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系統識別號 U0026-2612201811040800
論文名稱(中文) 血管生成素樣蛋白4有助於表皮生長因子刺激頭頸部鱗狀細胞癌的轉移
論文名稱(英文) Angiopoietin-like 4 (ANGPTL4) contributes to Epidermal growth factor (EGF)-stimulated metastasis of head and neck squamous cell carcinoma (HNSCC)
校院名稱 成功大學
系所名稱(中) 生物科技與產業科學系
系所名稱(英) Department of Biotechnology and Bioindustry Sciences
學年度 107
學期 1
出版年 107
研究生(中文) 廖禹涵
研究生(英文) Yu-Han Liao
學號 Z28991023
學位類別 博士
語文別 英文
論文頁數 99頁
口試委員 指導教授-陳炳焜
口試委員-張文昌
召集委員-王育民
口試委員-呂增宏
口試委員-洪文俊
中文關鍵字 表皮生長因子  血管生成素樣蛋白4  轉移  頭頸部鱗狀細胞癌 
英文關鍵字 EGF  ANGPTL4  metastasis  HNSCC 
學科別分類
中文摘要 大多數頭頸部癌細胞屬於鱗狀細胞類型,也稱為頭頸部鱗狀細胞癌(HNSCC)。大約有75%的頭頸癌是由酒精或煙草所造成的。其他風險因子包括檳榔、人乳頭瘤病毒、輻射暴露和愛潑斯坦- 巴爾病毒等。早期HNSCC 用單一療法(手術或放射治療)。然而,大約66%的患者屬晚期或抗藥性產生,這些患者中不到30%可以治癒。晚期HNSCC的治療經常需要多模式治療並且藥物對於患者有顯著的毒性及副作用。HNSCC會擴散並轉移到身體的其他部位,例如淋巴結或肺部。轉移是一個複雜的過程,需要移動並脫離原始位置的腫瘤細胞群,具有從原發性腫瘤內滲入全身循環的能力,在血液循環中存活下來的癌細胞,進一步在遠處的區域滲透出去,並轉移成功到原端的器官繼續生長。一旦HNSCC傳播出去,患有這種轉移性疾病的患者預後極差,存活率不到一年。因此,轉移仍然是HNSCC患者死亡的主要原因。有許多分子標記是HNSCC進展重要步驟中的關鍵參與者,包括EGF、EGFR、BCL-2、BAX、JUN、VEGFA、MMP2和MMP9。最值得注意的是,表皮生長因子受體(EGFR),也稱為ErbB1/HER1,是ErbB受體酪氨酸激酶家族的成員。EGFR在一些上皮惡性腫瘤中有過表達的情形,包含HNSCC,其中多達90%的腫瘤有EGFR過度表達的狀況。EGFR對於HNSCC的生長、侵襲、轉移和血管生成都有關鍵作用與角色。EGFR配體如表皮生長因子(EGF)在HNSCC的惡性轉化中起主要作用。EGFR透過調節HNSCC的侵襲、遷移和失巢凋亡進而促進HNSCC 轉移。ANGPTL4(血管生成素樣蛋白4),也稱為(ARP4,FIAF,HFARP,NL2,PGAR,pp1158),是蛋白質編碼基因。它是一種分泌蛋白,具有捲曲螺旋N-末端結構域和纖維蛋白原樣C-末端結構域。ANGPTL4蛋白屬於分泌蛋白的超家族,其與調節血管生成的因子結構相關,稱為血管生成素,可以充當血管生成的調節劑並且調節腫瘤發生。最初,ANGPTL4被研究認為僅參與脂質代謝的脂肪因子,是因為其在肝臟和脂肪組織中普遍存在。ANGPTL4是脂蛋白脂肪酶的內源性抑製劑,可調節脂質平衡、冠狀動脈粥樣硬化風險等。在內皮細胞中ANGPTL4蛋白會受到缺氧誘導而表達。研究表明,ANGPTL4通過PPARs調節其表達來介導代謝綜合徵(如糖尿病,肥胖和癌症),此外也有研究指出ANGPTL4可能也參與癌症進展和轉移。例如,ANGPTL4促進原發性黑色素瘤的惡性發展,具有轉移至腦的風險,除了促進轉移之外還能抑制結腸直腸癌細胞的凋亡。另外有研究指出,細胞因子TGFβ通過Smad信號通路在乳腺腫瘤微環境中誘導ANGPTL4的表達來促進癌細胞轉移至肺部。HNSCC是一種侵襲性危及生命的疾病,與高死亡率有關。許多研究正努力探索有助於HNSCC發展的影響因子以及導致疾病發展的分子機制。然而,ANGPTL4在EGF所增強HNSCC轉移發展中的功能和調節機制仍不清楚。我們確認EGF會刺激HNSCC分泌ANGPTL4蛋白。在本研究中,我們證明ANGPTL4表達增強了EGF促進頭頸癌細胞的抗失巢凋亡能力。除了EGF之外,ANGPTL4本身還可增強頭頸癌細胞的惡性發展,包括細胞遷移、侵襲和抗失巢凋亡能力。此外我們也證明EGF刺激頭頸癌細胞表達與分泌ANGPTL4參與EGF所促進的HNSCC遷移、侵襲和跨內皮入侵。單獨的ANGPTL4同樣也可以影響HNSCC遷移、侵襲和跨內皮入侵。我們利用消除ANGPTL4的表達來證明,EGF刺激細胞的抗失巢凋亡和腫瘤細胞與內皮細胞的相互作用會因此被顯著抑制。研究結果也顯示抑制ANGPTL4能阻斷EGF所誘導頭頸癌細胞產生基質金屬蛋白酶-1(MMP-1)的酶活化,進一步阻止頭頸癌細胞的遷移、侵襲和轉移。此外ANGPTL4通過ITGβ1信號途徑激活c-Jun的表達,從而影響激活蛋白-1(AP-1)與MMP-1啟動子的結合。c-Jun信號傳導途徑對於ANGPTL4調節的MMP-1表達是必需的並且參與在EGF/ANGPTL4/MMP-1促進HNSCC轉移機制。EGF誘導ANGPTL4的分泌產生刺激腫瘤-內皮細胞相互作用,然後促進腫瘤細胞滲入血管的能力。ANGPTL4的抑制顯著抑制EGF刺激的HNSCC侵入以及轉移到肺部。總之這些結果表明ANGPTL4刺激HNSCC產生MMP-1並影響EGF促進的頭頸癌細胞的轉移。ANGPTL4受刺激分泌或是癌細胞自分泌產生是表皮生長因子受體(EGFR)介導HNSCC轉移的重要標誌物。
英文摘要 Most head and neck cancers are squamous cell types, also called head and neck squamous cell carcinoma (HNSCC). About 75% of head and neck cancer is caused by the use of alcohol or tobacco. Other risk factors such as betel quid, some types of human papillomavirus, radiation exposure, specific workplace exposures, and the Epstein-Barr virus. Early period HNSCC is treated comparatively well with a single-modality therapy (either surgery or radiation alone). However, almost 66% of patients current with advanced sickness, and less than 30% of these patients can be cured. The treatment of advanced HNSCC frequently requires multimodality therapy and involves significant toxicity. HNSCC can spread and metastasize to other parts of the body, for example the lymph nodes or lungs. Metastasis is an complex sequential process that demands a discrete population of tumor cells to have the capacity to intravasate from the original tumor into systemic circulation, exist and survive in circulation, extravasate at a distant site, growth spurt and proliferate in a foreign hostile environment. Once HNSCC spreads, patients with metastatic disease have very poor prognosis with a survival rate of fewer than a year. Metastasis remains a main cause of decease in patients with HNSCC. There are many molecular markers that could be linchpin players in important procedures of HNSCC progression, including EGF, EGFR, BCL-2, BAX, JUN, VEGFA, MMP2 and MMP9. Most notably, epidermal growth factor receptor (EGFR), also known as ErbB1/HER1, is a member of the ErbB family of receptor tyrosine kinases. EGFR is overexpressed in several epithelial malignancies, including HNSCC, which exhibits EGFR overexpression in up to 90% of tumors. EGFR act a pivotal role in HNSCC growth, invasion, metastasis, and angiogenesis. EGFR ligands such as epidermal growth factor (EGF) play a major role in the malignant transformation of HNSCC. EGFR contributes to a metastatic HNSCC tumor cell phenotype through regulation of invasion, migration, and anoikis. ANGPTL4 (Angiopoietin Like Protein 4), which is also called (ARP4, FIAF, HFARP, NL2, PGAR, pp1158) is a protein coding gene. It is a secreted protein with a coiled-coil Nterminal domain and a fibrinogen-like C-terminal domain. The ANGPTL4 protein belongs to a superfamily of secreted proteins structurally related to factors modulating angiogenesis known as angiopoietins that may play as a regulator of angiogenesis and modulate tumorigenesis. Initially, ANGPTL4 was evaluated as an adipokine exclusive involved in lipid metabolism because of its widespread expression in liver and adipose tissue. ANGPTL4 is an endogenous inhibitor of lipoprotein lipase that modulates lipid standards, coronary atherosclerosis risk, and nutrient partitioning. Hypoxia-induced ANGPTL4 protein expression in endothelial cells. Studies show that ANGPTL4 mediates the cross talk between metabolic syndromes, for example diabetes, obesity, and cancer, through regulation of its expression by PPARs, and studies have also demonstrated that ANGPTL4 may be involved in cancer progression and metastasis. For example, ANGPTL4 boosts the malice phenotype of primary melanomas with risky of metastasizing to the brain, and it could be also promoted metastsis and curb the apoptosis of colorectal cancer cells. The induction of ANGPTL4 by the cytokine TGFβ via the Smad signaling pathway in the breast tumor microenvironment trigger cancer cells for metastasis to the lungs. HNSCC is an invasive life-threatening disease related to high mortality rates. Efforts have been made to probe the molecular mechanisms that promoted the initiation and progression of HNSCC. However, the functional role and regulatory mechanism of ANGPTL4 in the development of EGF-enhanced HNSCC metastasis is still unclear. We confirm that EGF stimulates the protein secretion of ANGPTL4 in HNSCC. In this study, we demonstrate that ANGPTL4 expression enhances EGF-promoted head and neck cancer cell anoikis resistance. In addition to EGF-, ANGPTL4 enhances HNSCC malignant behavior including migration, invasion and anoikis resistance. Furthermore, we demonstrated that ANGPTL4 expression and secretion by EGF is involved in EGF-promoted HNSCC migration, invasion, and transendothelial invasion. ANGPTL4 alone can also influence HNSCC migration, invasion, and transendothelial invasion. In addition, EGF-stimulated anoikis-resistant tumor cell interaction with endothelial cells is significantly repressed by abolishing the expression of ANGPTL4. Down-regulation of ANGPTL4 has been shown to block EGF-induced protein expression and enzyme activation of matrix metalloproteinases-1 (MMP-1) involved in head and neck cancer cell migration, invasion, and metastasis. Furthermore, ANGPTL4 activates the expression of c-Jun affect activator protein-1 (AP-1) binding to the MMP-1 promoter via the integrin β1 (ITGβ1) signal pathway. The c-Jun signaling pathway is essential for ANGPTL4-regulated expression of MMP-1 and is involved in the EGF/ANGPTL4/MMP-1 axis in HNSCC. EGF-induced ANGPTL4 autocrine production stimulates tumor-endothelial cell interactions, which then facilitates the ability of tumor cells to infiltrate into blood vessels. The repression of ANGPTL4 significantly suppresses EGF-stimulated HNSCC both in terms of extravasation and metastatic seeding into the lungs. All in all, these results indicate that ANGPTL4 facilitates EGF-promoted cancer metastasis via increasing the expression of MMP-1 in HNSCC. Both the protein secretion and autocrine production of ANGPTL4 are important markers in epidermal growth factor receptor (EGFR)-mediated HNSCC metastasis.
論文目次 Chinese Abstract............ I
Abstract............. IV
Acknowledgements............ IX
Table and Contents........... XI
Contents of Figures............ XIII
Abbreviations List........... XVIII
(I) Introduction........... 1
A. Head and neck squamous cell carcinoma (HNSCC) ..... 1
B. Epidermal growth factor (EGF) and Epidermal growth factor receptor (EGFR) in HNSCC
............. 2
C. Metastasis ........... 3
D. Epidermal growth factor (EGF) and Cell-Cell interaction in metastasis ... 4
E. Anoikis, Anoikis resistance and tumor metastasis ....... 4
F. Angiopoietin-like 4 (ANGPTL4) ........ 6
G. Angiopoietin-like 4 (ANGPTL4) and cancer progression .... 7
H. Research aims ........... 8
(II) Materials and methods .......... 9
1. Materials and Methods ........... 9
1-1. Cell culture .......... 9
1-2. Conditioned medium and antibodies ........ 10
1-3. Reverse transcription-PCR and real-time quantitative RT –PCR ... 10
1-4. Enzyme-linked immunosorbent assay (ELISA) ..... 11
1-5. Targeted gene knockdown experiments ...... 11
1-6. Transfection with siRNA oligonucleotides ...... 12
1-7. Transfection with small interfering RNA (siRNA) oligonucleotides ... 13
1-8. In vitro cell migration assay ....... 13
1-9. In vitro cell invasion assay ......... 14
1-10. Transendothelial invasion assay ........ 15
1-11. Cell adhesion assay .......... 16
1-12. Anoikis assay .......... 17
1-13. Plasmid vector construction and Luciferase assays ..... 17
1-14. Experimental pulmonary metastasis Assay in Vivo ..... 19
1-15. Pulmonary extravasation assay in Vivo ....... 19
1-16. Immunohistochemical (IHC) staining ....... 20
1-17. Statistical analysis ......... 20
(III) Results ........... 22
A. EGF induces the expression of ANGPTL4 mRNA in HNSCC ... 22
B. EGF induces the protein secretion of ANGPTL4 in HNSCC ... 22
C. EGF-induced ANGPTL4 enhances HNSCC migration .... 23
D. EGF-induced ANGPTL4 enhances HNSCC invasion ...... 25
E. EGF-induced ANGPTL4 enhances HNSCC transendothelial invasion .. 25
F. EGF-induced ANGPTL4 promotes tumor-endothelial cell interactions ... 26
G. Angiopoietin-like 4 (ANGPTL4) and cancer progression ..... 27
H. c-Jun is necessary for ANGPTL4-induced MMP-1 expression ... 28
I. Integrin β1 is required for MMP-1 expression and tumor-endothelial cell interactions following EGF- and ANGPTL4-induction ....... 31
J. The EGF/ANGPTL4/MMP-1 axis promotes HNSCC metastasis ... 32
(IV) Discussion ........... 35
(V) References .......... 41
(VI) Figures ........... 47
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