轉化生長因子-beta家族之訊息傳遞對物理性與化學性刺激調節細胞功能之機制探討:TGF-β1與流體剪力對平滑肌細胞分化與癌細胞程序性死亡之影響

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研究生：	連聖傑 Lien, Sheng-Chieh
論文名稱：	轉化生長因子-beta家族之訊息傳遞對物理性與化學性刺激調節細胞功能之機制探討:TGF-β1與流體剪力對平滑肌細胞分化與癌細胞程序性死亡之影響 Physical and Chemical Regulation of Cell Fate by Transforming Growth Factor Superfamily Signaling: Roles of TGF-β1 and Fluid Shear Stress in Smooth Muscle Cell Differentiation and Cancer Cell Death Programming
指導教授：	裘正健 Chiu, Jeng-Jiann 張俊彥 Chang, Jang-Yang 張大慈 Chang, Dah-Tsyr
口試委員:	裘正健 Chiu, Jeng-Jiann 張俊彥 Chang, Jang-Yang 張大慈 Chang, Dah-Tsyr 陳政男 Chen, Cheng-Nan 張順福 Chang, Shun-Fu
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子與細胞生物研究所 Institute of Molecular and Cellular Biology
論文出版年：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	94
中文關鍵詞：	凋亡、自噬反應、機械性流體力、過氧化物酶增生劑活化受體、平滑肌細胞型態轉變、轉化生長因子β1
外文關鍵詞：	Apoptosis, Autophagy, Mechanical Flow Force, PPAR, Smooth Muscle Cell Phenotypic Change, TGF-β1
相關次數：	點閱：1 下載：0
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細胞經常性地受到生化與物理微環境的影響，生化反應藉由化學物質與其特定受體結合產生刺激而機械力則藉由調節細胞膜上的力學感應器進而傳導訊息進入胞內並調控細胞功能。因此，化學與物理性因子在細胞訊息傳遞、基因表現、細胞結構與功能的調節作用上扮演重要角色。
為了證實轉化生長因子β1 (transforming growth factor beta 1, TGF-1)在調控間質幹細胞細胞週期與進行平滑肌細胞分化之機制，我們檢測了C3H10T1/2間質細胞受TGF-β1所調控之細胞週期與平滑肌細胞型態轉變功能。此外，近來在平滑肌功能調節的研究中，過氧化物酶增生劑活化受體 (peroxisome proliferator activated receptor, PPAR)與其興奮劑受到相當大的關注，在本研究的結果中，發現了(1) TGF-β1誘導C3H10T1/2細胞分化為平滑肌細胞型態是透過PI3K/Akt/p70S6K 訊息傳遞路徑。 (2) PPAR-α興奮劑(即WY14,643與clofibrate)可抑制C3H10T1/2細胞受TGF-β1誘發生成之平滑肌細胞標記蛋白表現和SRF與DNA結合活性的能力，但 PPAR-δ/β興奮劑 (GW501516)或PPAR-γ興奮劑(troglitazone)則無此功能。 (3) WY14,643與clofibrate 可抑制TGF-β1所造成的Smad3/Akt/P70S6K訊息傳遞路徑活化。 (4) Smad3分子調節 TGF-β1造成之細胞週期停滯。 (5) PPAR-α調控10T1/2細胞週期停滯於G0/G1時期，而此現象與 TGF-β受體無關。以上結果可推測PPAR-α 分子調控10T1/2 cells之細胞週期與其受TGF-β1誘導之平滑肌細胞型態轉變。
間隙流所造成的機械力可調控腫瘤細胞轉移與侵入以及抗癌藥物輸送等功能。為了釐清流體剪力調節腫瘤細胞生存之機制，我們將四種不同腫瘤細胞株施以不同剪力大小之層流或震盪流。實驗結果發現，當施以0.5到12 dynes/cm2之層流剪力時，將造成四種腫瘤細胞株的死亡。以Hep3B肝癌細胞作為模型進行研究時，發現此死亡現象僅在層流作用下可見，在震盪型剪力則不可見。兩種型態的流場對於正常的肝細胞則不會造成其死亡。在四種腫瘤細胞株中，層流剪力會增加細胞中凋亡標記annexin V-FITC之螢光染色以及cleaved caspase-8, -9, -3與PARP蛋白的表現。此外，藉由偵測酸性液泡微粒之生成、LC3B蛋白轉型以及p62/SQSTM1 降解等現象，發現層流剪力亦誘發Hep3B細胞之自噬反應。以小片段干擾型RNA進行短期轉殖，我們發現剪力造成Hep3B細胞所產生的凋亡與自噬反應是經由骨型態蛋白受體1B (BMPRIB)、Smad1/5與 p38 MAPK等分子所調控。
綜觀來說，我們的結果指出TGF-β 家族之訊息傳遞會調控間質細胞的平滑肌細胞型態轉變與機械性流體力所誘導的凋亡與自噬反應。我們的發現也提供機械性微環境調節分子信息、基因表現、細胞存亡與功能之機制的新觀點。TGF-β 家族之訊息傳遞調控可能對建立改善心血管或癌症疾病的新方法有所助益。此外，機械流體力學與TGF-β 家族的訊息途徑之間的相互關係對於治療腫瘤病人可能也可提供新的研究方向。

Cells are constantly influenced by their biochemical and physical microenvironments. Chemical ligands binding to their specific receptors under biochemical stimulation and mechanical forces regulating membrane mechanosensors, e.g., integrins, can transduce information into the cell and modulate cell functions. Thus, the modulation of cell signaling, gene expression, structure and function by both chemical and physical factors plays an important role in health and disease.
To demonstrate the mechanisms by which chemical stimuli of transforming growth factor-β1 (TGF-β1) regulating the cell cycle and the differentiation of mesenchymal cells into smooth muscle cells (SMCs), we examined the role of TGF-β1-mediated cell cycle control and SMC phenotypic modulation of C3H10T1/2 (10T1/2) mesenchymal cells. Furthermore, peroxisome proliferator-activated receptors (PPARs) and their agonists have recently gained more attention in the study of the SMC function. In this study, the results showed the following: (1) the PI3K/Akt/p70S6K signaling cascade is involved in TGF-β1-induced differentiation of 10T1/2 cells into cells with a SMC phenotype. (2) PPAR-α agonists (i.e., WY14,643 and clofibrate), but not a PPAR-δ/β agonist (GW501516) or PPAR-γ agonist (troglitazone), inhibit TGF-β1-induced SMC markers and the DNA binding activity of serum response factor (SRF) in 10T1/2 cells. (3) WY14,643 and clofibrate inhibit the TGF-β1 activation of the Smad3/Akt/P70S6K signaling cascade. (4) TGF-β1-induced cell cycle arrest at the G0/G1 phases is mediated by Smad3 in 10T1/2 cells. (5) The PPAR-α-mediated 10T1/2 cell cycle arrest at the G0/G1 phases is TGF-β receptor independent. These results suggest that PPAR-α mediates cell cycle control and TGF-β1-induced SMC phenotypic changes in 10T1/2 cells.
Mechanical forces, including interstitial fluid flow in and surrounding tissues, can modulate metastasis and invasion of tumor cells, and anticancer drug delivery. To elucidate the shear stress-regulated mechanism on tumor cell survival, four tumor cell lines (i.e., Hep3B, MG63, SCC25 and A549) were exposed to laminar or oscillatory flow at different magnitude of shear stress. We found that laminar shear stress (LSS) ranging from 0.5 to 12 dynes/cm2 induces death of these four tumor cell lines. Only laminar (0.5 dynes/cm2) but not oscillatory shear stress (0.5±4 dynes/cm2) could significantly induce the level of Hep3B hepatocarcinoma cell death. Both shear patterns had no effect on normal hepatocyte Chang liver cell line. LSS increased the percentage of cells positive for annexin V-FITC staining in all four cell lines up to 72 h after flow exposure, with cleaved caspase-8, -9, and -3, and PARP up-regulated by shear stress. In addition, LSS also induced Hep3B cell autophagy, as detected by acidic vesicular organelle formation, LC3B transformation, and p62/SQSTM1 degradation. By transiently transfecting small interfering RNA, we found that the shear-induced apoptosis and autophagy are mediated by bone morphogenetic protein receptor type 1B (BMPRIB), BMPR-specific Smad1 and Smad5, and p38 MAPK in Hep3B cells.
In summary, our results indicate that TGF-βsuperfamily signaling may mediate the smooth muscle phenotypic change of mesenchymal cells and the mechanical flow force-induced tumor cell apoptosis and autophagy. Our findings also provide new insights into the mechanisms by which the mechanical microenvironment modulates molecular signaling, gene expression, cell survival, and functions in tumor cells. The modulation of TGF-β-superfamily signaling may be useful in establishing new approaches to the treatment of a variety of cardiovascular or tumor disorders. Moreover, the communication between mechanical-flow forces and BMP signaling may contribute to new research directions for treating tumor patients, and further detailed investigations are needed.

LIST OF FIGURES………………………………………………………………………………… iii
LIST OF TABLES…………………………………………………………………………………...iv
ABSTRACT…………………………………………………………………………………….…...1
中文摘要………………………………………………………………………………………….….4
CHAPTER I. INTRODUCTION…………………………………………………………………..6
1.1    Transforming growth factor beta (TGF-β) superfamily signaling ………………………………7
1.2    TGF-βsignaling in cell cycle regulation and smooth muscle cell differentiation……………….8
1.3    Mechanical biology and its role in tumor regulation…………………………………………....10
1.4    Programmed cell death………………………………………………………………………….13
1.5 The aims of this study…………………………………………………………………………...15
CHAPTER II. MATERIALS AND METHODS………………………………………………....17
2.1 Materials………………………………………………………………………………………...18
2.2 Cell culture……………………………………………………………………………………...18
2.3 Western blot analysis……………………………………………………………………………19
2.4 Reporter gene construct and luciferase assay…………………………………………………...20
2.5 Electrophoretic mobility shift assay (EMSA)…………………………………………………..20
2.6 Flow Apparatus…………………………………………………………………………………21
2.7 Cell viability assay……………………………………………………………………………...21
2.8 Measurement of the formation of acidic vesicular organelles (AVOs) and annexin-V/propidium iodide (PI) binding assay……………………………………………………………………………22
2.9 Small interfering RNA transfection assay………………………………………………………22
2.10 Statistical analysis……………………………………………………………………………..23
CHAPTER III. RESULTS………………………………………………………………………..24
3.1 Activation of PPAR-α Induces Cell Cycle Arrest and Inhibits Transforming Growth Factor-β1 Induction of Smooth Muscle Cell Phenotype in 10T1/2 Mesenchymal Cells…...............................25
3.1.1 TGF-β1-induced differentiation of 10T1/2 cells into SMCs is mediated by the ALK5 receptor through the Akt/mTOR/p70S6K signaling cascade.…………………………………..25
3.1.2 PPAR-α, but not PPAR-δ/β or PPAR-γ, regulates the TGF-β1-induced differentiation of 10T1/2 into SMCs………….......................................................................................................26
3.1.3 PPAR-αinhibits TGF-β1-induced Akt and p70S6K phosphorylation through Smad3, but not Smad2, in 10T1/2 cells……………………………………………………………………...28
3.1.4 The roles of Smad2/3 and the Akt/mTOR/p70S6K signaling cascade in TGF-β1-mediated cell cycle regulatory protein expression in 10T1/2 cells.……....................................................28
3.1.5 PPAR-α agonist induces, but does not have a synergistic effect on, TGF-β1-induced cell cycle arrest in 10T1/2 cells by down-regulating cyclin D1 and Cdk2 and 4…………………..30
3.2 Mechanical Regulation of Cancer Cell Apoptosis and Autophagy: Roles of Bone Morphogenetic Protein Receptor, Smad1/5, and p38 MAPK………………………………………………………..31
3.2.1 LSS, but not oscillatory shear stress (OSS), induces cancer cell death..………………….31
3.2.2 LSS induces autophagy and apoptosis in cancer cells…………………………………….31
3.2.3 Interaction between shear stress-induced autophagy and apoptosis in cancer cells.……...32
3.2.4 Shear stress-induced autophagy and apoptosis in cancer cells are mediated by BMPs/Smads signaling pathway…………………………………………………………..…...33
3.2.5 p38 MAPK but not ERK and JNK mediate shear stress-induced autophagy and apoptosis in cancer cells………………………………………………………..........................................34
CHAPTER IV. DISCUSSION…………………………………………………………………….37
4.1 Activation of PPAR-α Induces Cell Cycle Arrest and Inhibits Transforming Growth Factor-β1 Induction of Smooth Muscle Cell Phenotype in 10T1/2 Mesenchymal Cells……………………...38
4.2 Mechanical Regulation of Cancer Cell Apoptosis and Autophagy : Roles of Bone Morphogenetic Protein Receptor, Smad1/5, and p38 MAPK ……………………………………...43
CHAPTER V. CONCLUSION……………………………………………………………………48
CHAPTER VI. FUTURE DIRECTION…………………………………………………………50
CHAPTER VII REFERENCES………………………………………………………………….53
FIGURES…………………………………………………………………………………………..64
TABLES…………………………………………………………………………………………….86
PUBLICATIONS…………………………………………………………………………………..94
 
LIST OF FIGURES
Figure 1-1 Smad-dependent and Smad-independent TGF-β signaling pathway…………………...65
Figure 1-2 Extrinsic and intrinsic apoptosis signaling pathway……………………………………66
Figure 3-1 TGF-β1-induced differentiation of 10T1/2 cells into SMCs is mediated by the ALK5 receptor through the Akt/mTOR/p70S6K signaling cascade……………………………………….67
Figure 3-2 PPAR-α, but not PPAR-δ/β or PPAR-γ, regulates the TGF-β1-induced differentiation of 10T1/2 into SMCs…………………………………………………………………………………..69
Figure 3-3 PPAR-α inhibits TGF-β1-induced Akt and p70S6K phosphorylation through Smad3, but not Smad2…………………………………………………………………………………………...72
Figure 3-4 The roles of Smad2/3 and the Akt/mTOR/p70S6K signaling cascade in TGF-β1-mediated cell cycle distribution and regulatory protein expression……….........................74
Figure 3-5 PPAR-α agonist induces, but does not have a synergistic effect on, TGF-β1-induced cell cycle arrest in 10T1/2 cells by down-regulating cyclin D1 and Cdk2 and 4.………………………76
Figure 3-6 LSS but not OSS induces cancer cell death.……………………………………………77
Figure 3-7 LSS induces autophagy and apoptosis in cancer cells.………….....................................79
Figure 3-8 Shear stress induces autophagic cell death earlier than apoptotic cell death.…………..82
Figure 3-9 P66Shc Shear-induced autophagy and apoptosis in Hep3B cells is mediated by Smad1/5 and the BMP receptors.………..........................................................................................................83
Figure 3-10 Shear-induced autophagy and apoptosis in Hep3B cells are mediated by p38 MAPK.85
Figure 4-1 Schematic representation of the signaling pathways regulating the cell cycle and differentiation in 10T1/2 cells in response to TGF-β1..…………………………………………....86
Figure 4-2 Schematic representation of the signaling pathways regulating autophagy and apoptosis in tumor cells in response to shear stress.…………………………………………………………..87
 
LIST OF TABLES
Table 1 TGF-β1 induces G0/G1 arrest in 10T1/2 cells.…………………………………………….89
Table 2 Smad3, but not Smad2, mediates the TGF-β1-induced G0/G1 arrest in 10T1/2 cells.….....90
Table 3 PI3K/AKT/mTOR inhibition has a synergistic effect on TGF-β1-induced G0/G1 arrest in 10T1/2 cells.………………………………………………………………………………………..91
Table 4 PPARα activation induces G0/G1 arrest in 10T1/2 cells.……………………………….....92
Table 5 WY14,643-induced G0/G1 arrest in 10T1/2 cells is independent on TGF-β receptor….....93

                                

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