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研究生:林琮傑
研究生(外文):Lin, Tsungchieh
論文名稱:食慾調控激素瘦體素與饑餓素於腎臟病變中扮演的角色及其作用機轉
論文名稱(外文):Roles and molecular mechanisms of appetite-regulating hormones, leptin and ghrelin in renal diseases
指導教授:徐士蘭徐士蘭引用關係楊重熙
指導教授(外文):Hsu, ShihlanYang, Chungshi
口試委員:楊重熙羅履維吳立真徐士蘭林赫
口試委員(外文):Yang, ChungshiLo, LeuweiWu, LichenHsu, ShihlanLin, Ho 
口試日期:2011-05-23
學位類別:博士
校院名稱:國防醫學院
系所名稱:生命科學研究所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:83
中文關鍵詞:瘦體素纖維化纖維母細胞饑餓素腎細胞癌
外文關鍵詞:snailAurora A
相關次數:
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  • 下載下載:12
  • 收藏至我的研究室書目清單書目收藏:1
瘦體素是一胜肽類賀爾蒙,其對於降低食慾,以及促進能量代謝的調控上,扮演相當重要角色;相反地,於胃臟中,發現了另一被命名為饑餓素的胜肽類賀爾蒙,其僅由二十八個胺基酸組合而成,饑餓素是生長激素分泌受體的內配體,而其具有促進生長因子釋放,以及增加饑餓感、食慾的功能,然而,近來對於瘦體素及饑餓素的研究中,分別發現了瘦體素及饑餓素與不同疾病之間的相關性,且其受體均可表現於腦部以外的器官組織中,說明了其功能不僅止於食慾以及能量代謝上的調控。而腎臟,就是被證實了表現瘦體素受體和饑餓素受體的器官之一,因此,我們分別探究了瘦體素及饑餓素於不同腎臟疾病惡化過程中的調控角色,於本論文中,我們提出了兩個主要的研究目標。研究目標一,由於瘦體素已經被證實為一促纖維化因子,因此,我們以促腎臟纖維化物質,馬兜鈴酸,模擬了腎纖維母細胞活化的狀態下,實驗結果發現處理馬兜鈴酸,能促進腎臟纖維母細胞釋放以及表現瘦體素。進一步探究其調控機制的研究中:證實了馬兜鈴酸藉由活化腎纖維母細胞內PI3K-Akt-mTOR的訊息傳遞路徑,而增加了瘦體素轉錄因子C/EBP α的轉錄活性,進而造成了瘦體素大量表達及釋放的現象。這些研究結果顯示,馬兜鈴酸誘導腎臟纖維化的過程中,可藉由上調促纖維化因子瘦體素的表達及釋放,促進腎臟纖維化疾病的惡化。研究目標二,探討饑餓素促進腫瘤細胞轉移及侵入作用中的角色定位。實驗結果顯示,饑餓素具有促進腎細胞癌轉移及侵入的作用,而其作用機轉與Akt-Aurora A訊息傳遞的活化相關。同時,研究中也發現,以饑餓素共同培養腎癌細胞後,可激活腎癌細胞內Akt的訊息路徑,進而增加snail蛋白的轉錄抑制能力,抑制了其標的基因,細胞間結合蛋白E-cadherin的基因表達。於此研究中,我們發現饑餓素除了具有促進食慾的功能外,同時,其於腎細胞癌的惡化過程中,也可能是一重要的造成腎癌細胞轉移及侵入的調控因子。
Leptin is a peptide hormone playing pivotal role in decreasing food intake and increasing energy expenditure. Conversely, another crucial hormone designated ghrelin, a 28-amino acid peptide hormone purified and identified from stomach, is discovered as endogenous ligand of growth hormone secretagogue receptor (GHS-R) that promotes growth hormone (GH) release and food intake. However, the subsequent discoveries about the involvements of leptin and ghrelin in various types of diseases, and leptin and ghrelin receptor expression beyond brain tissue implicate its action other than appetite regulation and energy metabolism. Kidney is the one of the organs with leptin and ghrelin receptor expression. Hence, we respectively evaluated the roles of leptin and ghrelin in the progression of renal diseases. In this thesis, two specific aims were proposed. In aim 1, our findings demonstrated the first that aristolochic acid (AA) could induce secretion and expression of fibrogenic leptin in kidney fibroblasts via the activation of PI3K-Akt-mTOR signaling and subsequent induction the transcriptional activation of leptin by CCAAT enhancer binding protein α (C/EBP α). These results reveal the potential involvement of leptin in the progression of kidney fibrosis in aristolochic acid nephropathy (AAN). In aim 2, we investigated the effect of ghrelin on regulating tumor cell migration and invasion. Our results indicated that ghrelin could augment both invasion and migration of renal cell carcinoma (RCC) through the activation of Akt-Aurora A signaling. Simultaneously, transcription repression activity of snail was increased by ghrelin-mediated Akt activation, which led to the downregulation of E-cadherin expression. In this study, we highlight the influence of ghrelin beyond appetite modulation, and manifest the crucial role of ghrelin in RCC progression.
Contents Ⅰ
Abbreviations Ⅲ
中文全文摘要 Ⅴ
Abstract Ⅶ
Introduction Ⅸ
References ⅩⅡ

Chapter 1. The Molecular Mechanism of Leptin Secretion and
Expression Induced by Aristolochic Acid in Kidney
Fibroblast 1
Abstract 2
Introduction 4
Rationale and Significance 9
Materials and Methods 10
Results 17
Discussion 21
References 25
Figures 34
Schematic Diagram 46

Chapter 2. Ghrelin Augments Invasion and Migration of Renal
Adenocarcinoma via Activating Akt-Aurora A signaling pathway 47
Abstract 48
Introduction 50
Rationale and Significance 52
Materials and Methods 54
Results 59
Discussion 62
References 65
Figures 69
Schematic Diagram 80

Chapter 3. Overall Conclusion 81
Overall Conclusion 82

Introduction
1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432.
2. Frayn KN, Karpe F, Fielding BA, Macdonald IA, Coppack SW (2003) Integrative physiology of human adipose tissue. Int J Obes Relat Metab Disord 27: 875-888.
3. Koutkia P, Canavan B, Johnson ML, DePaoli A, Grinspoon S (2003) Characterization of leptin pulse dynamics and relationship to fat mass, growth hormone, cortisol, and insulin. Am J Physiol Endocrinol Metab 285: E372-379.
4. Leibel RL (2002) The role of leptin in the control of body weight. Nutr Rev 60: S15-19; discussion S68-84, 85-17.
5. Slieker LJ, Sloop KW, Surface PL, Kriauciunas A, LaQuier F, et al. (1996) Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 271: 5301-5304.
6. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, et al. (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269: 540-543.
7. Meier U, Gressner AM (2004) Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 50: 1511-1525.
8. Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, et al. (1999) Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282: 1568-1575.
9. Rosicka M, Krsek M, Matoulek M, Jarkovska Z, Marek J, et al. (2003) Serum ghrelin levels in obese patients: the relationship to serum leptin levels and soluble leptin receptors levels. Physiol Res 52: 61-66.
10. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS (2000) Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 105: 1827-1832.
11. Wallace AM (2000) Measurement of leptin and leptin binding in the human circulation. Ann Clin Biochem 37 ( Pt 3): 244-252.
12. Tsiotra PC, Pappa V, Raptis SA, Tsigos C (2000) Expression of the long and short leptin receptor isoforms in peripheral blood mononuclear cells: implications for leptin's actions. Metabolism 49: 1537-1541.
13. Trayhurn P, Hoggard N, Mercer JG, Rayner DV (1999) Leptin: fundamental aspects. Int J Obes Relat Metab Disord 23 Suppl 1: 22-28.
14. Zabeau L, Lavens D, Peelman F, Eyckerman S, Vandekerckhove J, et al. (2003) The ins and outs of leptin receptor activation. FEBS Lett 546: 45-50.
15. Cohen B, Novick D, Rubinstein M (1996) Modulation of insulin activities by leptin. Science 274: 1185-1188.
16. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656-660.
17. Inui A (2001) Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2: 551-560.
18. Kojima M, Kangawa K (2002) Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract. Curr Opin Pharmacol 2: 665-668.
19. Hagemann D, Meier JJ, Gallwitz B, Schmidt WE (2003) [Appetite regulation by ghrelin - a novel neuro-endocrine gastric peptide hormone in the gut-brain-axis]. Z Gastroenterol 41: 929-936.
20. Wang G, Lee HM, Englander E, Greeley GH, Jr. (2002) Ghrelin--not just another stomach hormone. Regul Pept 105: 75-81.
21. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132: 387-396.
22. Shanado Y, Kometani M, Uchiyama H, Koizumi S, Teno N (2004) Lysophospholipase I identified as a ghrelin deacylation enzyme in rat stomach. Biochem Biophys Res Commun 325: 1487-1494.
23. Gualillo O, Lago F, Casanueva FF, Dieguez C (2006) One ancestor, several peptides post-translational modifications of preproghrelin generate several peptides with antithetical effects. Mol Cell Endocrinol 256: 1-8.
24. Zigman JM, Elmquist JK (2003) Minireview: From anorexia to obesity--the yin and yang of body weight control. Endocrinology 144: 3749-3756.

Chapter 1
1. Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 116: 288-296.
2. Graves JW (2008) Diagnosis and management of chronic kidney disease. Mayo Clin Proc 83: 1064-1069.
3. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT, Jr., et al. (2006) Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med 144: 172-180.
4. Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, et al. (2001) Analgesic use and renal function in men. Jama 286: 315-321.
5. Perazella MA (2003) Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 325: 349-362.
6. Liss P, Persson PB, Hansell P, Lagerqvist B (2006) Renal failure in 57 925 patients undergoing coronary procedures using iso-osmolar or low-osmolar contrast media. Kidney Int 70: 1811-1817.
7. Hashimoto K, Higuchi M, Makino B, Sakakibara I, Kubo M, et al. (1999) Quantitative analysis of aristolochic acids, toxic compounds, contained in some medicinal plants. J Ethnopharmacol 64: 185-189.
8. Lorz C, Benito-Martin A, Justo P, Sanz AB, Sanchez-Nino MD, et al. (2006) Modulation of renal tubular cell survival: where is the evidence? Curr Med Chem 13: 449-454.
9. Shankland SJ (2006) The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int 69: 2131-2147.
10. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24: 99-146.
11. Lan HY (2003) Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 12: 25-29.
12. Roberts IS, Burrows C, Shanks JH, Venning M, McWilliam LJ (1997) Interstitial myofibroblasts: predictors of progression in membranous nephropathy. J Clin Pathol 50: 123-127.
13. Takemoto M, Asker N, Gerhardt H, Lundkvist A, Johansson BR, et al. (2002) A new method for large scale isolation of kidney glomeruli from mice. Am J Pathol 161: 799-805.
14. Nangaku M, Miyata T (2008) [Mechanisms in remodeling of the kidney]. Nippon Rinsho 66: 1696-1700.
15. Sanz AB, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A (2008) Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 19: 1634-1642.
16. Bottinger EP, Bitzer M (2002) TGF-beta signaling in renal disease. J Am Soc Nephrol 13: 2600-2610.
17. Ruster C, Wolf G (2006) Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 17: 2985-2991.
18. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432.
19. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, et al. (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269: 540-543.
20. Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, et al. (1996) Molecular cloning of rat leptin receptor isoform complementary DNAs--identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun 225: 75-83.
21. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, et al. (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83: 1263-1271.
22. Qamar A, Sheikh SZ, Masud A, Jhandier MN, Inayat IB, et al. (2006) In vitro and in vivo protection of stellate cells from apoptosis by leptin. Dig Dis Sci 51: 1697-1705.
23. Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, et al. (2002) Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122: 1399-1410.
24. Wolf G, Hamann A, Han DC, Helmchen U, Thaiss F, et al. (1999) Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis [seecomments]. Kidney Int 56: 860-872.
25. Kumpers P, Gueler F, Rong S, Mengel M, Tossidou I, et al. (2007) Leptin is a coactivator of TGF-beta in unilateral ureteral obstructive kidney disease. Am J Physiol Renal Physiol 293: F1355-1362.
26. Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Dratwa M, et al. (1993) Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341: 387-391.
27. Depierreux M, Van Damme B, Vanden Houte K, Vanherweghem JL (1994) Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 24: 172-180.
28. Arlt VM, Stiborova M, Schmeiser HH (2002) Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 17: 265-277.
29. Huljic S, Bruske EI, Pfitzenmaier N, O'Brien E, Dietrich DR (2008) Species-specific toxicity of aristolochic acid (AA) in vitro. Toxicol In Vitro 22: 1213-1221.
30. Gold LS, Slone TH (2003) Aristolochic acid, an herbal carcinogen, sold on the Web after FDA alert. N Engl J Med 349: 1576-1577.
31. Li Y, Liu Z, Guo X, Shu J, Chen Z, et al. (2006) Aristolochic acid I-induced DNA damage and cell cycle arrest in renal tubular epithelial cells in vitro. Arch Toxicol 80: 524-532.
32. Pozdzik AA, Salmon IJ, Debelle FD, Decaestecker C, Van den Branden C, et al. (2008) Aristolochic acid induces proximal tubule apoptosis and epithelial to mesenchymal transformation. Kidney Int 73: 595-607.
33. Hsin YH, Cheng CH, Tzen JT, Wu MJ, Shu KH, et al. (2006) Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells. Apoptosis 11: 2167-2177.
34. Zhang C, Chen YP, Dong HR, Qiu CB (2005) [The therapeutic effects of bosentan and valsartan on renal interstitial fibrosis of chronic aristolochic acid nephropathy]. Zhonghua Yi Xue Za Zhi 85: 2601-2606.
35. Debelle FD, Nortier JL, Husson CP, De Prez EG, Vienne AR, et al. (2004) The renin-angiotensin system blockade does not prevent renal interstitial fibrosis induced by aristolochic acids. Kidney Int 66: 1815-1825.
36. Glasow A, Kiess W, Anderegg U, Berthold A, Bottner A, et al. (2001) Expression of leptin (Ob) and leptin receptor (Ob-R) in human fibroblasts: regulation of leptin secretion by insulin. J Clin Endocrinol Metab 86: 4472-4479.
37. Merabet E, Dagogo-Jack S, Coyne DW, Klein S, Santiago JV, et al. (1997) Increased plasma leptin concentration in end-stage renal disease. J Clin Endocrinol Metab 82: 847-850.
38. Aoyagi S, Archer TK (2007) Dynamic histone acetylation/deacetylation with progesterone receptor-mediated transcription. Mol Endocrinol 21: 843-856.
39. He Y, Chen H, Quon MJ, Reitman M (1995) The mouse obese gene. Genomic organization, promoter activity, and activation by CCAAT/enhancer-binding protein alpha. J Biol Chem 270: 28887-28891.
40. Lee MJ, Fried SK (2009) Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296: E1230-1238.
41. Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, et al. (2010) Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. Haematologica 95: 819-828.
42. Meng X, Shoemaker SF, McGee SO, Ip MM (2008) t10,c12-Conjugated linoleic acid stimulates mammary tumor progression in Her2/ErbB2 mice through activation of both proliferative and survival pathways. Carcinogenesis 29: 1013-1021.
43. Lau C, Wang X, Song L, North M, Wiehler S, et al. (2008) Syk associates with clathrin and mediates phosphatidylinositol 3-kinase activation during human rhinovirus internalization. J Immunol 180: 870-880.
44. Casamayor A, Morrice NA, Alessi DR (1999) Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 342 ( Pt 2): 287-292.
45. Lee MJ, Yang RZ, Gong DW, Fried SK (2007) Feeding and insulin increase leptin translation. Importance of the leptin mRNA untranslated regions. J Biol Chem 282: 72-80.
46. Fan QY, Zhou XL, Yang H, Tao ZX, Li Y, et al. (2009) [Molecular characterization of coxsackievirus B3 isolated from an outbreak of aseptic meningitis in Shandong Province, China]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 23: 455-457.
47. Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159-168.
48. Debelle FD, Vanherweghem JL, Nortier JL (2008) Aristolochic acid nephropathy: a worldwide problem. Kidney Int 74: 158-169.
49. Auwerx J, Staels B (1998) Leptin. Lancet 351: 737-742.
50. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, et al. (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3: 1029-1033.
51. Han DC, Isono M, Chen S, Casaretto A, Hong SW, et al. (2001) Leptin stimulates type I collagen production in db/db mesangial cells: glucose uptake and TGF-beta type II receptor expression. Kidney Int 59: 1315-1323.
52. Villarreal D, Reams G, Freeman RH (2000) Effects of renal denervation on the sodium excretory actions of leptin in hypertensive rats. Kidney Int 58: 989-994.
53. Orth SR, Amann K, Strojek K, Ritz E (2001) Sympathetic overactivity and arterial hypertension in renal failure. Nephrol Dial Transplant 16 Suppl 1: 67-69.
54. Houseknecht KL, Portocarrero CP (1998) Leptin and its receptors: regulators of whole-body energy homeostasis. Domest Anim Endocrinol 15: 457-475.
55. Darlington GJ, Wang N, Hanson RW (1995) C/EBP alpha: a critical regulator of genes governing integrative metabolic processes. Curr Opin Genet Dev 5: 565-570.
56. Hollenberg AN, Susulic VS, Madura JP, Zhang B, Moller DE, et al. (1997) Functional antagonism between CCAAT/Enhancer binding protein-alpha and peroxisome proliferator-activated receptor-gamma on the leptin promoter. J Biol Chem 272: 5283-5290.
57. Hwang CS, Mandrup S, MacDougald OA, Geiman DE, Lane MD (1996) Transcriptional activation of the mouse obese (ob) gene by CCAAT/enhancer binding protein alpha. Proc Natl Acad Sci U S A 93: 873-877.
58. Barr VA, Malide D, Zarnowski MJ, Taylor SI, Cushman SW (1997) Insulin stimulates both leptin secretion and production by rat white adipose tissue. Endocrinology 138: 4463-4472.
59. Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, et al. (1995) Transient increase in obese gene expression after food intake or insulin administration. Nature 377: 527-529.
60. Yoshida T, Hayashi M, Monkawa T, Saruta T (1996) Regulation of obese mRNA expression by hormonal factors in primary cultures of rat adipocytes. Eur J Endocrinol 135: 619-625.
61. Bradley RL, Cheatham B (1999) Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes. Diabetes 48: 272-278.
62. Schimmack G, Defronzo RA, Musi N (2006) AMP-activated protein kinase: Role in metabolism and therapeutic implications. Diabetes Obes Metab 8: 591-602.
63. Chakrabarti P, Anno T, Manning BD, Luo Z, Kandror KV (2008) The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5'-untranslated region in the expression of leptin messenger ribonucleic acid. Mol Endocrinol 22: 2260-2267.
64. Bakhiya N, Arlt VM, Bahn A, Burckhardt G, Phillips DH, et al. (2009) Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy. Toxicology 264: 74-79.
65. Wang YY, Chen YP, Rui HL (2009) [Organic anion transporter system mediates the transport of aristolochic acid in tubular epithelial cells]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 31: 476-480.

Chapter 2
1. Pantuck AJ, Zisman A, Belldegrun AS (2001) The changing natural history of renal cell carcinoma. J Urol 166: 1611-1623.
2. Campbell SC, Flanigan RC, Clark JI (2003) Nephrectomy in metastatic renal cell carcinoma. Curr Treat Options Oncol 4: 363-372.
3. Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. N Engl J Med 335: 865-875.
4. Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12: 895-904.
5. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656-660.
6. Inui A (2001) Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2: 551-560.
7. Kojima M, Kangawa K (2002) Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract. Curr Opin Pharmacol 2: 665-668.
8. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132: 387-396.
9. Shanado Y, Kometani M, Uchiyama H, Koizumi S, Teno N (2004) Lysophospholipase I identified as a ghrelin deacylation enzyme in rat stomach. Biochem Biophys Res Commun 325: 1487-1494.
10. Gualillo O, Lago F, Casanueva FF, Dieguez C (2006) One ancestor, several peptides post-translational modifications of preproghrelin generate several peptides with antithetical effects. Mol Cell Endocrinol 256: 1-8.
11. Meraldi P, Honda R, Nigg EA (2004) Aurora kinases link chromosome segregation and cell division to cancer susceptibility. Curr Opin Genet Dev 14: 29-36.
12. Meraldi P, Honda R, Nigg EA (2002) Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells. EMBO J 21: 483-492.
13. Wang LH, Xiang J, Yan M, Zhang Y, Zhao Y, et al. (2010) The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. Cancer Res 70: 9118-9128.
14. Mathieu R, Patard JJ, Stock N, Rioux-Leclercq N, Guille F, et al. (2010) [Study of the expression of Aurora kinases in renal cell carcinoma]. Prog Urol 20: 1200-1205.
15. Guan Z, Wang XR, Zhu XF, Huang XF, Xu J, et al. (2007) Aurora-A, a negative prognostic marker, increases migration and decreases radiosensitivity in cancer cells. Cancer Res 67: 10436-10444.
16. Wang X, Dong L, Xie J, Tong T, Zhan Q (2009) Stable knockdown of Aurora-A by vector-based RNA interference in human esophageal squamous cell carcinoma cell line inhibits tumor cell proliferation, invasion and enhances apoptosis. Cancer Biol Ther 8: 1852-1859.
17. Mori K, Yoshimoto A, Takaya K, Hosoda K, Ariyasu H, et al. (2000) Kidney produces a novel acylated peptide, ghrelin. FEBS Lett 486: 213-216.
18. Meier U, Gressner AM (2004) Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 50: 1511-1525.
19. Kageyama H, Funahashi H, Hirayama M, Takenoya F, Kita T, et al. (2005) Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept 126: 67-71.
20. Karapanagiotou EM, Polyzos A, Dilana KD, Gratsias I, Boura P, et al. (2009) Increased serum levels of ghrelin at diagnosis mediate body weight loss in non-small cell lung cancer (NSCLC) patients. Lung Cancer 66: 393-398.
21. Tsolakis AV, Portela-Gomes GM, Stridsberg M, Grimelius L, Sundin A, et al. (2004) Malignant gastric ghrelinoma with hyperghrelinemia. J Clin Endocrinol Metab 89: 3739-3744.
22. Duxbury MS, Waseem T, Ito H, Robinson MK, Zinner MJ, et al. (2003) Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness. Biochem Biophys Res Commun 309: 464-468.
23. Dixit VD, Weeraratna AT, Yang H, Bertak D, Cooper-Jenkins A, et al. (2006) Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J Biol Chem 281: 16681-16690.
24. Zhou BP, Deng J, Xia W, Xu J, Li YM, et al. (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6: 931-940.
25. Hemavathy K, Ashraf SI, Ip YT (2000) Snail/slug family of repressors: slowly going into the fast lane of development and cancer. Gene 257: 1-12.
26. Yang Z, Rayala S, Nguyen D, Vadlamudi RK, Chen S, et al. (2005) Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res 65: 3179-3184.
27. Du C, Zhang C, Hassan S, Biswas MH, Balaji KC (2010) Protein kinase D1 suppresses epithelial-to-mesenchymal transition through phosphorylation of snail. Cancer Res 70: 7810-7819.
28. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2: 442-454.
29. De Craene B, van Roy F, Berx G (2005) Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal 17: 535-547.
30. Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3: 155-166.
31. Bamburg JR, McGough A, Ono S (1999) Putting a new twist on actin: ADF/cofilins modulate actin dynamics. Trends Cell Biol 9: 364-370.
32. Kurita S, Gunji E, Ohashi K, Mizuno K (2007) Actin filaments-stabilizing and -bundling activities of cofilin-phosphatase Slingshot-1. Genes Cells 12: 663-676.
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