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研究生(外文):Jia-Hui Lin
論文名稱:染色質操控因子ARID3B 在肝癌進程中所扮演之角色
論文名稱(外文):The Role of the Chromatin Modifier ARID3B in the Progression of Hepatocellular Carcinoma
指導教授(外文):Muh-Hwa Yang
外文關鍵詞:Hepatocellular CarcinomaARID3Bcancer stem cellCD133SALL4Chromatin remodeling
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肝癌 (Hepatocellular carcinoma, HCC) 是指由肝細胞所發生的惡性腫瘤,在成人中是最常見的原發性肝癌。有許多研究指出 AT-rich 的轉錄因子 ARID 家族參與很多 與癌症相關的調控路徑。在實驗室先前的研究中證實 ARID3B 複合體可以調控幹細胞相關基因,進而促進頭頸癌和大腸癌的癌症進程。因此,在本篇研究我們想要探討在肝癌中 ARID3B 是如何調控幹細胞特性並且影響癌症進展過程。首先我們透過 Wurmbach Liver Statistics database 和 Gene ontology analysis 發現 ARID3B 的表現與肝癌風險因子和癌化相關路徑有正向相關性。我們也發現過量表現 ARID3B 在肝癌細胞株中,可以增加癌細胞遷移、侵犯、聚球和形成群落的能力。接著,我們透過 chromatin immunoprecipitation (ChIP) 發現 ARID3B可以增加肝癌細胞株的幹細胞特性透過調控 CD133 和 SALL4 上的甲基化程度。此外,我們發現在細胞核有 ARID3B 高表現的 Hep3B 細胞株中, ARID3A 可以
進入到核中與 ARID3B 形成複合體,一起調控目標基因。然而,在 ARID3B 低表現的 Mahlavu細胞株中則沒有上述結果。另外, 我們發現 ARID3A 也是 ARID3B 下游的目標基因,會隨著 ARID3B 表現量的變化而改變。最後,我們分析 193 例肝癌檢體,發現 ARID3A, ARID3B 和其調控的幹細胞相關基因與病人的存活率有正向相關性。從本篇研究中我們證實 ARID3B 複合體在肝癌進程中扮演重要的角色,在未來有機會可以做為診斷和治療肝癌的有力標的。
Hepatocellular carcinoma (HCC) which originates from hepatocytes, also known as hepatoma, is the most common form of primary liver cancer. Accumulating evidence suggests that ARID family members, AT–rich transcription factors, are involved in cancer-related signaling pathways. Our previous study have been validated ARID3B
complex could regulate stemness genes to promote HNSCC and colon cancer progression. Here, we tried to investigate the function of ARID3B in the regulation of
stem-like properties and the impact of ARID3B for HCC progression. First, using Wurmbach Liver Statistics database and Gene ontology analysis, we found that
ARID3B expression is related to the risk of HCC and cancer development associated pathway. Then, we verified ARID3B could promote the ability of migration, invasion,
sphere formation, and soft agar colony formation in HCC cells. Next, we demonstrated that ARID3B could promote the stem-like properties of HCC cells through epigenetic regulation at specific stemness gene, CD133 and SALL4. We also discovered that ARID3A could translocate in nucleus of Hep3B cells which expressed higher ARID3B in the nucleus than Mahlavu and interact with ARID3B. In addition, we confirmed that ARID3A was a target of ARID3B. Finally, we revealed the clinical significance of ARID3A, ARID3B and specific stemness gene in HCC cases. As a result, ARID3A-ARID3B complex could be a biomarker for HCC development and might be a potential target for the treatment of HCC.
I. Introduction......1
1-1 Liver cancer......1
1-2 Hepatocellular carcinoma......1
1-3 Hepatocellular carcinoma cancer stem cells (HCC CSCs)......2
1-4 ARID3A-ARID3B complex and ARID3A protein shuttling......4
1-5 ARID3A, ARID3B and cancer development ......5
1-6 ARID3A and ARID3B in hepatocellular carcinoma......6
1-7 CD133......6
1-8 SALL4 ......7
1-9 Project aim......7
II. Materials and methods......9
2-1 Cell lines and culture condition ...... 9
2-2 Plasmids, DNA constructs, and shRNA clones.......9
2-3 Lentivirus production, Infection and gene silencing ......9
2-4 RNA isolation and quantitative real-time reverse-transcription PCR analysis......10
2-5 Protein extraction and western blots analysis......11
2-6 Sphere formation assay...... 11
2-7 Soft agar colony formation assay...... 12
2-8 Cell migration and invasion assays......12
2-9 Chromatin Immunoprecipitation......13
2-10 Immunoprecipitation ......14
2-11 Nuclear/Cytosol Fractionation......15
2-12 Immunohistochemistry......15
2-13 Animal study......16
2-14 Statistical analysis......16
III. Results......17
3-1 ARID3B plays a key role for HCC development ......17
3-2 ARID3B is critical in the stem-like properties and tumorigenicity of HCC Cells ......17
3-3 ARID3B promotes the stem-like properties of HCC Cells through epigenetic regulation at specific stemness gene......18
3-4 ARID3A is also a ARID3B downstream target gene and interacts with nuclear ARID3B ......19
3-5 ARID3B complex and SALL4 overexpression correlates with a worse prognosis in HCC cases ...... 21
3-6 ARID3B promotes tumor formation in mice models......22
IV. Discussion......23
V. Conclusion......26
VI. Reference......27
VII. Figures......34
VIII. Tables......47
Table1. List of proteins tested by antibodies and characteristics of the corresponding...... 47
Table2. Sequence of the oligonucleotides for quantitative real-time PCR ......48
Table3. ChIP sequence of the oligonucleotides for quantitative real-time PCR......51
Table4. Gene ontology analysis for the expression profile of the
Mahlavu-ARID3B-transfected cells......52
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