Responsive image
博碩士論文 etd-0206113-110511 詳細資訊
Title page for etd-0206113-110511
論文名稱
Title
探討膠原蛋白基質對肝臟細胞中HDGF表現之影響
Role of collagen matrix on HDGF of hepatocytes
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
63
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2013-01-25
繳交日期
Date of Submission
2013-02-06
關鍵字
Keywords
PI3K/Akt訊息傳遞、膠原蛋白基質、肝癌衍生生長因子、肝臟纖維化、肝臟細胞
HDGF, collagen matrix, Hepatic fibrogenesis, PI3K/Akt pathway, hepatocyte
統計
Statistics
本論文已被瀏覽 5654 次,被下載 0
The thesis/dissertation has been browsed 5654 times, has been downloaded 0 times.
中文摘要
肝癌衍生生長因子(HDGF)為一細胞核生長因子並參與肝臟纖維化的過程。文獻指出,在肝臟細胞接觸膠原蛋白基質時HDGF具調控轉型生長因子(TGF-)的表現。除此之外,HDGF基因傳遞會增加小鼠肝臟內膠原蛋白基質的堆積。然而,膠原蛋白基質對於HDGF的調控性影響目前仍未清晰。本實驗旨在探討肝臟纖維化初期膠原蛋白基質對肝臟細胞中HDGF表現之影響。研究結果發現,膠原蛋白基質通過阻斷細胞週期中G0/G1期以抑制clone-9的細胞增生。在clone-9及HepG2細胞實驗發現,膠原蛋白基質會造成HDGF及nucleolin的表現量增加。此外,膠原蛋白基質亦誘發PI3K/Akt訊息傳遞。利用腺病毒載體傳遞HDGF RNAi後會減弱膠原蛋白基質所誘導的HDGF、nucleolin及PI3K/Akt訊息傳遞增加的情況,由此顯示,膠原蛋白基質通過HDGF來調控PI3K/Akt訊息傳遞。總結以上結果,膠原蛋白基質會誘發HDGF的表現,並透過HDGF來調控PI3K/Akt訊息傳遞,以達到肝臟細胞及肝癌細胞促進生存(pro-survival)的能力。
Abstract
Hepatoma-derived growth factor (HDGF) is a nuclear growth factor that is involved in the development of liver fibrosis. HDGF regulated the TGF- expression while hepatocyte exposed to collagen matrix in vitro. Besides, HDGF gene delivery in mice would enhance the collagen matrix deposition in liver. However, the regulatory effect of collagen matrix on HDGF expression is remaining to be explored. The aim of this study is to investigate the effect of collagen matrix on HDGF expression of hepatocytes in the early stage of hepatic fibrogenesis. It was found that collagen matrix potently inhibited the proliferation of hepatocytes via blocking the G0/G1 phase of cell cycle. Collagen matrix up-regulated the HDGF and nucleolin expression levels of clone-9 and HepG2 cells. Moreover, collagen matrix also induced the phosphoinositide 3-kinase (PI3K)/Akt pathway. Ad-HDGF RNAi gene delivery would attenuate the collagen matrix induced HDGF, nucleolin and PI3K/Akt pathway up-regulation. In conclusion, we showed that collagen matrix up-regulated the HDGF expression and regulated PI3K/Akt pathway via HDGF expression to promote the pro-survival activity of hepatocytes and hepatoma cells.
目次 Table of Contents
論文審定書 …………………………………………………… i
致 謝 ……………………………………………………… ii
Abstract in Chinese ……………………………………………… iii
Abstract in English ……………………………………………… iv
Introduction …………………………………………………… 1
Specific Aims …………………………………………………. 6
Materials and Methods ………………………………………….. 7
Results ………………………………………………………… 15
Discussion ……………………………………………………. 23
Figures and Figure legends …………………………………… 28
References ……………………………………………………… 52
參考文獻 References
1. Reeves, H.L. & Friedman, S.L. Activation of hepatic stellate cells--a key issue in liver fibrosis. Front Biosci 7, d808-826 (2002).
2. Mormone, E., George, J. & Nieto, N. Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem Biol Interact 193, 225-231 (2011).
3. Ahmad, A. & Ahmad, R. Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches. Saudi J Gastroenterol 18, 155-167 (2012).
4. Tsukada, Y., Nagaki, M., Suetsugu, A., Osawa, Y. & Moriwaki, H. Extracellular matrix is required for the survival and differentiation of transplanted hepatic progenitor cells. Biochem Biophys Res Commun 381, 733-737 (2009).
5. Taipale, J. & Keski-Oja, J. Growth factors in the extracellular matrix. Faseb J 11, 51-59 (1997).
6. Hu, T.H., et al. Expression of hepatoma-derived growth factor in hepatocellular carcinoma. Cancer 98, 1444-1456 (2003).
7. Zhang, J., et al. Down-regulation of hepatoma-derived growth factor inhibits anchorage-independent growth and invasion of non-small cell lung cancer cells. Cancer Res 66, 18-23 (2006).
8. Kishima, Y., et al. Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus by nuclear localization signals. J Biol Chem 277, 10315-10322 (2002).
9. Abouzied, M.M., et al. Hepatoma-derived growth factor. Significance of amino acid residues 81-100 in cell surface interaction and proliferative activity. J Biol Chem 280, 10945-10954 (2005).
10. Zhou, Y., Zhou, N., Fang, W. & Huo, J. Overexpressed HDGF as an independent prognostic factor is involved in poor prognosis in Chinese patients with liver cancer. Diagn Pathol 5, 58 (2010).
11. Sedlmaier, A., et al. Overexpression of hepatoma-derived growth factor in melanocytes does not lead to oncogenic transformation. BMC Cancer 11, 457 (2011).
12. Narron, J.V., Stoops, T.D., Barringhaus, K., Matsumura, M. & Everett, A.D. Hepatoma-derived growth factor is expressed after vascular injury in the rat and stimulates smooth muscle cell migration. Pediatr Res 59, 778-783 (2006).
13. Yoshida, K., et al. Hepatoma-derived growth factor is a novel prognostic factor for hepatocellular carcinoma. Ann Surg Oncol 13, 159-167 (2006).
14. Chen, S.C., et al. Hepatoma-derived growth factor regulates breast cancer cell invasion by modulating epithelial--mesenchymal transition. J Pathol 228, 158-169 (2012).
15. Chen, X., et al. Prognostic value of nuclear hepatoma-derived growth factor (HDGF) localization in patients with breast cancer. Pathol Res Pract 208, 437-443 (2012).
16. Chang, K.C., et al. Hepatoma-derived growth factor is a novel prognostic factor for gastrointestinal stromal tumors. Int J Cancer 121, 1059-1065 (2007).
17. Ren, H., et al. Expression of hepatoma-derived growth factor is a strong prognostic predictor for patients with early-stage non-small-cell lung cancer. J Clin Oncol 22, 3230-3237 (2004).
18. Uyama, H., et al. Hepatoma-derived growth factor is a novel prognostic factor for patients with pancreatic cancer. Clin Cancer Res 12, 6043-6048 (2006).
19. Mao, J., et al. Hepatoma-derived growth factor involved in the carcinogenesis of gastric epithelial cells through promotion of cell proliferation by Erk1/2 activation. Cancer Sci 99, 2120-2127 (2008).
20. Tsang, T.Y., et al. Mechanistic study on growth suppression and apoptosis induction by targeting hepatoma-derived growth factor in human hepatocellular carcinoma HepG2 cells. Cell Physiol Biochem 24, 253-262 (2009).
21. Kao, Y.H., et al. Upregulation of hepatoma-derived growth factor is involved in murine hepatic fibrogenesis. J Hepatol 52, 96-105 (2010).
22. Yoshiji, H., et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52, 1347-1354 (2003).
23. Corpechot, C., et al. Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 35, 1010-1021 (2002).
24. Okuda, Y., et al. Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor. Cancer Sci 94, 1034-1041 (2003).
25. Xia, H., Nho, R.S., Kahm, J., Kleidon, J. & Henke, C.A. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. J Biol Chem 279, 33024-33034 (2004).
26. Kung, M.L., et al. Hepatoma-derived growth factor stimulates podosome rosettes formation in NIH/3T3 cells through the activation of phosphatidylinositol 3-kinase/Akt pathway. Biochem Biophys Res Commun 425, 169-176 (2012).
27. Cutroneo, K.R. How is Type I procollagen synthesis regulated at the gene level during tissue fibrosis. J Cell Biochem 90, 1-5 (2003).
28. Godoy, P., et al. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor beta-induced apoptosis. Hepatology 49, 2031-2043 (2009).
29. Hansen, L.K. & Albrecht, J.H. Regulation of the hepatocyte cell cycle by type I collagen matrix: role of cyclin D1. J Cell Sci 112 ( Pt 17), 2971-2981 (1999).
30. Scott, J.E., Bosworth, T.R., Cribb, A.M. & Gressner, A.M. The chemical morphology of extracellular matrix in experimental rat liver fibrosis resembles that of normal developing connective tissue. Virchows Arch 424, 89-98 (1994).
31. Gressner, A.M., Weiskirchen, R., Breitkopf, K. & Dooley, S. Roles of TGF-beta in hepatic fibrosis. Front Biosci 7, d793-807 (2002).
32. Verrecchia, F. & Mauviel, A. Transforming growth factor-beta and fibrosis. World J Gastroenterol 13, 3056-3062 (2007).
33. Kanzler, S., et al. TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol 276, G1059-1068 (1999).
34. Clouthier, D.E., Comerford, S.A. & Hammer, R.E. Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. J Clin Invest 100, 2697-2713 (1997).
35. Rosmorduc, O., et al. Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol 155, 1065-1073 (1999).
36. Harris, H.E. & Raucci, A. Alarmin(g) news about danger: workshop on innate danger signals and HMGB1. EMBO Rep 7, 774-778 (2006).
37. Park, J.S., et al. Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol 284, C870-879 (2003).
38. Coffelt, S.B. & Scandurro, A.B. Tumors sound the alarmin(s). Cancer Res 68, 6482-6485 (2008).
39. Bianchi, M.E. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81, 1-5 (2007).
40. Semenkovich, C.F., Ostlund, R.E., Jr., Olson, M.O. & Yang, J.W. A protein partially expressed on the surface of HepG2 cells that binds lipoproteins specifically is nucleolin. Biochemistry 29, 9708-9713 (1990).
41. Meng, G.Z., Xiao, S.J., Zeng, S.E. & Li, Y.Q. [Downregulation of cell-surface-expressed nucleolin inhibits the growth of hepatocellular carcinoma cells in vitro]. Zhonghua Zhong Liu Za Zhi 33, 23-27 (2011).
42. Bremer, S., et al. Hepatoma-derived growth factor and nucleolin exist in the same ribonucleoprotein complex. BMC Biochem 14, 2 (2013).
43. Meng, J., Xie, W., Cao, L., Hu, C. & Zhe, Z. shRNA targeting HDGF suppressed cell growth and invasion of squamous cell lung cancer. Acta Biochim Biophys Sin (Shanghai) 42, 52-57 (2010).
電子全文 Fulltext
本電子全文僅授權使用者為學術研究之目的,進行個人非營利性質之檢索、閱讀、列印。請遵守中華民國著作權法之相關規定,切勿任意重製、散佈、改作、轉貼、播送,以免觸法。
論文使用權限 Thesis access permission:自定論文開放時間 user define
開放時間 Available:
校內 Campus:永不公開 not available
校外 Off-campus:永不公開 not available

您的 IP(校外) 位址是 3.81.30.41
論文開放下載的時間是 校外不公開

Your IP address is 3.81.30.41
This thesis will be available to you on Indicate off-campus access is not available.

紙本論文 Printed copies
紙本論文的公開資訊在102學年度以後相對較為完整。如果需要查詢101學年度以前的紙本論文公開資訊,請聯繫圖資處紙本論文服務櫃台。如有不便之處敬請見諒。
開放時間 available 永不公開 not available

QR Code