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姓名 張伯鴻(Po-Hong Zhang) 查詢紙本館藏 畢業系所 生命科學系 論文名稱 探討 Mef2c 和 Mrf4 的機制於肌肉新生及癌症惡病質
(The investigation of Mef2c and Mrf4 mechanism in Myogenesis and Cancer Cachexia)相關論文 檔案 [Endnote RIS 格式]
[相關文章]
[文章引用]
[完整記錄]
[館藏目錄]
至系統瀏覽論文 (2026-1-18以後開放)
摘要(中) 癌症惡病質是一種複雜的綜合症，與多種因素相關，導致持續的肌肉和脂肪流失，
這種流失並不能完全通過營養補充來逆轉。骨骼肌的消耗是惡病質中最嚴重的副作用，
其潛在的分子機制在很大程度上尚不清楚。為了理解參與癌症惡病質的機制，我們使用
癌症惡病質異種移植老鼠，誘導癌症惡病質，並收集其組織進行 RNA-seq 分析。在 RNAseq 數據中，我們觀察到 Mef2c 的嚴重下調，並藉由組織切片發現，發現了中心細胞核
於癌症惡病質中明顯上升，確認了癌症惡病質對肌肉再生的影響，而 Mef2c 涉及 Mrf4
的調控，Mrf4 通過抑制 Mef2 活性來負向調節骨骼肌的生長。為了調查 Mef2c 和 Mrf4
在癌症惡病質的關係，我們在 C2C12 細胞中誘導 Mef2c 和 Mrf4 的過度表達。令人驚訝
的，我們觀察到 Mef2c 過度表達細胞在肌肉生成和萎縮方面的分化較差。我們認為 Mef2c
亞型 1 在肌肉生成和萎縮中的肌原性活性較低，通過 Mef2c 的過度表達並未恢復其肌肉
新生能力。同時我們觀察到誘導 Mrf4 過度表達成功地導致更高的肌原性，表明 Mrf4 水
平在肌原性過程中具有關鍵的調節作用。然而即使在肌肉新生中，通過 Mrf4 過度表達
也未能拯救 C2C12-Mrf4 細胞在接受癌症惡病質培養液處理後的肌肉新生能力。有趣的
是，Mrf4 的 RNA 和蛋白質並不會被癌症惡病質抑制，但抑制了 Mrf4 在肌肉新生中的
功能，為了調查此情形，我利用了三重比對挑選出 Mrf4 的結合位基因，發現了下游基
因 Kcnn3 會受到癌症病質和 Mrf4 調控，證實了癌症惡病質可能藉由影響下游基因結合
位來影響 Mrf4 的表現能力。總結來說，本論文證實了癌症惡病質的肌肉狀態異常無法
藉由大量表現 Mef2c 和 Mrf4 來挽救，但未來可以藉由調查 Mrf4 新的機制來進一步尋
找挽救的方式。摘要(英) Cancer cachexia is a complex syndrome associated with multiple factors results in ongoing muscle
and fat loss that is not completely reversible by nutritional supplementation. Skeletal muscle wasting is
the most severe side effect in cachexia, and the underlying molecular mechanisms are largely unknown.
To understand the mechanisms involved in cancer cachexia, we used cancer cachectic xenograft mice,
induced cancer cachexia, and collected their tissues for RNA-seq analysis. In the RNA-seq data, we
observed severe down-regulation of Mef2c, and found through tissue sections that central cell nuclei
were significantly increased in cancer cachexia, confirming the impact of cancer cachexia on muscle
regeneration, and Mef2c is involved in the regulation of Mrf4. Mrf4 negatively regulates skeletal muscle
growth by inhibiting Mef2 activity. To investigate the relationship between Mef2c and Mrf4 in cancer
cachexia, we induced overexpression of Mef2c and Mrf4 in C2C12 cells. Surprisingly, we observed that
Mef2c-overexpressing cells were poorly differentiated with respect to myogenesis and atrophy. We
believe that Mef2c isoform 1 has low myogenic activity in myogenesis and atrophy, and its myogenic
capacity is not restored by overexpression of Mef2c. At the same time, we observed that inducing Mrf4
overexpression successfully resulted in higher myogenicity, indicating that Mrf4 levels have a critical
regulatory role in the myogenic process. However, even in myogenesis, Mrf4 overexpression failed to
rescue the myogenesis ability of C2C12-Mrf4 cells after being treated with cancer cachexia culture
medium. Interestingly, the RNA and protein of Mrf4 are not inhibited by cancer cachexia, but inhibit
the function of Mrf4 in muscle regeneration. In order to investigate this situation, I used triple alignment
to select the binding site genes of Mrf4 and discovered the downstream The gene Kcnn3 is regulated by
cancer cachexia and Mrf4, confirming that cancer cachexia may affect the expression ability of Mrf4 by
affecting downstream gene binding sites.In conclusion, this paper confirms that the abnormal muscle
status of cancer cachexia cannot be rescued by excessive expression of Mef2c and Mrf4, but in the future,
we can further find ways to rescue it by investigating the new mechanism of Mrf4.關鍵字(中) ★ 癌症惡病質 關鍵字(英) ★ Mef2c
★ Mrf4
★ Cancer cachexia論文目次 摘要.....................................................................................................................................i
Abstract .............................................................................................................................ii
致謝 (Acknowledgement).............................................................................................. iii
目錄...................................................................................................................................iv
縮寫與全名表(Abbreviations) .........................................................................................x
第一章 緒論......................................................................................................................1
1.1 癌症惡病質 (Cancer cachexia) ............................................................................1
1.1.1 癌症惡病質簡介..............................................................................................1
1.1.2 癌症惡病質的機制..........................................................................................2
1.2 骨骼肌(Skeletal Muscle)........................................................................................4
1.3 肌肉新生(Myogenesis)...........................................................................................5
1.4 Mef2c 轉錄因子(Myocyte enhancer factor 2C)....................................................8
1.4.1 癌症惡病質對 Mef2c 的調控........................................................................ 11
1.5 MRF4 轉錄因子(Myogenic regulatory factor 4)................................................ 11
1.5.1 Mef2c 和 MRF4 的互相調控.........................................................................12
1.6 研究動機與目的...................................................................................................14
第二章 材料及方法........................................................................................................15
2.1 實驗材料（Experiment materials）..................................................................15
2.1.1 小鼠肌纖維母細胞：Mouse myoblast cells (C2C12) ................................15
2.1.2 人胚胎腎細胞：Human embryonic kidney epithelial cells (HEK293FT)
..........................................................................................................................................15
2.1.3 小鼠纖維母細胞：Fibroblast cells (C3H/10T1/2)......................................15
2.1.4 穩定細胞株：C2C12-tTA-puro...................................................................15
2.1.5 穩定細胞株：C2C12-tTA-Mef2c.................................................................15
2.1.6 穩定細胞株：C2C12-tTA-Mrf4...................................................................16
2.1.7 小鼠大腸癌細胞：Mouse colon carcinoma (C26) .....................................16
2.2 質體建構（plasmid construction） ...................................................................16
2.2.1 Vector 建構.....................................................................................................16
2.2.2 Insert 製備......................................................................................................17
2.2.3 Ligation...........................................................................................................18
2.2.4 Transformation ..............................................................................................18
2.2.5 Minipreparation.............................................................................................18
2.2.6 正反接確認....................................................................................................19
2.3 細胞轉染(Cell Transfection)...............................................................................19
2.3.1 細胞培養........................................................................................................19
2.3.2 細胞轉染作用................................................................................................19
2.4 冷光素酵素報導檢測(Luciferase reporter assay).............................................20
2.5 RNA 萃取(RNA extraction).................................................................................20
2.6 反轉錄聚合酵素連鎖反應(Reverse-transcription)...........................................21
2.7 即時定量聚合酵素連鎖反應(Quantitative real-time PCR, qRT-PCR) ..........21
2.8 細胞免疫螢光染色(Immunofluroescence).........................................................22
2.9 小鼠組織切取(Muscle tissue extraction) ...........................................................22
2.10 組織石蠟切片(Paraffin section) .......................................................................23
2.10.1 組織包埋辦法及準備..................................................................................23
2.10.2 石蠟切片......................................................................................................23
2.11 蘇木精及伊紅染色(H&E staining)...................................................................23
2.12 抗原修復(Antigen Retrieval)............................................................................24
2.13 AEC 染色(AEC Staining)...................................................................................24
2.14 西方墨點法(Western blot).................................................................................24
2.14.1 聚丙烯醯氨凝膠電泳(SDS-polyacrylamide gel electrophoresis)............25
2.14.2 蛋白質轉印(Transfer).................................................................................25
2.14.3 Blocking 及抗體辨識...................................................................................25
2.14.4 蛋白質上的抗體脫附(Stripping) ...............................................................26
2.15 RNAseq 資料分析...............................................................................................26
2.15.1 Deseq 分析....................................................................................................26
2.15.2 KEGG 分析..................................................................................................26
2.15.3 GO 分析(Gene Ontology)............................................................................27
2.15.4 DO 分析(Disease Ontology)........................................................................27
2.16 腺病毒製造 (Adeno-associated virus production) .........................................27
第三章 結果....................................................................................................................29
3.1 癌症惡病質對 MRFs 的表現 ..............................................................................29
3.2 在癌症惡病質中 Mef2c 的下調...........................................................................29
3.3 癌症惡病質與中心核的關係...............................................................................30
3.4 質體建構...............................................................................................................30
3.5 建構 C2c12-tTA-Mef2c 穩定細胞株..................................................................31
vii
3.6 癌症惡病質對 Mef2c 啟動子的影響...................................................................31
3.7 大量表現 Mef2c 對 C2C12 增生及分化的表現.................................................32
3.8 在癌症惡病質大量表達 Mef2c 第一種亞型的表現...........................................33
3.9 在癌症惡病質中對 Mef2c 不同領域的影響.......................................................33
3.10 建構 AAV 系統...................................................................................................34
3.11 建構 C2c12-tTA-Mrf4 穩定細胞株..................................................................34
3.12 大量表現 Mrf4 對 C2c12 增生及分化的表現..................................................35
3.13 在肌肉新生中大量表達 Mrf4 的表現...............................................................35
3.14 在肌肉萎縮中大量表達 Mrf4 的表現...............................................................36
3.15 Mrf4 與癌症惡病質的機制探討.........................................................................37
3.16 Wnt3a 蛋白的生產..............................................................................................38
第 四 章 討論................................................................................................................39
4.1 Mef2c 於癌症惡病質和肌肉新生中的調控.........................................................39
4.2 Mrf4 於癌症惡病質和肌肉新生中的調控...........................................................40
4.3 結論及未來展望...................................................................................................41
第 五 章 圖表................................................................................................................42
Fig.5-1 癌症惡病質對 MRFs 的表現....................................................................42
Fig.5-2 在癌症惡病質中 Mef2c 的下調................................................................43
Fig.5-3 癌症惡病質與中心核的關係 ....................................................................44
Fig.5-4 質體建構 ....................................................................................................48
Fig.5-5 癌症惡病質對 Mef2c 啟動子的影響........................................................49
Fig.5-6 大量表現 Mef2c 對 C2C12 增生及分化的表現.......................................50
Fig5-7 在癌症惡病質大量表達 Mef2c 第一種亞型的表現..................................51
Fig.5-8 在癌症惡病質中對 Mef2c 不同結構域的影響.........................................52
..........................................................................................................................................53
..........................................................................................................................................53
Fig.5-9 AAV 系統的架構........................................................................................53
..........................................................................................................................................54
Fig5-10. 大量表現 Mrf4 對 C2c12 增生及分化的表現.......................................54
Fig5-11. 在肌肉新生中大量表達 Mrf4 的表現....................................................57
Fig5-12. 在肌肉萎縮中大量表達 Mrf4 的表現....................................................59
Fig5-13. Mrf4 與癌症惡病質的機制探討..............................................................63
Fig5-14. Wnt3a 蛋白的生產...................................................................................64
第六章 參考資料............................................................................................................65
第七章 附錄....................................................................................................................71
7.1 溶劑及溶液配方 (The protocol of solvent and solution) .................................71
30% acrylamide/bisacrylamide:............................................................................71
Aprotinin stock solution:........................................................................................71
PBST:.......................................................................................................................71
G418 (geneticin) stock solution (100 mg/mL): .....................................................71
2X HEPES:..............................................................................................................71
1xTransfer buffer (1L):..........................................................................................71
10%APS: .................................................................................................................71
FBS: .........................................................................................................................72
5x Tank buffer: .......................................................................................................72
PMSF stock solution (100mM):.............................................................................72
ix
Plasmid extraction..................................................................................................72
Bacteria culture.......................................................................................................72
RNA extraction .......................................................................................................72
7.2 引子目錄...............................................................................................................73
7.3 R 語言程式碼 .......................................................................................................75
DEG 分析 ...............................................................................................................75
KEGG 分析............................................................................................................75
GO 分析 DO 分析................................................................................................76
7.4 Mef2c 亞型胺基酸序列 ........................................................................................77
Mef2c 一號亞型.......................................................................................................77
Mef2c 二號亞型.......................................................................................................77
Mef2c 三號亞型.......................................................................................................77
Mef2c 四號亞型.......................................................................................................78
Mef2c 五號亞型.......................................................................................................78
Mef2c 六號亞型.......................................................................................................79
Mef2c 七號亞型.......................................................................................................79
Mef2c 八號亞型.......................................................................................................79
7.5 中心細胞核計算的原始資料...............................................................................80
7.6 實驗室 RNA-seq 數據圖......................................................................................81
VOCANOL PLOT..................................................................................................81
KEGG analysis........................................................................................................82
Go analysis ..............................................................................................................83
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310-324. 10.1074/jbc.M114.606277.指導教授 陳盛良(Shen-Liang Chen) 審核日期 2024-1-26 推文 plurk
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