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系統識別號 U0026-2208201217310600
論文名稱(中文) 精胺基琥珀酸裂解酶在癌症中所扮演之角色
論文名稱(英文) The Role of Argininosuccinate Lyase in Cancer
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 黃浩綸
研究生(英文) Hau-Lun Huang
學號 s58941549
學位類別 博士
語文別 英文
論文頁數 116頁
口試委員 指導教授-賴明德
召集委員-呂增宏
口試委員-沈孟儒
口試委員-馬明琪
口試委員-洪文俊
中文關鍵字 內質網壓力  精胺基琥珀酸裂解酶  細胞週期蛋白A2  一氧化氮 
英文關鍵字 ER stress  Argininosuccinate lyase  Cyclin A2  Nitric oxide 
學科別分類
中文摘要 最近,在人類癌症的氨基酸代謝也被認為是不同於正常細胞的。內質網是
負責合成蛋白質和檢測環境養分之胞器。腫瘤細胞通常生長在一個不良的環
境,如營養缺乏。因此,內質網壓力反應往往在人類癌症中被觀察到。精氨酸
和天冬酰胺分別被認為是某些類型的肝癌和白血病所必需的氨基酸。胺基酸代
謝及內質網壓力之間的訊息連結有很大的程度是未知的。此外,由於精氨酸的
一些代謝產物對於細胞生長來說是重要的而且內質網壓力的誘發者包含了B 型
肝炎病毒表面蛋白及C 型肝炎病毒核心蛋白在肝癌發展過程中扮演著重要角
色。再加上C 型肝炎病毒核心蛋白被報導會誘發精胺基琥珀酸裂解酶的表現。
因此,我們測試了精胺基琥珀酸裂解酶在癌症的進展中是很重要的此一假設。
首先,我們觀察到肝癌細胞HuH-7 中表現B 型肝炎病毒的PreS2 蛋白可以誘發精胺基琥珀酸裂解酶的表現。我們也發現不論是在肝癌、乳癌及大腸直腸癌細胞株和小鼠活體肝臟中其精胺基琥珀酸裂解酶的表現均可被內質網壓力所誘
導。在檢驗臨床檢體中精胺基琥珀酸裂解酶的表現量,我們也觀察到肝癌、乳
癌及大腸直腸癌檢體中精胺基琥珀酸裂解酶過度表現的情形。從shASL 的穩定轉染細胞株中發現到當細胞中精胺基琥珀酸裂解酶的表現被壓抑時,則會抑制了細胞的生長速率和非固著依賴性生長。此外,在BALB/c 及 NOD/SCID 小鼠皮下注射腫瘤細胞的模式中,當精胺基琥珀酸裂解酶的表現被壓抑時,亦會使得其腫瘤生長變慢而延長其存活率。再者,給予腫瘤老鼠注射帶有精胺基琥珀酸裂解酶shRNA 的慢病毒也可以抑制腫瘤生長。而檢驗細胞週期相關蛋白表現時,只發現到cyclin A2 蛋白的表現量降低且其信使核醣核酸的表現量則不變。另外處理過蛋白酶抑制劑的細胞其cyclin A2 蛋白表現量降低的情形則可被回復。另一方面細胞週期的分析也顯示G2/M 週期的延遲。此外,當過度表現精胺基琥珀酸裂解酶時也可增加cyclin A2 蛋白表現量。當精胺基琥珀酸裂解酶的表現被壓抑時,細胞也有自噬作用的產生,同時細胞內的一氧化氮含量也有減少的現象,但是細胞內的精胺酸含量則不受影響。當給予細胞多量的精胺酸則並不會使細胞生長及細胞內一氧化氮含量有回復的情形。最後給予細胞額外的一氧化氮則可以部分地回復精胺基琥珀酸裂解酶表現被壓抑時所導致的細胞生長抑制之情形。過度表達cyclin A2 或是精胺基琥珀酸裂解酶則能回復精胺基琥珀酸裂解酶表現被壓抑時所產生的細胞生長抑制之情形。總而言之,此研究有以下的一些結果: (1) 內質網壓力是透過轉錄的方式來誘發精胺基琥珀酸裂解酶,(2) 我們也觀察到肝癌、乳癌及大腸直腸癌檢體中精胺基琥珀酸裂解酶有過度表現的情形,(3) 當精胺基琥珀酸裂解酶的表現被壓抑時會誘發細胞的自噬作用但會使細胞中的cyclin A2 蛋白表現量和一氧化氮含量減少,而這些現象則在抑制腫瘤生長中扮演著一定的角色。
英文摘要 Recently, the amino acid metabolism in human cancer was found to be different from that in normal cells. The endoplasmic reticulum is an organelle responsible for synthesizing proteins and sensing environmental nutrients. Cancer cells often grow in a poor environment such as nutrient deprivation. Therefore, the endoplasmic reticulum (ER) stress is often observed in human cancer. Arginine and asparagine are considered essential amino acids for certain types of liver cancer and leukemia, respectively. Until now, the signal link between endoplasmic reticulum stress and amino acid metabolism is largely unknown. Since arginine metabolic products play an important role in cell growth, and ER stress inducers including surface protein of hepatitis B virus (HBV) and core protein of hepatitis C virus (HCV) are important in the formation of hepatocellular carcinoma (HCC). We tested the hypothesis that argininosuccinate lyase (ASL) is important for the tumorigenesis. Here we first found that HBV Pre S2 could induce ASL expression in HuH-7 cells. The expression of ASL was induced by ER stress not only in liver, breast and colon cancer cells but also in mice livers. Examination of ASL expression in cancer specimens indicated that ASL was over-expressed in HCC, breast and colon cancers. Cells expressing shASL inhibited proliferation rates and anchorage -independent growth in vitro and tumor formation in vivo in BALB/c and NOD/SCID mice. Furthermore, lentiviral infection of ASL shRNA inhibited HuH-7 tumor growth in a therapeutic animal model. Examination of the expression of protein related to cell cycle revealed that only cyclin A2 was decreased. The cyclin A2 mRNA was unaltered by ASL shRNA and the proteasome inhibitor restored the expression of cyclin A2. On the other hand, analyses of the cell cycle effects of ASL shRNA revealed a G2/M delay. In addition, overexpression of ASL in liver cancer cells up-regulates cyclin A2. Autophagy was observed in the cells treated with ASL shRNA. Stable knockdown of ASL reduced NO content but did not affect arginine level. Addition of extra arginine did not increase the level of NO and cell growth. Finally, incubation with nitric oxide donor partially recovered the growth inhibition by ASL shRNA. Ectopic expression of cyclin A2 or ASL could rescue the growth attenuation in ASL-knockdown cells. In summary, our report has the following findings; (1) ER stress induced ASL transcriptionally, (2) ASL is over-expressed in HCC, breast and colon cancers, (3) knockdown of ASL caused the increase of autophagy, the decrease of cyclin A2, and the cellular NO content which is in part mediated attenuation of tumor growth.
論文目次 Page number list
Abstract in Chinese
Abstract
I. Introduction………………………………………………………………….....01
I-1. Endoplasmic Reticulum Stress……………………………………………01
I-2. Endoplasmic Reticulum Stress and cell metabolism…………………….03
I-3. Endoplasmic Reticulum Stress and Cancer………………………...........05
I-4. Cancer and Cell Metabolism………………………………………...........08
I-5. Amino Acid Metabolism in Cancer………………………………………11
I-6. Endoplasmic Reticulum Stress, Amino Acid Metabolism, and
Cancer…………………………………………………………………......14
I-7. Arginine and Argininosuccinate lyase........................................................15
I-8. Autophagy.....................................................................................................17
II. Materials and Methods…………………………………………………...........22
II-1. Cell Culture……………………………………………………………….22
II-2. Chemicals, Reagents and Antibodies……………………………............22
II-3. Reverse transcription-Polymerase Chain Reaction (RT-PCR)
Analysis…………………………………………………………….....23
II-4. Lysate collection and Western blot analysis…………………………….24
II-5. In vivo induction of ER stress by tunicamycin………………….............25
II-6. Plasmid Transfection and Reporter Gene Assay……………………….26
II-7 Tissue Samples…………………………………………………………….26
II-8. RNA interference…………………………………………………............27
II-9. Proliferation assay (MTT assay)………………………………………...28
II-10. Foci formation assay…………………………………………….............28
II-11. Soft Agar Assay………………………………………………………….28
II-12. Production and titration of lenti-virus…………………………………29
II-13. Animals and Tumor model………………………………………...........29
II-14. Treatment of HuH-7 tumor in NOD/SCID mice………………………30
II-15. Monodansylcadaverine (MDC) staining……………………….............30
II-16. Measurement of intracellular arginine content……………………….31
II-17. Intracellular nitric oxide detection……………………………………..32
II-18. Statistical analysis……………………………………………………….32
III. Results………………………………………………………………………....33
III-1. ASL expression is induced by ER stress……………………………….33
III-2. Induction of ASL by ER stress is through transcriptional
regulation………………………………………………………………...34
III-3. ASL is over-expressed in liver, breast and, colon cancer……………...34
III-4. Knockdown of ASL expression by ASL shRNA inhibited cell
growth, migration and anchorage-independent ability……………….35
III-5. Decreased tumorigenicity of shASL stable transfectants in
BALB/c and NOD/SCID mouse tumor model…………………............36
III-6. Knockdown of ASL in liver, breast and colorectal cancer cells
reduced cyclin A2 expression……………………………………..........38
III-7. Over-expression of ASL in liver cancer cells up-regulates
cyclin A2………………………………………………………………….39
III-8. Induction of cellular autophagy were observed in different kinds
of cancer cells bearing ASL shRNA…………………………………….40
III-9. Reduction of ASL expression affects cellular nitric oxide level………41
III-10. Reduced NO content of cancer cells inhibited cell growth……..........42
III-11. The cyclin A2 expression was not affected under treatment of
NOS Inhibitor ….………………………………………………………43
III-12. The NO content in cells could affect the level of cellular
autophagy………………………………………………………………44
III-13. Excess arginine did not restore either the cell growth or the
content of NO……………………………………………………..........44
III-14. Downregulation of cyclin A2 by shASL may be independent of
the activity of ASL..................................................................................45
III-15. Ectopic expression of cyclin A2 restored the inhibition of cell
growth in ASL-knockdown cells……………………………………...45
IV. Discussion...........................................................................................................47
V. Conclusions..........................................................................................................53
VI. References..........................................................................................................54
VII. Figures..............................................................................................................67
VIII. C.V.................................................................................................................116









Figure list
Fig. 1 Urea cycle and citrulline-NO cycle………………………………..............67
Fig. 2 ASL was induced in HuH-7 overexpressed HBV wild type or pre-S2
deletion mutant large surface protein……………………………….........68
Fig. 3 Induction of ASL mRNA in liver cancer cells under ER stress…………69
Fig. 4 Induction of ASL protein in liver cancer cells under ER stress…............70
Fig. 5 Induction of ASL protein in response to ER stress in vivo………............71
Fig. 6 Induction of ASL in breast cancer cells under ER stress………..............72
Fig. 7 Induction of ASL protein in colon cancer cells under ER stress…..........73
Fig. 8 ASL promoter activity was induced by TM treatment and induction
of ASL by ER stress was attenuated by actinomycin D treatment...........74
Fig. 9 Induction of ASL by ER stress was attenuated by 2-AP…………...........75
Fig. 10 Overexpression of ASL was observed in hepatocellular
carcinoma…………………………………………………………...............76
Fig. 11 Over-expression of ASL was observed in breast cancer………………..77
Fig. 12 Over-expression of ASL was observed in colon cancer………………...78
Fig. 13 Reduction of Asl expression with Asl shRNA in liver
cancer cells………………………………………………………………...79
Fig. 14 ASL shRNA inhibited cell growth in liver cancer cells…………............80
Fig. 15 ASL shRNA inhibited anchorage-independent growth growth………..81
Fig. 16 Reduction of ASL expression inhibited cell growth anchorage
-independent ability in human breast and colon cancer cells………….82
Fig. 17 ASL shRNA inhibited cell migration in ML-1 cells…………………….83
Fig. 18 shASL inhibited tumor formation (liver) in BALB/c mice……………..84
Fig. 19 shASL inhibits tumor formation (liver) in NOD/SCID mice……..........85
Fig. 20 shASL inhibits tumor formation (breast and colon) in
NOD/SCID mice……………………………………………………..........86
Fig. 21 Lenti-viral shASL inhibited tumor formation in mice…………………87
Fig. 22 ASL knockdown reduced cyclin A2 expression in different
cancer cells…………………………………………………………...........88
Fig. 23 Downregulation of ASL induces a G2/M delay…………………………89
Fig. 24 ASL knockdown does not reduce the mRNA expression of
cyclins………………………………………………………………...........90
Fig. 25 Proteasome inhibitor restores the expression of Cyclin A2……………91
Fig. 26 Over-expression of ASL upregulates cyclin A2…………………………92
Fig. 27 Over-expression of ASL upregulates cyclin A2 in protein level but
not in mRNA level…………………………………………………...........93
Fig. 28 Downregulation of ASL induces cellular autophagy in different
cancer cell lines……………………………………………………………94
Fig. 29 Downregulation of ASL induces cellular autophagy in cancer
cells…………………………………………………………………...........95
Fig. 30 The effects of autophagic inhibitors on cell growth……………………96
Fig. 31 The effects of downregulation of ASL on cellular nitric oxide levels
in liver, breast, and colon cancer cell lines……………………………...97
Fig. 32 The effects of NO inhbitor on cellular nitric oxide levels in liver,
breast, and colon cancer cell lines……………………………………….98
Fig. 33 The effects of downregulation of ASL on cellular arginine
levels……………………………………………………………………….99
Fig. 34 Inhibition of NO production decreased cell growth……………..........100
Fig. 35 Inhibition of NO production decreased cell growth
(MTT assay)………………………………………………………...........101
Fig. 36 The effects of NO donor on cell growth………………………………..102
Fig. 37 The effects of NO inhibitor on cellular cyclin A2 levels………………103
Fig. 38 The effects of NO donor on cellular cyclin A2 levels………………….104
Fig. 39 The NO content could affect the level of cellular autophagy…………105
Fig. 40 The addition of excess arginine did not affect the colony forming
ability……………………………………………………………..............106
Fig. 41 The addition of excess arginine did not affect the nitric oxide
level……………………………………………………………….............107
Fig. 42 Both wild-type and mutant-type of ASL increased cyclin A2
level……………………………………………………….........................108
Fig. 43 Ectopic expression of cyclin A2 or ASL rescued the inhibition of
cell growth in shASL stable transfectants…………………………109, 110
Fig. 44 The proposed model of ASL function in our study……………............111
Supplementary Fig. 1 ATF4 candidate binding site in the promoter region
of ASL gene…………………………………….................112
Supplementary Fig. 2 The prognosis of patients with breast cancer from the Kaplan-Meier plotter database
(ASL expression level)…………………………………….113
Supplementary Fig. 3 The prognosis of patients with breast cancer from
the Kaplan-Meier plotter database (ASL in ER
negative or ER negative and HER2 overexpression
group)……………………………………………………...114
Supplementary Fig. 4 The expression of cyclins in cells incubated in the
arginine depleted medium……………………………..115
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