MEHP及癌症惡病質症對骨骼肌萎縮的加乘性影響

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廖怡萱(Yi-Shiuan Liao) 查詢紙本館藏

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MEHP及癌症惡病質症對骨骼肌萎縮的加乘性影響
(The synergistic effect of MEHP and cancer cachexia on skeletal muscle atrophy)

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至系統瀏覽論文 (2026-7-31以後開放)

摘要(中)

塑化劑廣泛存在於人們的日常生活中，保鮮膜、化妝品、藥品、醫療器材與保健食品膠囊等，都含有塑化劑。其中Di(2-ethylhexyl)phthalate (DEHP)是最常見的塑化劑，經各種途徑吸收了DEHP後會迅速代謝成MEHP進入循環系統中，進而影響內分泌、生殖、生長與代謝等生理功能。先前研究發現，加入MEHP會抑制肌肉細胞生長分化(myogenesis)。癌症惡病質症(cancer cachexia)是一種不可逆的併發症，癌細胞會釋放促發炎因子(TNFα、IL-6、INFγ)等可溶性因子影響遠端器官，活化泛素蛋白酶系統(ubiquitin-proteasome system)及自噬途徑，導致肌肉嚴重萎縮。癌症惡病質症患者大部分是癌症晚期的患者，在長期住院治療下大幅增加了從點滴管醫療器材吸收DEHP的風險。因此本計畫假設暴露在高量的DEHP中會加劇癌症惡病質症的骨骼肌流失，以探討MEHP及癌症惡病質症對骨骼肌萎縮的加乘性影響。我利用C26結腸癌細胞釋放出的可溶性物質(C26M)來模擬cancer cachexia的環境。實驗發現，C26M藉由調控C2C12肌肉細胞中MuRF1與Atrogin 1的啟動子與mRNA穩定性來使MuRF1表現量下降，Atrogin 1表現量上升。MuRF1與Atrogin 1相反的趨勢指出C26M透過不同路徑影響其表現。此外，MEHP與C26M共同抑制C2C12肌管的形成與細胞中肌肉分化因子(MyoG、Mef2c)的mRNA表現量，且C2C12細胞中ROS含量也受到MEHP與C26M共同上調。in vivo的實驗發現，DEHP使C26小鼠腓腸肌(GC)更加萎縮，且只有在DEHP/C26組別的小鼠中發現比目魚肌(Soleus)有萎縮的情形。在分子層面，C26小鼠肥腸白肌中的E3-泛素連接酶(MuRF1、Atrogin 1)表現量皆上升，而DEHP對E3-泛素連接酶表現量並無加乘影響。C26小鼠骨骼肌中MuRF1 mRNA表現量上升的趨勢與in vitro實驗中觀察到的現象相反，推測有其他系統(如神經系統、免疫系統等)參與其中。與正常小鼠相比，C26小鼠脾臟明顯腫大，暗示其體內可能發生嚴重發炎反應。Raw264.7巨噬細胞培養液(RM)及受C26M刺激之巨噬細胞培養液(RC)會與C26M共同促進C2C12成熟肌管的萎縮，未來還需探討免疫細胞是否調控E3-泛素連接酶mRNA表現量。綜合以上所述，DEHP/MEHP會加劇癌症惡病質症的肌肉流失，造成癌症惡病質症的惡化。

摘要(英)

Plasticizers are widely present in people′s daily life, found in items such as cling film, cosmetics, pharmaceuticals, medical equipment, and health food capsules. Among them, Di (2-ethylhexyl) phthalate (DEHP) is the most common plasticizer, which is easily leached out from PVC products. Once it enters the human body, it is rapidly metabolized to mono-2-ethylhexyl phthalate (MEHP) and then enters the circulatory system, affecting physiological functions such as endocrine system, reproductive, growth, and metabolism. Previous studies have shown that MEHP represses skeletal muscle (SKM) differentiation. Cancer cachexia is an irreversible wasting syndrome of muscle and fat induced by signals from cancer and immune cells. Given the high levels of DEHP exposure in long-term hospitalized cancer patients due to continuous contact with PVC tubing and medical equipment, we hypothesize that DEHP exposure exacerbates muscle wasting in cancer patients. Here I found that cancer cachexia factors contained in the C26 colon cancer cells conditioned medium (C26M) differentially modulate the promoter activity and mRNA stability of E3 ligases MuRF1 and Atrogin1, resulting in decreased MuRF1 expression and increased Atrogin 1 expression in C2C12 myoblasts and myotubes. Moreover, MEHP and C26M synergistically inhibited the myogenic capacity of C2C12 and the mRNA expression of muscle differentiation factors (MyoG, Mef2c), along with elevated ROS levels in these cells. In vivo experiments showed that DEHP caused further atrophy of the gastrocnemius (GC) muscle in mice with C26 tumor (C26 mice). Of note, soleus atrophy was only observed in mice treated with DEHP/C26. In contrast to the observations in C2C12 myoblasts, the mRNA expression of MuRF1 and Atrogin 1 was both increased in the GC muscle of C26 mice, suggesting the involvement of other cell types, such as neuron and immune cells, in vivo. Additionally, C26 mice exhibited significant splenomegaly compared to normal mice, indicating severe inflammatory responses. Culturing with Raw264.7 macrophage conditioned medium (RM) and C26M-stimulated macrophage conditioned medium (RC) intensified myotube atrophy in C2C12, suggesting a potential role of immune cells in regulating E3 ubiquitin ligase mRNA expression. In conclusion, DEHP/MEHP exacerbates muscle wasting in cancer cachexia, contributing to its deterioration.

關鍵字(中)

★ 塑化劑
★ 癌症惡病質症
★ 骨骼肌
★ 萎縮

關鍵字(英)

★ MEHP
★ DEHP
★ cancer cachexia
★ skeletal muscle
★ atrophy

論文目次

摘要 v
Abstract vi
聲明(Declaration) viii
誌謝(Acknowledgment) ix
目錄 x
縮寫與全名對照表 (Abbreviations) xiv
第一章、緒論 1
1-1. 肌肉生成過程(Myogenesis) 1
1-2. 塑化劑(DEHP/MEHP) 2
1-3. 癌症惡病質症(Cancer cachexia) 4
1-4. E3-泛素連接酶與肌肉萎縮 5
1-5. 研究動機及研究問題 7
第二章、實驗材料及方法 9
2-1. 細胞株(Cell lines) 9
2-1.1. 老鼠肌纖維母細胞: Mouse myoblast cells (C2C12) 9
2-1.2. 小鼠纖維母細胞: Fibroblast cells (C3H/10T1/2) 9
2-1.3. 穩定細胞株: C2C12-pStable、C2C12-MuRF1 promoter、C2C12-Atrogin 1 promoter 9
2-1.4. 穩定細胞株: C2C12-tTA-MyoD、C2C12-tTA-MyoG 9
2-1.5. 穩定細胞株: 10T1/2-tTA-MyoD 9
2-1.6. 小鼠結腸癌細胞: Mouse colon carcinoma (C26) 10
2-2. 質體列表(Plasmid list) 10
2-3. 細胞轉染(Cell transfection) 11
2-4. 冷光素酶報導檢測(Luciferase reporter assay) 11
2-5. RNA萃取(RNA extraction) 11
2-6. 反轉錄聚合酶連鎖反應(Reverse-transcription PCR, RT-PCR) 12
2-7. 即時定量聚合酶連鎖反應(qRT-PCR) 13
2-8. 細胞免疫螢光染色(Immunofluorescence) 13
2-9. 活性氧物質(Reactive oxygen species, ROS)含量檢測 14
2-9.1. DCFDA反應 14
2-9.2. 細胞懸浮及檢測 14
2-9.3. 蛋白質檢測及標準化 14
2-10. 抽取gDNA (gDNA extraction) 14
2-11. 粒線體含量測定(Mitochondria content determination) 15
2-12. 西方墨點法(Western blot) 15
2-12.1. Total protein extraction 15
2-12.4. Blocking及抗體辨識 16
2-12.5. 蛋白質上的抗體脫附(Stripping) 16
2-13. 小鼠管餵(mouse oral gavage)及皮下注射 17
2-13.1. 實驗動物 17
2-13.2. 試驗物質 17
2-13.3. 皮下注射 17
2-13.4. 管餵 17
2-14. 小鼠組織切取(mouse tissue dissection) 18
2-14.1. 麻醉小鼠 18
2-14.2. 心臟採血 18
2-14.3. 灌流 18
2-14.4. 取組織 18
第三章、結果 20
3-1. MuRF1與Atrogin 1為肌肉專一性基因，且在肌肉發育過程中大量表現 20
3-2. DEHP及cachexia signal對BALB/c小鼠的影響 20
3-1.1 第一批小鼠實驗 20
3-1.2 第二批小鼠實驗 21
3-3. MEHP及C26M共同誘導成熟肌管的萎縮 23
3-4. MEHP及C26M共同抑制C2C12的分化能力 24
3-5. MEHP與C26M對MuRF1及Atrogin 1 promoters活性的影響 24
3-6. 探討癌症惡病質訊號對MuRF1、Atrogin 1之mRNA穩定度的影響 25
3-7. MEHP與C26M提升C2C12中ROS含量，但不影響mtDNA含量 26
3-8. C26M與Raw264.7分泌之因子共同誘導肌管萎縮 26
3-9. MyoG調控MuRF1與Atrogin 1的表現 27
3-10. MyoD調控MuRF1與Atrogin 1的表現 28
第四章、討論 30
4-1. DEHP/MEHP與癌症惡病質症對肌肉分化的影響 30
4-2. C26M對MuRF1與Atrogin 1的調控 30
4-3. DEHP對快縮肌與慢縮肌的影響 31
4-4. MuRF1與Atrogin 1在C26小鼠心臟中的表現 31
4-5. 探討C26小鼠的免疫細胞是否影響骨骼肌分化 32
4-6. 利用C26-tTA-luciferase穩定細胞株觀察腫瘤細胞的形成與轉移 33
4-7. 結論與未來方向 33
第五章、圖表 34
Fig. 5-1 MuRF1與Atrogin 1為肌肉專一性基因，且在肌肉發育過程中大量表現 35
Fig. 5-2 第一批小鼠實驗 37
Fig. 5-3 第二批小鼠實驗 39
Fig. 5-4 MEHP及C26M對C2C12成熟肌管的影響 41
Fig. 5-5 MEHP及C26M對C2C12分化時期的影響 43
Fig. 5-6 MEHP與C26M對MuRF1及Atrogin 1 promoter活性的影響 44
Fig. 5-7 C26M對肌肉分化時MuRF1及Atrogin 1 mRNA穩定度的影響 45
Fig. 5-8 MEHP與C26M提升C2C12中ROS含量，但不影響mtDNA含量 46
Fig. 5-9 C26M與Raw264.7分泌之因子共同誘導肌管萎縮 47
Fig. 5-10 MyoG調控MuRF1與Atrogin 1的表現 49
Fig. 5-11 MyoD調控MuRF1與Atrogin 1的表現 51
第十章、參考文獻 52
第十一章、附錄 60
附錄一、補充圖表 60
附錄二、Primer list 65
附錄三、溶劑及溶液配方 67
附錄四、藥品試劑及抗體 69
附錄五、pStable-mMuRF1 promoter Sequence alignment 70
附錄六、pStable-mAtrogin 1 promoter Sequence alignment 72

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指導教授

陳盛良(Shen-Liang Chen)

審核日期

2024-7-23

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