進階搜尋


下載電子全文  
系統識別號 U0026-1901201119405300
論文名稱(中文) 惡性肋膜積液中肺腺癌細胞顯示糖代謝調控基因的異常表現且該癌細胞之Stat1磷酸化狀態與腫瘤抗藥性相關
論文名稱(英文) Malignant pleural effusion cells show aberrant glucose metabolism gene expression and the level of cellular Stat1 phosphorylation reflects the chemoresistance
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 99
學期 1
出版年 100
研究生(中文) 林建中
研究生(英文) Chien-Chung Lin
學號 s9893101
學位類別 博士
語文別 英文
論文頁數 108頁
口試委員 指導教授-蘇五洲
指導教授-賴明德
口試委員-薛尊仁
口試委員-黃奇英
口試委員-施能耀
召集委員-林秋烽
中文關鍵字 惡性肋膜積水  肺腺癌  醣解作用  流式細胞儀  Stat1磷酸化 
英文關鍵字 Malignant pleural effusion  lung adenocarcinoma  glycolysis  flow cytomety  Stat1 phosphorylation 
學科別分類
中文摘要 肺癌為癌症死因第一位。而其中15%病人一開始以惡性肋膜積水表現,50%肺癌病人晚期會有惡性肋膜積水產生。不同於其它固體腫瘤有周圍血管提供營養,惡性肋膜積水的癌細胞可自主地增殖並具有高轉移能力和抗藥性。而這些肺腺癌的病人最近更被證實其預後應視同對側肺轉移。我們利用惡性肋膜積水的癌細胞去探討這些肺腺癌的基因表現與訊息傳導以了解這些癌細胞如何維持生長及了解訊息傳導的變化是否可預估其化學治療反應。我們針對三個組群(7位健康女性、13位惡性肋膜積水及18位I至III期肺癌病人)將其正常肺組織或腫瘤細胞及相鄰正常組織作微陣列分析晶片分析;首先比較7位健康女性肺組織及13位惡性肋膜積水中腫瘤細胞表現差異最多前500基因,這500基因再與18位I至III期肺癌病人做相關基因比較並做相關限制的標準;最後總共有20個基因符合標準,利用生物資訊平台進一步發現大部分基因與代謝有關尤其是醣類代謝-這包括了 aldolase A (ALDOA), sorbitol dehydrogenase (SORD), transketolase (TKT), and tuberous sclerosis 1 (TSC1)。我們利用定量real time PCR、免疫螢光染色分析、免疫組織化學染色作定性及定量分析病人的肺癌組織,確認這些基因的表現在病人的肺癌組織與正常組織有所差異。在細胞實驗中,我們一方面確認肺癌細胞較正常肺組織及支氣管上皮細胞株有不同的表現,另一方面TKT 的抑制劑(oxythiamine)及TSC1-AMPK的促進劑(metformin)抑制癌細胞的增生能力及VEGF的分泌。利用siRNA系統去剔除TKT的表現亦抑制癌細胞的增生能力及VEGF的分泌。證實有氧醣解作用在惡性肋膜積水癌細胞的自主地增生能力增加及而且與VEGF增加惡性肋膜積水相關。我們進一步利用Ingenuity Pathway Analysis找尋可能調控這些在惡性肋膜積水表現異常基因之上游可能之轉錄因子,發現HNF4A (hepatocyte nuclear factor 4A)不但在肺癌細胞較正常肺組織有不同的表現,而且利用HNF4A抑制劑(MEDICA16)抑制了肺癌細胞生長。
其次,我們亦探討惡性肋膜積水的癌細胞訊息傳導的變化是否可預估其化學治療反應,之前在白血病的研究發現,單一細胞磷酸化流式細胞儀(Single cell phospho-specific flow cytometry, SCPFC)對於細胞內訊息磷酸化變化,可以預估白血病對化學治療的反應,而Stat1 (Signal transducer and activator of transcription 1)已被證實與化學治療如紫杉醇及順鉑之抗藥性相關,因此,我們進一步用惡性肋膜積水的癌細胞去探討Stat1磷酸化高低變化是否可以決定順鉑治療效果好壞。我們首先確認單一細胞磷酸化流式細胞儀可以在肺癌細胞、動物轉移腹水及皮下腫瘤模式和人類惡性肋膜積水樣本,測試給予干擾素-γ刺激後Stat1磷酸化的反應。我們進一步發現這些惡性肋膜積水中的肺癌細胞經順鉑處理後細胞凋亡情形與pStat1螢光強度變化之相關性。最後再利用對順鉑抗藥性細胞株轉染siRNA- Stat1去抑制Stat1表現,確認了Stat1表現與否決定對順鉑的感受性。而最近的研究,而醣解作用的異常表現影響化學治療之抗藥性,而metformin可加強乳癌化學治療之療效。因此,惡性肋膜積水的癌細胞有氧醣解作用異常表現及Stat1磷酸化的反應,將可作為判斷肺癌病人是否產生癌症抗藥性的指標,而針對這些醣解作用相關基因及上游調節因子之促進劑或抑制劑可用以加強化學治療之療效。
英文摘要 Lung cancer is the leading cause of cancer deaths worldwide. Approximately 15% of lung cancer patients have complications with malignant pleural effusion (MPE) at their initial diagnosis, and 50% of patients develop MPE later in the course of the disease. Unlike other solid cancers with surrounding vascular structures to provide conduits for travel and nutrient delivery, malignant cells within MPE are uniquely capable of surviving and proliferating without a solid-phase scaffolding. These characteristics contribute their potential of metastasis and chemoresistance. The prognosis of patients with MPE is comparable to M1 cases with metastases to the contralateral lung. Our study aimed at disclosing the genes involved in MPE formation and associated signal pathway which may account for high chemoresistance and become the predictor of chemotherapy. We first identified the genes contributing to the formation of MPE. Three cohorts were included in the study of whole genome expression using an Affymetrix Human U133 oligonucleotide microarray. By restricting to genes that were at least a two-fold change between MPE and normal tissue and expressed differentially from early to late stage, 20 genes were identified. Bioinformatics platform analysis demonstrated that most of the identified genes are related to glucose metabolism, including aldolase A (ALDOA), sorbitol dehydrogenase (SORD), transketolase (TKT), and tuberous sclerosis 1 (TSC1). Then we used quantitative RTPCR to confirm the aberrant expression of these genes in the patient's lung cancer compared to normal tissue. Using the specimens from different stages of lung cancer and pleural metastasis in lung cancer tissues, we verified the dysregulation of these genes by immunohistochemistry and immunofluorescence staining. And the TKT inhibitor (oxythiamine) and TSC1/AMPK activator (metformin) were proved to inhibit the proliferation of lung cancer cell. We further used siRNA expression system to knockdown TKT and demonstrated the inhibition of cell proliferation, VEGF secretion cell line in vitro, vascular permeability in vivo. Using Ingenuity Pathway Analysis (IPA) to examine the relation between the dysregulated genes in MPE and the biological networks involved, hepatocyte nuclear factor-4α (HNF4A) was identified as the central molecules of these pathways. We further proved that the HNF4A was upregulated in cancer tissue and HNF4A inhibitor interfered lung cancer cell proliferation. Secondly, we investigated the signal pathway which may involve the chemoresistance in lung cancer. Most human neoplasms have aberrant signal transduction elements. Understanding the structure and the regulation of these signal transductions offers the progress in treatment of lung cancer. Single cell phospho-specific flow cytometry (SCPFC) has been used to monitor phosphorylation change of intracellular signal after certain stimuli treatment and predict response to chemotherapy in leukemia patients. And Stat1 has been proved to determine the sensitivity to cisplatin in ovarian cancer. We first demonstrated SCPFC is applicable in monitoring pStat1 after IFN-γ stimulation in lung cancer cell lines, cancer cells from animal models of subcutaneous tumor metastasis and ascites and MPEs of lung cancer patients. Furthermore, cancer cells from different patient MPEs have different sensitivities to IFN-γ stimulation. The activation of Stat1 by lower doses of IFN-γ predicts cancer cell vulnerability to cisplatin. The reverse of cisplatin sensitivity of cancer cell after transfection with Stat1 siRNA further confirmed the role of Stat1 in cisplatin sensitivity. It has been report that glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells. Metformin increased the pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer Taken together, malignant pleural effusion cells show aberrant glucose metabolism gene expression and Stat1 phosphoryaltion predict the cisplatin sensitivity of MPE cancer cells. The predictor role of pStat1 is promising and the activator or inhibitor targeting these glucose metabolism genes and upstream transcription factor may become new treatment strategies for MPE-associated lung adenocarcinoma.
論文目次 Contents
Abstract in Chinese-I
Abstract in English-III
Acknowledgement-V

Chapter 1. Introduction-1
Lung cancer-2
Malignant pleural effusion cancer cell-3
Single cell phospho-specific flow cytometry-4
Signal transducer and activator of transcription 1 (Stat1) and chemoresistance-4

Chapter 2. Materials and Methods-6
MPE cancer cells, healthy normal lung tissue, and stage I-III lung cancer for microarray analysis-7
Blood and pleural effusion collection and cancer cell purification from malignant pleural effusions for SCPFC-8
Statistical analysis of micro-array data-9
RNA extraction and quantitative RT-PCR-10
Immunohistochemistry and immunofluorescent images-10
Immuno-fluorescent images and quantitative analyses-11
Cell lines, cell lysates, and Western blot-12
TKT inhibitor-oxythiamine, TSC1-AMPK activator-metformin, HNF4A inhibitor-MEDICA 16 and MTT test-13
Transfection with Small Interfering RNA (siRNA) against Stat1 using lipofectamine-15
Antibodies for flow cytometry-16
Collection of cancer cells from animal, aubcutaneous and ascites tumor models for SCPFC-16
E-cadherin staining-17
Single Cell Phospho-specific Flow Cytometry (SCPFC)-17
Apoptosis analysis after cisplatin treatment-18
Statistical analysis-18

Chapter 3. Malignant Pleural Effusion Cells Show Aberrant Glucose Metabolism Gene Expression-20
ABSTRACT-21
INTRODUCTION-22
RESULTS-23
DISCUSSION-32

Chapter 4. Single Cell Phospho-Specific Flow Cytometry Can Detect Dynamic Changes of Phospho-Stat1 Level in Lung Cancer Cells-37
ABSTRACT-38
INTRODUCTION-39
RESULTS-41
DISCUSSION-47

Chapter 5. Discussion-51
REFERENCES-57
TABLES-65
FIGURES-68
CURRICULUM VITAE-103
THESIS ASSOCIATED PUBLICATIONS-108

參考文獻 1.Spiro SG, Silvestri GA. One hundred years of lung cancer. Am J Respir Crit Care Med 2005; 172: 523-529.
2.Coscio AM, Garst J. Lung cancer in women. Curr Oncol Rep 2006; 8: 248-251.
3.Trompezinski S, Denis A, Schmitt D, Viac J. IL-10 is unable to downregulate VEGF expression in human activated keratinocytes. Arch Dermatol Res 2002; 294: 377-379.
4.Wu SG, Gow CH, Yu CJ, Chang YL, Yang CH, Hsu YC, Shih JY, Lee YC, Yang PC. Frequent EGFR mutations in malignant pleural effusion of lung adenocarcinoma. Eur Respir J 2008.
5.Yeh HH, Lai WW, Chen HH, Liu HS, Su WC. Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion. Oncogene 2006; 25: 4300-4309.
6.Kassis J, Klominek J, Kohn EC. Tumor microenvironment: what can effusions teach us? Diagn Cytopathol 2005; 33: 316-319.
7.Zebrowski BK, Yano S, Liu W, Shaheen RM, Hicklin DJ, Putnam JB, Jr., Ellis LM. Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res 1999; 5: 3364-3368.
8.Postmus PE, Brambilla E, Chansky K, Crowley J, Goldstraw P, Patz EF, Jr., Yokomise H. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol 2007; 2: 686-693.
9.Walker-Renard PB, Vaughan LM, Sahn SA. Chemical pleurodesis for malignant pleural effusions. Ann Intern Med 1994; 120: 56-64.
10.Yen CC, Liang SC, Jong YJ, Chen YJ, Lin CH, Chen YM, Wu YC, Su WC, Huang CY, Tseng SW, Whang-Peng J. Chromosomal aberrations of malignant pleural effusions of lung adenocarcinoma: different cytogenetic changes are correlated with genders and smoking habits. Lung Cancer 2007; 57: 292-301.
11.Stathopoulos GT, Kollintza A, Moschos C, Psallidas I, Sherrill TP, Pitsinos EN, Vassiliou S, Karatza M, Papiris SA, Graf D, Orphanidou D, Light RW, Roussos C, Blackwell TS, Kalomenidis I. Tumor necrosis factor-alpha promotes malignant pleural effusion. Cancer Res 2007; 67: 9825-9834.
12.Irish JM, Hovland R, Krutzik PO, Perez OD, Bruserud O, Gjertsen BT, Nolan GP. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell 2004; 118: 217-228.
13.Kotecha N, Flores NJ, Irish JM, Simonds EF, Sakai DS, Archambeault S, Diaz-Flores E, Coram M, Shannon KM, Nolan GP, Loh ML. Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. Cancer Cell 2008; 14: 335-343.
14.Bardet V, Tamburini J, Ifrah N, Dreyfus F, Mayeux P, Bouscary D, Lacombe C. Single cell analysis of phosphoinositide 3-kinase/Akt and ERK activation in acute myeloid leukemia by flow cytometry. Haematologica 2006; 91: 757-764.
15.Nolan GP. Deeper insights into hematological oncology disorders via single-cell phospho-signaling analysis. Hematology Am Soc Hematol Educ Program 2006: 123-127, 509.
16.Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer 2004; 4: 97-105.
17.Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol 1997; 17: 5328-5337.
18.Xu X, Fu XY, Plate J, Chong AS. IFN-gamma induces cell growth inhibition by Fas-mediated apoptosis: requirement of STAT1 protein for up-regulation of Fas and FasL expression. Cancer Res 1998; 58: 2832-2837.
19.Khodarev NN, Beckett M, Labay E, Darga T, Roizman B, Weichselbaum RR. STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. Proc Natl Acad Sci U S A 2004; 101: 1714-1719.
20.Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N, Su AW, Shaikh AY, Roach P, Kreike B, Roizman B, Bergh J, Pawitan Y, van de Vijver MJ, Minn AJ. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci U S A 2008; 105: 18490-18495.
21.Chen YM, Tsai CM, Whang-Peng J, Perng RP. Double signal stimulation was required for full recovery of the autologous tumor-killing effect of effusion-associated lymphocytes. Chest 2002; 122: 1421-1427.
22.Su LJ, Chang CW, Wu YC, Chen KC, Lin CJ, Liang SC, Lin CH, Whang-Peng J, Hsu SL, Chen CH, Huang CY. Selection of DDX5 as a novel internal control for Q-RT-PCR from microarray data using a block bootstrap re-sampling scheme. BMC Genomics 2007; 8: 140.
23.Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999; 286: 531-537.
24.Landsittel D, Donohue-Babiak N. Effect of adding fold-change criteria to significance testing of microarray data. Journal of Statistical Computation and Simulation 2010; 80: 89 - 97.
25.Kerstens HM, Robben JC, Poddighe PJ, Melchers WJ, Boonstra H, de Wilde PC, Macville MV, Hanselaar AG. AgarCyto: a novel cell-processing method for multiple molecular diagnostic analyses of the uterine cervix. J Histochem Cytochem 2000; 48: 709-718.
26.Barnes DM, Harris WH, Smith P, Millis RR, Rubens RD. Immunohistochemical determination of oestrogen receptor: comparison of different methods of assessment of staining and correlation with clinical outcome of breast cancer patients. Br J Cancer 1996; 74: 1445-1451.
27.Al-Shahrour F, Minguez P, Tarraga J, Montaner D, Alloza E, Vaquerizas JM, Conde L, Blaschke C, Vera J, Dopazo J. BABELOMICS: a systems biology perspective in the functional annotation of genome-scale experiments. Nucleic Acids Res 2006; 34: W472-476.
28.Jimenez-Marin A, Collado-Romero M, Ramirez-Boo M, Arce C, Garrido JJ. Biological pathway analysis by ArrayUnlock and Ingenuity Pathway Analysis. BMC Proc 2009; 3 Suppl 4: S6.
29.Moldvay J, Jackel M, Bogos K, Soltesz I, Agocs L, Kovacs G, Schaff Z. The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas. Pathol Oncol Res 2004; 10: 85-88.
30.Gomez-Fernandez C, Jorda M, Delgado PI, Ganjei-Azar P. Thyroid transcription factor 1: a marker for lung adenoarinoma in body cavity fluids. Cancer 2002; 96: 289-293.
31.Szczepulska-Wojcik E, Langfort R, Roszkowski-Sliz K. [A comparative evaluation of immunohistochemical markers for the differential diagnosis between malignant mesothelioma, non-small cell carcinoma involving the pleura, and benign reactive mesothelial cell proliferation]. Pneumonol Alergol Pol 2007; 75: 57-69.
32.Chen YF, Chou CY, Wilkins RJ, Ellory JC, Mount DB, Shen MR. Motor protein-dependent membrane trafficking of KCl cotransporter-4 is important for cancer cell invasion. Cancer Res 2009; 69: 8585-8593.
33.Rais B, Comin B, Puigjaner J, Brandes JL, Creppy E, Saboureau D, Ennamany R, Lee WN, Boros LG, Cascante M. Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle. FEBS Lett 1999; 456: 113-118.
34.Katare R, Andrea C, Emanueli C, Madeddu P. Benfotiamine improves functional recovery of the infarcted heart via activation of pro-survival G6PD/Akt signaling pathway and modulation of neurohormonal response. Journal of Molecular and Cellular Cardiology; In Press, Uncorrected Proof.
35.Kwiatkowski DJ, Manning BD. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 2005; 14 Spec No. 2: R251-258.
36.Gotlieb WH, Saumet J, Beauchamp MC, Gu J, Lau S, Pollak MN, Bruchim I. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol Oncol 2008; 110: 246-250.
37.Ammit AJ, Hoffman RK, Amrani Y, Lazaar AL, Hay DW, Torphy TJ, Penn RB, Panettieri RA, Jr. Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate. Am J Respir Cell Mol Biol 2000; 23: 794-802.
38.Lee DF, Kuo HP, Chen CT, Hsu JM, Chou CK, Wei Y, Sun HL, Li LY, Ping B, Huang WC, He X, Hung JY, Lai CC, Ding Q, Su JL, Yang JY, Sahin AA, Hortobagyi GN, Tsai FJ, Tsai CH, Hung MC. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 2007; 130: 440-455.
39.Schwartz B, Algamas-Dimantov A, Hertz R, Nataf J, Kerman A, Peri I, Bar-Tana J. Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4alpha. Int J Cancer 2009; 124: 1081-1089.
40.Warburg O. On the origin of cancer cells. Science 1956; 123: 309-314.
41.Sanchez-Armengol A, Rodriguez-Panadero F. Survival and talc pleurodesis in metastatic pleural carcinoma, revisited. Report of 125 cases. Chest 1993; 104: 1482-1485.
42.Duysinx B, Corhay JL, Larock MP, Nguyen D, Bury T, Hustinx R, Louis R. Prognostic value of metabolic imaging in non-small cell lung cancers with neoplasic pleural effusion. Nucl Med Commun 2008; 29: 982-986.
43.Langbein S, Zerilli M, Zur Hausen A, Staiger W, Rensch-Boschert K, Lukan N, Popa J, Ternullo MP, Steidler A, Weiss C, Grobholz R, Willeke F, Alken P, Stassi G, Schubert P, Coy JF. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 2006; 94: 578-585.
44.Tammali R, Ramana KV, Srivastava SK. Aldose reductase regulates TNF-alpha-induced PGE2 production in human colon cancer cells. Cancer Lett 2007; 252: 299-306.
45.Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13: 472-482.
46.Ryan HE, Lo J, Johnson RS. HIF-1 alpha is required for solid tumor formation and embryonic vascularization. EMBO J 1998; 17: 3005-3015.
47.Lutz NW, Tome ME, Cozzone PJ. Early changes in glucose and phospholipid metabolism following apoptosis induction by IFN-gamma/TNF-alpha in HT-29 cells. FEBS Lett 2003; 544: 123-128.
48.Hunt TK, Aslam R, Hussain Z, Beckert S. Lactate, with oxygen, incites angiogenesis. Adv Exp Med Biol 2008; 614: 73-80.
49.Ojika T, Imaizumi M, Watanabe H, Abe T, Kato K. [An immunohistochemical study on three aldolase isozymes in human lung cancer]. Nippon Kyobu Geka Gakkai Zasshi 1992; 40: 382-386.
50.Mori S, Chang JT, Andrechek ER, Matsumura N, Baba T, Yao G, Kim JW, Gatza M, Murphy S, Nevins JR. Anchorage-independent cell growth signature identifies tumors with metastatic potential. Oncogene 2009; 28: 2796-2805.
51.Zhang X, Xu LH, Yu Q. Cell aggregation induces phosphorylation of PECAM-1 and Pyk2 and promotes tumor cell anchorage-independent growth. Mol Cancer 2010; 9: 7.
52.Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera SA, Liang MC, Cai D, Naumov GN, Bao L, Contreras CM, Li D, Chen L, Krishnamurthy J, Koivunen J, Chirieac LR, Padera RF, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, Janne PA, Johnson BE, Meyerson M, Kwiatkowski DJ, Castrillon DH, Bardeesy N, Sharpless NE, Wong KK. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007; 448: 807-810.
53.Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29: 254-258.
54.Dowling RJ, Zakikhani M, Fantus IG, Pollak M, Sonenberg N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 2007; 67: 10804-10812.
55.Hakoda T, Yamamoto K, Terada R, Okano N, Shimada N, Suzuki T, Mizuno M, Shiratori Y. A crucial role of hepatocyte nuclear factor-4 expression in the differentiation of human ductular hepatocytes. Lab Invest 2003; 83: 1395-1402.
56.Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, Duncan SA. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 2003; 34: 292-296.
57.Cattin AL, Le Beyec J, Barreau F, Saint-Just S, Houllier A, Gonzalez FJ, Robine S, Pincon-Raymond M, Cardot P, Lacasa M, Ribeiro A. Hepatocyte nuclear factor 4alpha, a key factor for homeostasis, cell architecture, and barrier function of the adult intestinal epithelium. Mol Cell Biol 2009; 29: 6294-6308.
58.Sladek FM. Orphan receptor HNF-4 and liver-specific gene expression. Receptor 1993; 3: 223-232.
59.Sladek FM. Orphan receptor HNF-4 and liver-specific gene expression. Receptor 1994; 4: 64.
60.Sladek R, Giguere V. Orphan nuclear receptors: an emerging family of metabolic regulators. Adv Pharmacol 2000; 47: 23-87.
61.Reijnen MJ, Sladek FM, Bertina RM, Reitsma PH. Disruption of a binding site for hepatocyte nuclear factor 4 results in hemophilia B Leyden. Proc Natl Acad Sci U S A 1992; 89: 6300-6303.
62.Sladek FM, Dallas-Yang Q, Nepomuceno L. MODY1 mutation Q268X in hepatocyte nuclear factor 4alpha allows for dimerization in solution but causes abnormal subcellular localization. Diabetes 1998; 47: 985-990.
63.Raney AK, Eggers CM, Kline EF, Guidotti LG, Pontoglio M, Yaniv M, McLachlan A. Nuclear covalently closed circular viral genomic DNA in the liver of hepatocyte nuclear factor 1 alpha-null hepatitis B virus transgenic mice. J Virol 2001; 75: 2900-2911.
64.Hirota K, Sakamaki J, Ishida J, Shimamoto Y, Nishihara S, Kodama N, Ohta K, Yamamoto M, Tanimoto K, Fukamizu A. A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding. J Biol Chem 2008; 283: 32432-32441.
65.Sugai M, Umezu H, Yamamoto T, Jiang S, Iwanari H, Tanaka T, Hamakubo T, Kodama T, Naito M. Expression of hepatocyte nuclear factor 4 alpha in primary ovarian mucinous tumors. Pathol Int 2008; 58: 681-686.
66.Darsigny M, Babeu JP, Seidman EG, Gendron FP, Levy E, Carrier J, Perreault N, Boudreau F. Hepatocyte Nuclear Factor-4{alpha} Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species. Cancer Res 2010; 70: 9423-9433.
67.Ning BF, Ding J, Yin C, Zhong W, Wu K, Zeng X, Yang W, Chen YX, Zhang JP, Zhang X, Wang HY, Xie WF. Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res 2010; 70: 7640-7651.
68.Sun K, Montana V, Chellappa K, Brelivet Y, Moras D, Maeda Y, Parpura V, Paschal BM, Sladek FM. Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization. Mol Endocrinol 2007; 21: 1297-1311.
69.Basak SK, Veena MS, Oh S, Huang G, Srivatsan E, Huang M, Sharma S, Batra RK. The malignant pleural effusion as a model to investigate intratumoral heterogeneity in lung cancer. PLoS One 2009; 4: e5884.
70.Jain N, Zhang T, Kee WH, Li W, Cao X. Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J Biol Chem 1999; 274: 24392-24400.
71.Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM, Duncan SA. Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci U S A 2006; 103: 8419-8424.
72.Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000; 19: 2474-2488.
73.Huang S, Bucana CD, Van Arsdall M, Fidler IJ. Stat1 negatively regulates angiogenesis, tumorigenicity and metastasis of tumor cells. Oncogene 2002; 21: 2504-2512.
74.Hoffman PC, Mauer AM, Vokes EE. Lung cancer. Lancet 2000; 355: 479-485.
75.Hung TL, Chen FF, Liu JM, Lai WW, Hsiao AL, Huang WT, Chen HH, Su WC. Clinical evaluation of HER-2/neu protein in malignant pleural effusion-associated lung adenocarcinoma and as a tumor marker in pleural effusion diagnosis. Clin Cancer Res 2003; 9: 2605-2612.
76.Su WC, Lai WW, Chen HH, Hsiue TR, Chen CW, Huang WT, Chen TY, Tsao CJ, Wang NS. Combined intrapleural and intravenous chemotherapy, and pulmonary irradiation, for treatment of patients with lung cancer presenting with malignant pleural effusion. A pilot study. Oncology 2003; 64: 18-24.
77.Krutzik PO, Nolan GP. Intracellular phospho-protein staining techniques for flow cytometry: monitoring single cell signaling events. Cytometry A 2003; 55: 61-70.
78.Simsir A, Fetsch P, Mehta D, Zakowski M, Abati A. E-cadherin, N-cadherin, and calretinin in pleural effusions: the good, the bad, the worthless. Diagn Cytopathol 1999; 20: 125-130.
79.Roberts D, Schick J, Conway S, Biade S, Laub PB, Stevenson JP, Hamilton TC, O'Dwyer PJ, Johnson SW. Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells. Br J Cancer 2005; 92: 1149-1158.
80.Patterson SG, Wei S, Chen X, Sallman DA, Gilvary DL, Zhong B, Pow-Sang J, Yeatman T, Djeu JY. Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells. Oncogene 2006; 25: 6113-6122.
81.Irish JM, Czerwinski DK, Nolan GP, Levy R. Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. Blood 2006; 108: 3135-3142.
82.Krutzik PO, Irish JM, Nolan GP, Perez OD. Analysis of protein phosphorylation and cellular signaling events by flow cytometry: techniques and clinical applications. Clin Immunol 2004; 110: 206-221.
83.Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, Naoe T. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000; 19: 624-631.
84.Pallis M, Seedhouse C, Grundy M, Russell N. Flow cytometric measurement of phosphorylated STAT5 in AML: lack of specific association with FLT3 internal tandem duplications. Leuk Res 2003; 27: 803-805.
85.Tochio T, Tanaka H, Nakata S, Hosoya H. Fructose-1,6-bisphosphate aldolase A is involved in HaCaT cell migration by inducing lamellipodia formation. J Dermatol Sci; 58: 123-129.
86.Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-957.
87.Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 2005; 65: 613-621.
88.Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27: 3297-3302.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2016-01-26起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2016-01-26起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw