探討bFGF與癌症惡病質信號對MRFs的調控機制

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黃凱帆(Kai-Fan Huang) 查詢紙本館藏

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生命科學系

論文名稱

探討bFGF與癌症惡病質信號對MRFs的調控機制
(The transcriptional regulation of MRFs by bFGF and cancer cachexia signals)

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至系統瀏覽論文 (2026-7-31以後開放)

摘要(中)

MRFs包含了Myf5、MyoD、Myogenin和MRF4，它們負責決定肌肉細胞命運及分化，因此對於骨骼肌生成扮演著重要的角色。而鹼性纖維母細胞生長因子(bFGF)常被用來培養肌肉幹細胞，但同時也會抑制肌肉生成及MyoD的表現，反之，會活化Myf5的表現。此外，有一種常在癌症末期病人中出現的併發症稱為癌症惡病質，會抑制肌肉生成及誘導肌肉萎縮，同時也會抑制MyoD的表現。此篇研究想探討鹼性纖維母細胞生長因子和癌症惡病質訊號是如何調控MRFs的表現。首先，實驗結果證實GST-bFGF重組蛋白以及C26癌細胞的條件培養基可以成功模擬bFGF和癌症惡病質訊號。接著，實驗結果發現，bFGF和癌症惡病質訊號會增加MyoD的RNA穩定度。我們也找出了許多位於MyoD啟動子上游且會被bFGF和癌症惡病質信號調控的順式因子(cis-elemts)。先前研究發現，MyoD有一段增強子可以轉錄出一段不會被轉譯成蛋白質的RNA，它可以幫助MyoD的表現，因此我們發現bFGF信號會抑制此段RNA的轉錄，然而，大量表現此段RNA沒辦法挽救被bFGF信號抑制的MyoD表現。因此，詳細的調控機制還需要再進一步研究。此外，我們發現Myf5啟動子會被bFGF和癌症惡病質信號抑制，這與Myf5的RNA表現是相反的結果，詳細的調控機制還需要更進一步的研究。

摘要(英)

Myogenic regulatory factors (MRFs), including Myf5, MyoD, Myogenin and MRF4, are essential for skeletal muscle (SKM) lineage determination and differentiation. Basic Fibroblast Growth Factor (bFGF) is commonly used for culturing myogenic stem cells (MuSC, or satellite cells) but is known to activate Myf5 while inhibiting MyoD expression. In terminal-stage cancers, serious SKM wasting (cachexia) occurs, and MyoD expression is similarly repressed while Myf5 expression is upregulated by cachexia signals. Our lab has confirmed that recombinant GST-bFGF and C26 cell-conditioned medium (C26M) inhibit both myogenesis and MyoD expression in C2C12 cells. However, this inhibition is less pronounced in satellite cells as compared to C2C12 cells, necessitating further investigation into the reasons for this difference. Also, MyoD mRNA stability is increased by bFGF in both growth medium (GM) and differentiation medium (DM), as well as by cachexia signals, suggesting a complex regulatory mechanism affecting MyoD expression at multiple levels. Moreover, various MyoD cis-elements have been identified as targets of bFGF signaling at different myogenic stages. Multiple MyoD cis-elements are also targeted by C26M. Additionally, the Myf5 promoter is repressed by bFGF and C26M signals, which presents a discrepancy between promoter activity and mRNA level that needs further investigation. Furthermore, CREeRNA, a non-coding RNA transcribed from CRE and critical for MyoD epigenetic activation, is repressed by bFGF. However, overexpression of CREeRNA does not rescue the bFGF-repressed MyoD mRNA expression in GM. Additionally, Myf5 promoter activity is repressed by bFGF and C26M, which is opposite to the transcriptional expression. Thus, the mechanism needs to be further investigated. Currently, efforts are focused on identifying the transcription factors mediating the repressive effects of bFGF and C26M on MyoD expression. Understanding these mechanisms will provide deeper insights into the regulation of MyoD and potential therapeutic strategies for muscle-wasting conditions associated with cancer cachexia.

關鍵字(中)

★ 肌肉生成
★ 癌症惡病質
★ 鹼性纖維母細胞生長因子

關鍵字(英)

★ bFGF
★ cancer cachexia
★ myogenesis
★ MRFs

論文目次

摘要 i
Abstract ii
Graphical Abstract iv
Declaration v
Acknowledgment vi
Table of contents vii
List of Figures xi
I. Introduction 1
I-1、 Myogenesis 1
I-1-1. Postnatal skeletal muscle differentiation 1
I-1-2. Myogenic regulatory factors (MRFs) 2
I-1-2-2. MyoD 3
I-1-2-3. Myf5 and MRF4 4
I-2、 Basic fibroblast growth factor 5
I-2-1. bFGF and FGFR expression in satellite cells and skeletal muscle regeneration 5
I-2-2. Role of bFGF in muscle and skeleton development 6
I-3、 Cancer cachexia 7
I-3-1. Definition of cancer cachexia 7
I-3-2. Signaling involved in skeletal muscle wasting 7
I-3-3. Pro-inflammatory factors in cancer cachexia 8
I-3-4. The revealed regulation of MyoD expression in cancer cachexia 9
I-4、 Aims 10
II. Materials and methods 12
II-1、 List of cloning strategies of various plasmids 12
II-2、 Site-directed mutagenesis by overlapping PCR 17
II-3、 Cell culture 17
II-3-1. Cell line 18
II-3-2. Stable clone 18
II-3-3. Satellite cell 19
II-3-4. Transient transfection 19
II-4、 Luciferase assay 19
II-5、 mRNA stability assay 20
II-6、 Immunoflueoresense 22
II-7、 Purification of recombinant protein 22
II-8、 Western blot 24
II-9、 Statistical Analysis 25
III. Results 26
III-1、 GST-bFGF is purified successfully. 26
III-2、 Our homemade GST-bFGF has the same effect as commercial bFGF to C2C12. 26
III-3、 bFGF and cancer cachexia signals inhibit myogenesis and myogenic-related gene expression. 27
III-4、 The effect of GST-bFGF on various signaling pathways at different myogenic stages. 28
III-5、 GST-bFGF and C26M repress MyoD transcriptional level without decreasing mRNA stability 29
III-6、 bFGF and cancer cachexia signals repress MyoD expression by targeting different cis-elements. 30
III-7、 GST-bFGF represses MyoD transcriptional level expression in GM not by inhibiting CREeRNA expression instead of MyoD transactivational activity. 31
III-8、 The effects of C26M on the overexpression of MyoD and its downstream genes were examined. 33
III-9、 The effect of bFGF and cancer cachexia signals on Myf5 and MRF4 promoters. 34
III-10、 The effects of bFGF and cancer cachexia signals on the different promoters 35
IV. Discussion 37
IV-1、 Differential effects of C26M on myogenesis and myogenic-related genes in C2C12 cells and satellite cells 37
IV-2、 The effect of GST-bFGF on the signaling pathways. 38
IV-3、 The effect of bFGF and C26M on MyoD mRNA stability 38
IV-4、 The cis-elements of MyoD targeted by bFGF and cancer cachexia signals 39
IV-5、 The effects of bFGF and cancer cachexia signals on Myf5 and MRF4 promoters. 40
V. Figures 42
VI. Reference 62
VII. Appendixes 69
VII-1、 Cloning strategies 69
VII-1-1. Restriction enzyme digestion 69
VII-1-2. Polymerase 69
VII-1-3. Klenow 69
VII-1-4. PNK (T4 Polynucleotide Kinase) 70
VII-1-5. Quick CIP (calf intestinal alkaline phosphatase) 70
VII-1-6. T4 DNA Ligase 70
VII-2、 Solutions 71
VII-3、 Primer lists 72

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指導教授

陳盛良(Shen-Liang Chen)

審核日期

2024-8-19

推文