之角色

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研究生：	吳怡儒 Wu, Yi-Ju
論文名稱：	探討14-3-3ε調控第一型金屬硫蛋白Metallothionein-1 在肝癌腫瘤進展中所扮演之角色 The Roles of 14-3-3ε-regulated Metallothionein-1 in Tumor Progression of Hepatocellular Carcinoma
指導教授：	劉俊揚 Liou, Jun-Yang 陳令儀 Chen, Linyi
口試委員:	王慧菁 Wang, Hui-Ching 陳盛良 Chen, Shen-Liang 郭呈欽 Kuo, Cheng-Chin
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	118
中文關鍵詞：	肝細胞癌、第一型金屬硫蛋白、醛酮還原酶家族、吡咯烷二硫代氨基甲、表觀遺傳
外文關鍵詞：	14-3-3ε, AKR1B10, Metallothionein-1, PDTC, ZNF479, DNMT1, ASH2L
相關次數：	點閱：1 下載：0
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肝細胞癌 (Hepatocellular carcinoma, HCC) 為肝癌中最常見之種類，多發於亞洲及非洲肝癌患者，常與病患是否感染B型肝炎病毒 (HBV) 或 C型肝炎病毒 (HCV) 有高度關聯。近年來由於醫學的進步，許多肝癌腫瘤雖可經由手術切除及化療獲得控制，但是仍有部分患者於術後或治療後復發並轉移，因此研發診斷腫瘤的生物標記對於患者預後的治療策略有相當重要的益處。
14-3-3ε屬於14-3-3家族之一，功能上作為螯合蛋白與目標蛋白結合，進而改變目標蛋白磷酸化及結構，調控細胞代謝、訊息傳遞及細胞週期。從過去的研究顯示，在肝細胞癌腫瘤中偵測到過度表現14-3-3ε的病患，具有較低存活率及較高轉移風險。為了更進一步了解14-3-3ε如何誘導肝癌腫瘤惡化的發生，並探討下游潛在的調控分子，我們透過DNA微陣列分析研究基因表現圖譜；我們發現第一型金屬硫蛋白 (Metallothionein-1, MT-1) 及醛酮還原酶家族 (aldo-keto reductase family 1 member B10, AKR1B10) 受到14-3-3ε所調控。在本研究中，我們證明第一型金屬硫蛋白可受到14-3-3ε的調控，並且大量表現第一型金屬硫蛋白可抑制被14-3-3ε所誘導的細胞及腫瘤生長。14-3-3ε透過MEK-ERK、mTOR及PI3K/AKT訊息傳遞途徑抑制第一型金屬硫蛋白的表現;在肝細胞癌中表現第一型金屬硫蛋白顯著抑制由14-3-3ε所調控的細胞及腫瘤生長。此外，吡咯烷二硫代氨基甲 (pyrrolidine dithiocarbamate, PDTC) 可經由非NFκB途徑顯著地提高第一型金屬硫蛋白表現量，並減少由14-3-3ε所誘導的腫瘤生長。
除此之外，我們發現在14-3-3ε調控第一型金屬硫蛋白的途徑間存在一個具有調控表觀遺傳 (epigenetic regulatory) 潛力的轉錄因子ZNF479。ZNF479結構中帶有KRAB結構域 (Krüppel associated box, KRAB)，我們證明ZNF479對細胞生長、轉移和腫瘤生長具有顯著影響。ZNF479經由誘導DNA甲基化蛋白 (DNMT1和UHRF1) 與MLL融合蛋白 (ASH2L和Menin)，調控組蛋白H3在離胺酸的甲基化(H3K4)。透過抑制DNMT1與ASH2L的表現，皆可以回復由ZNF479所抑制的第一型金屬硫蛋白表現量。
除此之外，我們證明了14-3-3ε可經由活化β-catenin調控AKR1B10之表現，進而誘導細胞生長及轉移。由於AKR1B10具有抗氧化能力，並於臨床上觀察到在肝細胞癌腫瘤中表現量顯著提高；經由實驗結果顯示，抑制AKR1B10的表現能夠阻斷14-3-3ε促進細胞及腫瘤的生長能力。我們也發現AKR1B10透過提高Vimentin與Snail的表現量來調節細胞轉移的能力。
本研究數據顯示，透過研究14-3-3ε對肝癌的調控機制，β-catenin/AKR1B10與ZNF479/MT-1對表觀遺傳因子的調控方式可能是治療該細胞癌的潛在策略。

Liver cancer is one of the major prevalent malignancies in the areas of Africa and Southeast Asia. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the occurrence of HCC is highly correlated with the incidence of hepatitis B or C virus infection. Some HCC patients with operable tumors receive high risk of recurrence and metastasis although the overall survival and clinical outcome are significantly improved by progressively therapeutic treatment. Thus, to identify the prognostic biomarkers will be of great benefit for developing therapeutic strategy to improve the outcomes of HCC patients. We have previously reported that 14-3-3ε is overexpressed in HCC and its expression is associated with poor survival outcome and higher metastasis risk. Moreover, we have found that 14-3-3ε overexpression promotes in vitro cell proliferation, migration, epithelial-mesenchymal transition (EMT) and in vivo tumor growth of HCC. To investigate the potential downstream effectors of 14-3-3ε in regulating HCC progression, we have examined the gene expression profile by microarray analysis.
We have identified that aldo-keto reductase family 1 member B10 (AKR1B10) and metallothionein-1 (MT-1) are potentially regulated by 14-3-3ε in HCC. Here, we have demonstrated that MT-1 expression is downregulated by 14-3-3ε, and overexpression of MT-1 abrogated 14-3-3ε-induced cell proliferation and tumor growth. Results from treatment with pharmacological inhibitors reveal that 14-3-3ε-suppressed MT-1 expression is mediated by activation of MEK-ERK, mTOR and PI3K/AKT signaling. Intriguingly, treatment with pyrrolidine dithiocarbamate (PDTC) abundantly stimulated MT-1 by an NFκB independent mechanism and significantly reduced 14-3-3ε-induced tumor growth.
Furthermore, we have identified ZNF479, a potential transcription regulator with Krüppel associated box (KRAB) domain is involved in the regulation of 14-3-3ε-suppressed MT-1. ZNF479 induced the expression of DNA methyltransferase 1 (DNMT1), ubiquitin-like with PHD and ring finger domains 1 (UHRF1), mixed-lineage leukemia (MLL) complex proteins ASH2 like histone lysine methyltransferase complex subunit (ASH2L) and Menin, as well as tri-methylation of histone H3 at lysine 4 (H3K4me3), but suppressed di-methylation of H3K4 (H3K4me2). The ZNF479-suppressed MT-1 expression was restored by siRNA silencing of ASH2L and DNMT1. Thus, our study defines ZNF479 as a potential epigenetic regulator of MT-1 expression by regulating MLL complex components, DNMT1 and UHRF1 in HCC.
Moreover, we demonstrated that AKR1B10 is upregulated by 14-3-3ε and β-catenin signaling. AKR1B10 possesses the antioxidant activity and is considered to be upregulated in the early progression of HCC. Our results indicated that depletion of AKR1B10 abolished 14-3-3ε-induced cell proliferation and tumor growth. We also found that AKR1B10 regulates EMT process through upregulating expression of vimentin and snail.
Finally, we have confirmed that ZNF479 contributes to the regulation of HCC cell proliferation, migration and EMT as well as tumor growth. Taken together, our data show for the first time that 14-3-3ε downregulates MT-1 via inducing MT-1 upregulates expression via inducing ZNF479 expression and AKR1B10 expression is mediated by activating β-catenin signaling. Therefore, approaches targeting the machinery of 14-3-3ε, ZNF479/MT-1, β-catenin/AKR1B10or related factors of epigenetic regulation might be potential therapeutic strategies for HCC.

LIST OF CONTENTS

Publication List    i
ABSTRACT    ii
中文摘要    iv
致謝    vi
LIST OF CONTENTS    1
LIST OF TABLES    3
LIST OF FIGURES    4
ABBREVIATION    6
CHAPTER Ⅰ: Introduction    9
Hepatocellular carcinoma (HCC)    10
14-3-3 proteins    10
Metallothionein (MT)    12
The regulation of MT-1    13
Zinc finger protein, ZNF479    13
Aldo-keto-reductase family 1 member B10 (AKR1B10)    14
Figures and Tables    16
CHAPTER Ⅱ: Materials and Methods    25
Cell culture and reagents    26
Plasmid constructs, siRNAs and transfection    26
Western blot analysis    27
Quantitative real-time RT-PCR (qPCR)    27
Microarray analysis    28
Cell viability assay    28
Anchorage-independent growth assay    28
Tumor xenograft experiments    28
Small-hairpin RNA (shRNA) xenograft experiment    29
Migration and invasion assay    30
Immunofluorescence confocal microscopy    30
Statistical analysis for clinical pathology    30
Promoter methylation analysis    31
Public domain data    31
Statistical analysis    32
Tables    33
CHAPTER Ⅲ: ZNF479 contributes to 14-3-3ε-regulated metallothionein-1 through ASH2L and DNMT1 in hepatocellular carcinoma    41
Ⅲ-1. Rationale    42
Ⅲ-2. Result    43
Ⅲ-3. Discussion    48
Ⅲ-4. Figure    54
CHAPTER Ⅳ: 14-3-3ε regulates aldo-keto-reductase family 1 B10 and its impact on the prognostic of hepatocellular carcinoma    91
Ⅳ-1. Rationale    92
Ⅳ-2. Result    92
Ⅳ-3. Discussion    94
Ⅳ-4. Figure    97
CHAPTER Ⅴ: Conclusion    100
Appendix    103
Reference    105

 
LIST OF TABLES

Table I- 1 Studies related to 14-3-3 proteins in HCC.    23
Table I- 2 The expression level of MT-1 and 2 in tumors (as compared with adjacent healthy tissue).    24
Table II- 1 The pharmacological inhibitors used in this study.    33
Table II- 2 Primer sequences for the constructs and oligonucleotides synthesis.    34
Table II- 3 Sequences of siRNA used in this study.    35
Table II- 4 Antibodies used in this study.    36
Table II- 5 Primer sequences for Q-PCR used in this study.    37
Table II- 6 Sequences of the shRNAs used in the study.    38
Table II- 7 Primer sequences for DNA methylation sequencing in this study.    39
Table II- 8 Primer sequences for MSP analysis in this study.    40
Table III- 1 Gene expression profile in microarray analysis.    89
Table III- 2 Expression levels of ZNF479, DNMT1, UHRF1, ASH2L, Menin, MT-1M, MT-1G and MT-1H in HCC by Oncomine database analysis    90



 
LIST OF FIGURES

Figure I- 1 The incidence of liver cancer in the world.    16
Figure I- 2 The occurrence of cancer types in Asia.    17
Figure I- 3 The functions of 14-3-3 proteins in cells.    18
Figure I- 4 The regulation and function of MT gene.    19
Figure I- 5 The prediction of structural domains in ZNF479.    20
Figure I- 6 The epigenetic regulation compounds of the KRAB domain-containing zinc finger protein.    21
Figure I- 7 The catalytic reaction of AKR family in vitamin A metabolism.    22
Figure III- 1 The MT-1 expression level in 14-3-3ε-overexpressed HCC cells.    54
Figure III- 2 Silence of 14-3-3ε in the 14-3-3ε cells affected MT-1 expression.    55
Figure III- 3 The MT-1 expression in overexpression of difopein.    56
Figure III- 4 The cell proliferation effect of MT-1 in 14-3-3ε cells.    57
Figure III- 5 The xenograft mice model in overexpression of 14-3-3ε and MT-1M.    58
Figure III- 6 The expression of MT-1 in 14-3-3ε cells treated with pharmacological inhibitors.    59
Figure III- 7 The cell proliferation effect of U0126, rapamycin and wortmannin in 14-3-3ε cells.    60
Figure III- 8 The MT-1 expression in PDTC-treated 14-3-3ε cells.    61
Figure III- 9 The MT-1 expression in knockdown of p65 and PDTC treatment.    62
Figure III- 10 The tumor xenograft model of 14-3-3ε cells in PDTC treatment.    63
Figure III- 11 The expression of ZNF479 in human tissues.    64
Figure III- 12 The ZNF479 expression in the overexpression of 14-3-3ε and PDTC treatment.    65
Figure III- 13 The MT-1 expression in knockdown of ZNF479.    66
Figure III- 14 The cell proliferation effect of ZNF479.    67
Figure III- 15 The EMT markers and cell migration effect of ZNF479.    68
Figure III- 16 The EMT effect of MT-1.    69
Figure III- 17 The tumor xenograft model in silence of ZNF479 by siRNA.    70
Figure III- 18 The tumor xenograft model in silence of ZNF479 by shRNA.    71
Figure III- 19 Expression of markers of histone modification by 14-3-3ε and ZNF479.    72
Figure III- 20 The effect of ASH2L expression in ZNF479.    73
Figure III- 21 The effect of Menin expression in ZNF479.    74
Figure III- 22 The effect of DNMT1 expression in ZNF479.    75
Figure III- 23 The effect of UHRF1 expression in ZNF479.    76
Figure III- 24 Result of bisulfite DNA sequencing analysis of the MT-1M promoter.    77
Figure III- 25 Result of bisulfite DNA sequencing analysis of the MT-1H promoter.    78
Figure III- 26 The MSP analysis of MT-1 gene.    79
Figure III- 27 The gene expression profile of PDTC treatment in the xenograft mice model.    80
Figure III- 28 mRNA expression of ZNF479 and MT-1M in human tissue cDNA array.    81
Figure III- 29 The transcript levels of the gene in this study in HCC cohorts.    82
Figure III- 30 Protein expression in overexpression of ZNF479 siRNA in HepG2 cells.    86
Figure III- 31 Gene expression in HCC cell lines.    87
Figure III- 32 Model of ZNF479 involved in the 14-3-3ε-suppressed MT-1 expression by activating ASH2L/Menin and DNMT1/UHRF1 in HCC.    88
Figure IV- 1 14-3-3ε regulated AKR1B10 through activating β-catenin.    98
Figure IV- 2 The EMT markers and AKR1B10 expression in the highly invasive cells.    99
Figure V- 1 Model of factors involves in the 14-3-3ε-promoted HCC cell proliferation, migration and tumor growth.    102
Figure S- 1 14-3-3ε promotes tumor growth through β-catenin and AKR1B10.    103
Figure S- 2 Prognostic analysis of 14-3-3ε and AKR1B10 in HCC tumors.    104


                                

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