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研究生:陳怡芬
研究生(外文):Yi-Fen Chen
論文名稱:微型核糖核酸211透過抑制TCF12使FAM213A表現增加進而促進口腔癌發展
論文名稱(外文):MicroRNA-211 enhances the oncogenicity of oral carcinoma through targeting TCF12 and up-regulating FAM213A antioxidant molecule
指導教授:張國威
指導教授(外文):Kuo-Wei Chang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:口腔生物研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:100
中文關鍵詞:FAM213ATCF12微型核糖核酸211微型核糖核酸口腔癌頭頸癌
外文關鍵詞:FAM213ATCF12miR-211microRNAOral CancerHNSCC
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miR-211在口腔鱗狀上皮細胞癌中會促進腫瘤的生成和轉移,導致患者預後及存活率不佳。本研究欲進一步探討miR-211在口腔癌中詳細的致病機轉,因此建立了K14-GFP-miR-211轉殖鼠,大量表現miR-211於鱗狀上皮,並利用餵食4NQO誘導小鼠產生口腔癌。實驗結果顯示miR-211的表現會促進小鼠口腔癌的發展。並且發現在口腔癌細胞株中4NQO和檳榔鹼的刺激皆會增加miR-211的表現。TCF12為miR-211的目標基因,在口腔癌中表現下降,扮演抑癌基因的角色。利用基因晶片和生物資訊軟體分析找出可能被TCF12調控的基因,透過報導者試驗分析和染色質免疫沈澱試驗證明TCF12透過負轉錄調控FAM213A的表現。FAM213A為抗氧化基因,當受到抑制時會增加細胞中活性氧化物質、抑制癌細胞表現型並減少具有ALDH1活性的細胞。TCGA資料庫分析顯示口腔癌中TCF12和FAM213A的表現呈現負相關。FAM213A高表現於口腔癌組織中,導致患者存活率有下降的趨勢。本研究證明了癌化的刺激例如4NQO會促進miR-211的表現,透過標的TCF12進而使FAM213A表現量增加促進口腔癌的發展,並在轉殖鼠模式和人類口腔癌組織中皆驗證了此分子及病理機轉。
miR-211 expression has been reported to be associated with the invasion and poor patient survival of human oral squamous cell carcinoma (OSCC). To further address the oncogenic roles of miR-211, we generated K14-EGFP-miR-211 transgenic mice tagged with green fluorescence protein. Upon the 4-nitroquinoline 1-oxide (4NQO) induction, the transgenic mice exhibited more extensive and severe tumorigenesis in tongue compared to the controls. 4NQO and arecoline up-regulated miR-211 expression in OSCC cells. miR-211 directly targeted transcription factor 12 (TCF12), which mediated suppressor activities in OSCC cells and was drastically down-regulated in tumor tissues. GeneChip analysis and bioinformatic algorithms annotated the transcriptional signature and functional targets of TCF12. Reporter analysis and ChIP assay pinpointed that Family with Sequence Similarity 213, Member A (FAM213A), a peroxiredoxins-like anti-oxidative protein, was transcriptionally repressed by TCF12. Knockdown of FAM213A decreased oncogenic activity and ALDH1-positive cell population, and increased reactive oxygen species in OSCC cells. The expression of TCF12 and FAM213A was inversely correlated in head and neck squamous cell carcinoma (HNSCC) samples according to The Cancer Genome Atlas (TCGA). OSCC patients carrying tumors with high FAM213A expression tended to have worse survival. Furthermore, 4NQO treatment down-regulated TCF12 and up-regulated FAM213A through modulating miR-211 both in vitro and in vivo. The K14-EGFP-miR-211 Tg mice recaptures the molecular changes and histopathological changes as seen in human OSCC pathogenesis. This study highlights that miR-211 responds to oncogenic stimuli to promote the neoplastic process of OSCC by targeting TCF12 and up-regulating FAM213A.
Contents
Contents i
Abstract v
中文摘要 vii
Introduction 1
A. Oral Cancer 1
B. MicroRNAs 2
C. Transcription factor 12 (TCF12) 4
D. Reactive oxygen species (ROS) 5
E. Family with sequence similarity 213, member A (FAM213A) 7
F. 4NQO inducted mouse OSCC model 8
Aim of the study 10
Material and Methods 11
Generation of K14-GFP-miR-211 transgenic mice and tumor induction 11
Genotyping and tissue analysis of transgenic mouse lines 11
Cell culture and reagents 12
Quantitative (q)RT-PCR 13
Western blot analysis 14
Plasmids and establishment of stable cell subclones 14
Subcellular fractionation 15
Analysis of cellular phenotypes 15
Orthotopic and subcutaneous xenograft 15
Reporter plasmids and assays 16
OSCC tissue samples and tissue microarray (TMA) 17
Immunohistochemistry (IHC) 18
In situ hybridization (ISH) 18
Transcription factor binding sites analysis 19
Bioinformative annotation 19
Chromatin immunoprecipitation (ChIP) assay 19
ROS assay 20
Oxidative stress detection 21
Statistical analysis 21
Results 22
A. Establishment of K14-EGFP-miR-211 transgenic mouse model 22
B. miR-211 expression is associated with more advanced oncogenesis and metastasis 24
C. miR-211 targeted TCF12 in OSCC cells 26
D. TCF12 mediated the tumor suppressor effects on OSCC cells 30
E. Identification of FAM213A as a downstream effector of TCF12 32
F. TCF12 down-regulates FAM213A oncogene through promoter repression 35
G. FAM213A expression protects cells from oxidative stress 37
H. Association between FAM213A expression and poor patient survival of OSCC 38
Discussion 41
Figures 48
Fig 1. Genotyping of K14-EGFP-miR-211 transgenic mouse model 48
Fig 2. Immunoreactivity of GFP and thickness in squamous epithelium 49
Fig 3. Immunohistochemistry of the cell proliferation and survival proteins in tongue epithelium 50
Fig 4. Induction of mouse tongue tumorigenesis using 4NQO 51
Fig 5. Induction of mouse esophageal tumorigenesis using 4NQO 52
Fig 6. Assay of neck metastasis using orthotopic model 53
Fig 7. miR-211 expression in carcinogen-treated OSCC cells. 54
Fig 8. Analysis of miR-211 targeted genes in OSCC cells 55
Fig 9. miR-211 targets TCF12 in OSCC cells 56
Fig 10. TCF12 expression in K14-EGFP-miR-211 transgenic mouse 57
Fig 11. Establishment of TCF12 expression cell lines 58
Fig 12. Subcellular fractionation analysis of TCF12 59
Fig 13. Phenotypic analysis of TCF12 expression cells 60
Fig 14. Phenotypic analysis of TCF12 knockdown cells 61
Fig 15. Phenotypes associated with miR-211 inhibition were rescued by the knockdown of TCF12 62
Fig 16. TCF12 and miR-211 expression in human OSCC tissue pairs 63
Fig 17. miR-211 staining and TCF12 immunoreactivity in OSCC TMA 64
Fig 18. miR-211 staining and TCF12 immunoreactivity in mouse tongue tissues 65
Fig 19. Identification of TCF12 downstream genes 66
Fig 20. Analysis of TCF12 associated biological processes and gene interaction networks 67
Fig 21. Prediction of the regulation of TCF12 on the downstream genes promoter using Jasper software 68
Fig 22. qRT-PCR analysis to confirm the regulation of TCF12 on downstream genes across different OSCC cells 69
Fig 23. Identification of FAM213A as a downstream gene of TCF12 70
Fig 24. Correlation between miR-211, TCF12, and FAM213A mRNA expression in OSCC 71
Fig 25. miR-211-TCF12-FAM213A regulation in OSCC 72
Fig 26. TCF12 down-regulates FAM213A through promoter inactivation 73
Fig 27. Phenotypic analysis of FAM213A knockdown cells 74
Fig 28. Phenotypes of miR-211 and siTCF12 were rescued by the knockdown of FAM213A 75
Fig 29. ALDH1-positive cell populations in OSCCs with knockdown of FAM213A 76
Fig 30. FAM213A immunoreactivity 77
Fig 31. FAM213A expression abrogated the ROS-associated deleterious effects on cell migration 78
Fig 32. FAM213A silencing and/or the 4NQO treatment increased protein oxidation 79
Fig 33. Nuclear and protein oxidation in transgenic mice 80
Fig 34. miR-211 staining and FAM213A immunoreactivity in OSCC TMA 81
Fig 35. Clinical implication of FAM213A expression in OSCC 82
Fig 36. miR-211 staining and FAM213A immunoreactivity in multistep carcinogenesis 83
Fig 37. TCF12 immunoreactivity in mouse multistep carcinogenesis 84
Fig 38. Summary of this study 85
Tables 86
Table 1. The complementarity between miR-211 and the 3’UTR of TCF12 gene 86
Table 2. Jaspar prediction scores 86
Supplementary Figures 87
Figure S1. Tg mouse construct: K14-GFP-mmu-miR-211-HS4 87
Figure S2. Map of pBABE-puro 87
Figure S3. Map of pMIR-REPORTTM Luciferase 87
Figure S4. Map of pGL3-Basic 88
Figure S5. Predicted transgene insertion in mouse genome detected by Southern blot 88
Figure S6. Timeline of 4NQO treatment 88
Figure S7. Tcf12 transcription factor binding site prediction 88
Supplementary Tables 89
Table S1. Primers used in the present study 89
Table S2. Cell cultivation conditions 90
Table S3. RNAs used in the present study 91
Table S4. TaqMan® assay probes used in the present study 91
Table S5. Primary antibodies or associated reagents used in the present study 92
Table S6. shRNAs used in the present study 92
Table S7. Paired OSCC samples for qRT-PCR and Western blot analysis 93
Table S8. OSCC samples in TMA for IHC and ISH analysis 93
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