跳到主要內容

臺灣博碩士論文加值系統

(100.26.196.222) 您好!臺灣時間:2024/02/29 22:52
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:王律凱
研究生(外文):Lu-Kai Wang
論文名稱:MiR-133a以及接合蛋白Syntenin在肺癌細胞侵襲及轉移之角色研究
論文名稱(外文):The Role of MicroRNA-133a and Adaptor Protein Syntenin in Lung Cancer Metastasis
指導教授:楊泮池楊泮池引用關係
指導教授(外文):Pan-Chyr Yang
口試委員:洪澤民周玉山楊瑞彬潘思樺
口試委員(外文):Tse-Ming HongYuh-Shan JouRuey-Bing YangSzu-Hua Pan
口試日期:2014-05-16
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:2014
畢業學年度:102
語文別:英文
論文頁數:135
中文關鍵詞:肺癌癌轉移miR-133asynteninSlug
外文關鍵詞:lung cancermetastasismiR-133asynteninSlug
相關次數:
  • 被引用被引用:0
  • 點閱點閱:378
  • 評分評分:
  • 下載下載:5
  • 收藏至我的研究室書目清單書目收藏:0
癌轉移是導致肺癌病患死亡的重要環節,現今研究指出許多微核醣核酸(miRNAs)、膜蛋白接收器(receptors)和上皮-間質轉化(EMT)調控因子(EMT-inducing transcription factor)在癌轉移過程中都扮演重要的角色。為了釐清肺癌轉移的作用機制與找尋新的標的物,我們針對微核醣核酸133a (miRNA-133a)與syntenin接合蛋白在肺癌進程中是否扮演重要的角色,以及是否具有控制癌轉移相關因子的能力進行探討。首先我們証明微核醣核酸133a能透過抑制許多相同功能的膜蛋白接收器的表現來減少下游訊號傳遞誘發的癌細胞生長與侵襲,如IGF-1R與TGFBR1所誘發的AKT訊號鏈。其次,我們發現syntenin能進入細胞核參與EMT調控因子Slug的轉錄抑制作用,進而強化Slug控制的各項癌轉移能力,例如EMT以及癌細胞侵襲與轉移。此外我們發現微核醣核酸133a和syntenin與Slug聯合的表現可以在臨床上作為預測肺癌患者的癒後指標。綜合以上的結果,我們認為在肺癌轉移的進程中微核醣核酸133a為抑癌基因,而接合蛋白syntenin為轉錄輔助蛋白,本研究能為癌症治療發展提供新的方向。
Cancer metastasis is the leading cause of death for lung cancer patients. Recent literatures indicated that microRNAs, dysregulation of membrane receptor and transcription factor act the central role in lung cancer progression. To investigate the new modulators and dissect the regulation mechanism through these metastatic regulators, we try to explore the role of miRNA-133a and adaptor protein syntenin played in lung cancer metastasis. In this thesis, we reported that miR-133a and syntenin were proposed to participate in regulation of cell invasiveness during lung cancer metastasis by regulating multiple oncogenic membrane receptors and transcriptional repressor Slug. Our results revealed that the inhibition of cell invasiveness by miR-133a results from suppressing the expression of multiple oncogenic receptors, such as the insulin-like growth factor 1 receptor (IGF-1R) or TGF-beta receptor type-1 (TGFBR1) followed by affecting the downstream AKT-signaling in lung cancer cell lines. We also showed that syntenin enhanced Slug-mediated EMT and cancer cell invasion/metastasis in lung adenocarcinoma cell lines depend on its nuclear translocation and the level of co-repressor HDAC1 recruitment. We also observed that the expression of miR-133a and syntenin/Slug could be used to predict the clinical outcome of lung cancer patients. In summary, we identified the tumor suppressor role of miR-133a and proposed the possible role of syntenin in acting as a transcriptional cofactor during the progression of lung cancer.
中文摘要 1
Abstract 2
Chapter one: General introduction 3
1.1 Lung cancer and metastasis 4
1.1.1 Cancer invasion and epithelial-to-mesenchymal transition (EMT) 5
1.2 Metastatic regulators 6
1.2.1 Dysregulation of receptor 7
1.2.2 EMT-inducing transcription factors 7
1.3 MicroRNA 9
1.3.1 MicroRNA and lung cancer metastasis 9
1.3.2 MiR-133 12
1.4 Amplification of adaptor proteins and cancer metastasis 12
1.4.1 Syntenin and cancer metastasis 13
1.5 Specific aims of this thesis 13
Chapter two: MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma 15
2.1 Abstract 16
2.2 Introduction 18
2.2.1 The dysregulation of receptors in lung cancer 18
2.2.2 MicroRNA-133a 18
2.2.3 MicroRNA-133a and membrane receptors 19
2.2.4 Summary 21
2.3 Materials and methods 22
2.3.1 Cell culture and antibodies 22
2.3.2 Gene and miRNA Expression Profiles 23
2.3.3 Quantitative PCR analysis 23
2.3.4 Invasion assay 24
2.3.5 Lentiviral vector transduction 24
2.3.6 Luciferase reporter assay 25
2.3.7 Human phospho-receptor tyrosine kinase array 26
2.3.8 Transfection and cell treatments 26
2.3.9 Experimental metastasis in vivo 27
2.3.10 Clinical lung cancer samples and immunohistochemistry 28
2.3.11 Statistical Analysis 28
2.4 Results 30
2.4.1 MiR133a is downregulated in malignant lung cancer cells and inhibits the cell invasive capacity 30
2.4.2 MiR-133a suppresses cancer metastasis in vivoanchorage-independent growth in vitro and xenograft tumor formation in vivo 31
2.4.3 Multiple oncogenic receptors are directly regulated by miR-133a 32
2.4.4 Knockdown of IGF-1R or TGFBR1 inhibits lung cancer invasion and proliferation through AKT-mediated signaling 34
2.4.5 MiR-133a regulates AKT activity through suppressing downstream targets of IGF-1R and TGFBR1 36
2.4.6 MiR-133a acts as a prognostic indicator of the clinical outcome 37
2.5 Discussions 38
Chapter three: Syntenin enhances Slug-mediated Epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma 60
3.1 Abstract 61
3.2 Introduction 63
3.2.1 Slug 63
3.2.2 Syntenin 63
3.2.3 Summary 64
3.3 Materials and methods 66
3.3.1 Plasmids 66
3.3.2 Cell Culture, Transfection and Viral Infection 66
3.3.3 Yeast two-hybrid assay 67
3.3.4 Immunoprecipitation and immunoblotting 68
3.3.5 Modified Boyden chamber invasion assay 68
3.3.6 Immunofluorescence 69
3.3.7 Reverse-transcriptase PCR 70
3.3.8 Cell fractionation 70
3.3.9 Luciferase reporter assay 71
3.3.10 Experimental metastasis in vivo 71
3.3.11 EMSA 71
3.3.12 ChIP 72
3.3.13 Patient selection and tumor specimens 73
3.3.14 Immunohistochemistry 74
3.3.15 Statistical analysis 74
3.4 Results 76
3.4.1 Syntenin associates with Slug and co-localizes in the nucleus 76
3.4.2 Over-expression of syntenin enhances Slug-mediated cancer cell invasion and filopodia formation. 77
3.4.3 Syntenin enhances Slug-mediated EMT regulation and cell invasion 78
3.4.4 Syntenin expression modulates Slug-mediated cancer metastasis in vivo 79
3.4.5 Slug uses its linker region to interacts with syntenin at the PDZ1 domain and the interaction increases the nuclear translocation of syntenin 80
3.4.6 Syntenin enhances Slug-mediated transcription repression through the recruitment of HDAC1 82
3.4.7 Syntenin-enhanced Slug-mediated cancer invasion is dependent on its nuclear localization and co-repressor recruitment 84
3.4.7 High syntenin and high Slug expressions are associated with poor survival in patients with lung adenocarcinoma 85
3.5 Discussions 87
Chapter four: Conclusion and future works 115
Abbreviations 119
References 121
Appendix 129

List of figures

Chapter two: MicroRNA-133a suppresses multiple oncogenic membrane receptors and cell invasion in non-small cell lung carcinoma
Figure 1: The expression levels of miR-133a in tissues and cell line. 42
Figure 2: Inhibition of miR-133a enhances cell invasiveness in BEAS-2B cell. 43
Figure 3: MiR-133a regulates cell invasiveness and cell proliferation in lung cancer cell lines. 44
Figure 4: MiR-133a-expressing cells suppresses tumor metastasis in mice. 46
Figure 5: Schematic diagram of the predicted miR-133a binding sites in FGFR1, EGFR, TGFBR1, IGF-1R and INSR. 47
Figure 6: The mRNA expression level of receptors in miR-133a-expressing cells. 48
Figure 7: MiR-133a suppresses the expression of FGFR, EGFR, IGF-1R, and TGFBR1. 49
Figure 8: MiR-133a inhibits the expression of four receptors and decreases the phosphorylation of IGF-1R in lung adenocarcinoma cell lines. 50
Figure 9: IGF-1R, TGFBR1 and EGFR regulates cell invasion and proliferation in lung cancer cell lines. 52
Figure 10: Cell invasiveness and proliferation may regulated through the AKT-mediated signal in CL1-5 cell lines. 54
Figure 11: MiR-133a inhibits AKT activation and AKT-mediated cell invasion. 55
Figure 12: MiR-133a regulates IGF-1- and TGF-β-mediated AKT signaling. 56
Figure 13: Overall survival of NSCLC patients with different levels of miR-133a expression. 57
Chapter three: Syntenin enhances Slug-mediated Epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma
Figure 14: Syntenin is a candidate of Slug-associating protein. 92
Figure 15: Syntenin associates with Slug and co-localizes in the cell nucleus. 93
Figure 16: Syntenin and Slug proteins are highly expressed in high-invasive lung and breast cancer cell lines. 94
Figure 17: Syntenin enhance Slug-mediated cell invasion and the expression of syntenin positively correlated with invasive morphology. 95
Figure 18: Syntenin is involved in Slug-mediated E-cadherin regulation and cell invasion in lung adenocarcinoma cell lines. 96
Figure 19: Knockdown of syntenin expression decreases Slug-promoted cancer metastasis in vivo. 98
Figure 20: The PDZ1 domain of syntenin is required to interact with Slug. 100
Figure 21: The PDZ1 domain and the nucleus localization of syntenin are required to interact with Slug. 101
Figure 22: Slug can affect the distribution of syntenin in cells. 104
Figure 23: Syntenin facilitates Slug-dependent transcription repression not through modulate Slug protein stability. 105
Figure 24: Syntenin associates with Slug on the oligonucleotides with E-box sequence from E-cadherin promoter. 106
Figure 25: Syntenin increases the association with HDAC1 in Slug-overexpressed cells. 107
Figure 26: Both PDZ domains of nuclear syntenin are required for enhancing Slug- regulated cell invasion. 108
Figure 27: The expression of Slug/syntenin expressions is associated with poor survival in patients with lung adenocarcinoma. 110
Figure 28: Schematic representation depicting that nuclear syntenin modulates Slug-mediated cancer cell invasion through transcription co-repressor recruitment. 111

List of tables
Chapter one: General introduction
Table 1: The list of lung cancer invasion and metastasis associated miRNAs. 10
Chapter two: The motor protein KIF14 inhibits tumor growth and cancer metastasis in lung adenocarcinoma
Table 2: The list of the miR-133a predicted targets belong to membrane receptor. 20
Table 3: MiR-133a expression in relation to clinical parameters and pathological characteristics. 58
Table 4: Hazard ratios for death among patient with NSCLC in real-time quantitative RT-PCR analysis, according to multivariable Cox regression analysis. 59
Chapter three: Syntenin enhances Slug-mediated Epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma
Table 5: Functional assay of Syntenin mutants to Slug-mediated regulation. 112
Table 6: Syntenin and Slug expression in relation to clinical parameters and pathological characteristics. 113
Table 7: Hazard ratios for death among patients with lung adenocarcinoma, deterimined using immunohistochemistry staining according to multivariable Cox regression analysis 114

1. Hoffman PC, Mauer AM, Vokes EE. Lung cancer. Lancet. 2000;355(9202):479-85.
2.Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-cell lung cancer: recent developments. Lancet. 2013;382(9893):709-19.
3.Cooper WA, Lam DC, O'Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis. 2013;5(Suppl 5):S479-S90.
4.Rosell R, Bivona TG, Karachaliou N. Genetics and biomarkers in personalisation of lung cancer treatment. Lancet. 2013;382(9893):720-31.
5.Perlikos F, Harrington KJ, Syrigos KN. Key molecular mechanisms in lung cancer invasion and metastasis: a comprehensive review. Crit Rev Oncol Hematol. 2013;87(1):1-11.
6.March TH, Marron-Terada PG, Belinsky SA. Refinement of an orthotopic lung cancer model in the nude rat. Vet Pathol. 2001;38(5):483-90.
7.Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559-64.
8.Miller YE. Pathogenesis of lung cancer: 100 year report. Am J Respir Cell Mol Biol. 2005;33(3):216-23.
9.Sato M, Shames DS, Hasegawa Y. Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis. Respirology. 2012;17(7):1048-59.
10.De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97-110.
11.Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871-90.
12.Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009;119(6):1438-49.
13.Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8.
14.Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011;32(9):1299-304.
15.Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415-28.
16.Fujimoto D, Ueda H, Shimizu R, Kato R, Otoshi T, Kawamura T, et al. Features and prognostic impact of distant metastasis in patients with stage IV lung adenocarcinoma harboring EGFR mutations: importance of bone metastasis. Clin Exp Metastasis. 2014.
17.Pei J, Lou Y, Zhong R, Han B. MMP9 activation triggered by epidermal growth factor induced FoxO1 nuclear exclusion in non-small cell lung cancer. Tumour Biol. 2014.
18.Whitsett TG, Fortin Ensign SP, Dhruv HD, Inge LJ, Kurywchak P, Wolf KK, et al. FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion. Clin Exp Metastasis. 2014.
19.Qian J, Dong A, Kong M, Ma Z, Fan J, Jiang G. Suppression of type 1 Insulin-like growth factor receptor expression by small interfering RNA inhibits A549 human lung cancer cell invasion in vitro and metastasis in xenograft nude mice. Acta Biochim Biophys Sin (Shanghai). 2007;39(2):137-47.
20.Giaginis C, Tsoukalas N, Bournakis E, Alexandrou P, Kavantzas N, Patsouris E, et al. Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival. BMC Clin Pathol. 2014;14(1):8.
21.Vazquez PF, Carlini MJ, Daroqui MC, Colombo L, Dalurzo ML, Smith DE, et al. TGF-beta specifically enhances the metastatic attributes of murine lung adenocarcinoma: implications for human non-small cell lung cancer. Clin Exp Metastasis. 2013;30(8):993-1007.
22.Nieto MA, Sargent MG, Wilkinson DG, Cooke J. Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science. 1994;264(5160):835-9.
23.Shih JY, Tsai MF, Chang TH, Chang YL, Yuan A, Yu CJ, et al. Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res. 2005;11(22):8070-8.
24.Wang SP, Wang WL, Chang YL, Wu CT, Chao YC, Kao SH, et al. p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug. Nat Cell Biol. 2009;11(6):694-704.
25.Kao SH, Wang WL, Chen CY, Chang YL, Wu YY, Wang YT, et al. GSK3beta controls epithelial-mesenchymal transition and tumor metastasis by CHIP-mediated degradation of Slug. Oncogene. 2013.
26.Tufman A, Tian F, Huber RM. Can MicroRNAs Improve the Management of Lung Cancer Patients? A Clinician's Perspective. Theranostics. 2013;3(12):953-63.
27.Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597-610.
28.Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, et al. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell. 2008;13(1):48-57.
29.Voortman J, Goto A, Mendiboure J, Sohn JJ, Schetter AJ, Saito M, et al. MicroRNA expression and clinical outcomes in patients treated with adjuvant chemotherapy after complete resection of non-small cell lung carcinoma. Cancer Res. 2010;70(21):8288-98.
30.Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12(11):847-65.
31.Ebert MS, Sharp PA. Roles for microRNAs in conferring robustness to biological processes. Cell. 2012;149(3):515-24.
32.Pacurari M, Addison JB, Bondalapati N, Wan YW, Luo D, Qian Y, et al. The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells. Int J Oncol. 2013;43(2):548-60.
33.Peng Y, Dai Y, Hitchcock C, Yang X, Kassis ES, Liu L, et al. Insulin growth factor signaling is regulated by microRNA-486, an underexpressed microRNA in lung cancer. Proc Natl Acad Sci U S A. 2013;110(37):15043-8.
34.Lin CW, Chang YL, Chang YC, Lin JC, Chen CC, Pan SH, et al. MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1. Nat Commun. 2013;4:1877.
35.Koutsoulidou A, Mastroyiannopoulos NP, Furling D, Uney JB, Phylactou LA. Expression of miR-1, miR-133a, miR-133b and miR-206 increases during development of human skeletal muscle. BMC Dev Biol. 2011;11:34.
36.Uchida Y, Chiyomaru T, Enokida H, Kawakami K, Tatarano S, Kawahara K, et al. MiR-133a induces apoptosis through direct regulation of GSTP1 in bladder cancer cell lines. Urol Oncol. 2013;31(1):115-23.
37.Nohata N, Hanazawa T, Kikkawa N, Mutallip M, Fujimura L, Yoshino H, et al. Caveolin-1 mediates tumor cell migration and invasion and its regulation by miR-133a in head and neck squamous cell carcinoma. Int J Oncol. 2011;38(1):209-17.
38.Kojima S, Chiyomaru T, Kawakami K, Yoshino H, Enokida H, Nohata N, et al. Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer. Br J Cancer. 2012;106(2):405-13.
39.Moriya Y, Nohata N, Kinoshita T, Mutallip M, Okamoto T, Yoshida S, et al. Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma. J Hum Genet. 2012;57(1):38-45.
40.Cui W, Zhang S, Shan C, Zhou L, Zhou Z. microRNA-133a regulates the cell cycle and proliferation of breast cancer cells by targeting epidermal growth factor receptor through the EGFR/Akt signaling pathway. FEBS J. 2013;280(16):3962-74.
41.Guo J, Xia B, Meng F, Lou G. miR-133a suppresses ovarian cancer cell proliferation by directly targeting insulin-like growth factor 1 receptor. Tumour Biol. 2013.
42.Dong Y, Zhao J, Wu CW, Zhang L, Liu X, Kang W, et al. Tumor suppressor functions of miR-133a in colorectal cancer. Mol Cancer Res. 2013;11(9):1051-60.
43.Qiu T, Zhou X, Wang J, Du Y, Xu J, Huang Z, et al. MiR-145, miR-133a and miR-133b inhibit proliferation, migration, invasion and cell cycle progression via targeting transcription factor Sp1 in gastric cancer. FEBS Lett. 2014;588(7):1168-77.
44.Akanuma N, Hoshino I, Akutsu Y, Murakami K, Isozaki Y, Maruyama T, et al. MicroRNA-133a regulates the mRNAs of two invadopodia-related proteins, FSCN1 and MMP14, in esophageal cancer. Br J Cancer. 2014;110(1):189-98.
45.Ji F, Zhang H, Wang Y, Li M, Xu W, Kang Y, et al. MicroRNA-133a, downregulated in osteosarcoma, suppresses proliferation and promotes apoptosis by targeting Bcl-xL and Mcl-1. Bone. 2013;56(1):220-6.
46.Beekman JM, Coffer PJ. The ins and outs of syntenin, a multifunctional intracellular adaptor protein. J Cell Sci. 2008;121(Pt 9):1349-55.
47.Cui ZL, Han FF, Peng XH, Chen X, Luan CY, Han RC, et al. YES-associated protein 1 promotes adenocarcinoma growth and metastasis through activation of the receptor tyrosine kinase Axl. Int J Immunopathol Pharmacol. 2012;25(4):989-1001.
48.Lau AN, Curtis SJ, Fillmore CM, Rowbotham SP, Mohseni M, Wagner DE, et al. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis. EMBO J. 2014;33(5):468-81.
49.Jin Y, Li F, Zheng C, Wang Y, Fang Z, Guo C, et al. NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition. Int J Cancer. 2014;134(10):2294-304.
50.Kang BS, Cooper DR, Jelen F, Devedjiev Y, Derewenda U, Dauter Z, et al. PDZ tandem of human syntenin: crystal structure and functional properties. Structure. 2003;11(4):459-68.
51.Grembecka J, Cierpicki T, Devedjiev Y, Derewenda U, Kang BS, Bushweller JH, et al. The binding of the PDZ tandem of syntenin to target proteins. Biochemistry. 2006;45(11):3674-83.
52.Beekman JM, Vervoort SJ, Dekkers F, van Vessem ME, Vendelbosch S, Brugulat-Panes A, et al. Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output. Oncogene. 2012;31(21):2668-79.
53.Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology (PIONEER). J Thorac Oncol. 2014;9(2):154-62.
54.Mitsudomi T, Suda K, Yatabe Y. Surgery for NSCLC in the era of personalized medicine. Nat Rev Clin Oncol. 2013;10(4):235-44.
55.Scagliotti GV, Novello S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev. 2012;38(4):292-302.
56.Santibanez JF, Quintanilla M, Bernabeu C. TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin Sci (Lond). 2011;121(6):233-51.
57.Tao J, Wu D, Xu B, Qian W, Li P, Lu Q, et al. microRNA-133 inhibits cell proliferation, migration and invasion in prostate cancer cells by targeting the epidermal growth factor receptor. Oncol Rep. 2012;27(6):1967-75.
58.Zhou Y, Wu D, Tao J, Qu P, Zhou Z, Hou J. MicroRNA-133 inhibits cell proliferation, migration and invasion by targeting epidermal growth factor receptor and its downstream effector proteins in bladder cancer. Scand J Urol. 2013;47(5):423-32.
59.Tai CJ, Wu AT, Chiou JF, Jan HJ, Wei HJ, Hsu CH, et al. The investigation of mitogen-activated protein kinase phosphatase-1 as a potential pharmacological target in non-small cell lung carcinomas, assisted by non-invasive molecular imaging. BMC Cancer. 2010;10:95.
60.Chen Y, Zhao YH, Di YP, Wu R. Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5'-flanking region. Am J Respir Cell Mol Biol. 2001;25(5):542-53.
61.Chu YW, Yang PC, Yang SC, Shyu YC, Hendrix MJ, Wu R, et al. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 1997;17(3):353-60.
62.Hsu YC, Yuan S, Chen HY, Yu SL, Liu CH, Hsu PY, et al. A four-gene signature from NCI-60 cell line for survival prediction in non-small cell lung cancer. Clin Cancer Res. 2009;15(23):7309-15.
63.Wu W, Bi C, Credille KM, Manro JR, Peek VL, Donoho GP, et al. Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET. Clin Cancer Res. 2013;19(20):5699-710.
64.Cheung M, Testa JR. Diverse mechanisms of AKT pathway activation in human malignancy. Curr Cancer Drug Targets. 2013;13(3):234-44.
65.Kano M, Seki N, Kikkawa N, Fujimura L, Hoshino I, Akutsu Y, et al. miR-145, miR-133a and miR-133b: Tumor-suppressive miRNAs target FSCN1 in esophageal squamous cell carcinoma. Int J Cancer. 2010;127(12):2804-14.
66.Seccareccia E, Brodt P. The role of the insulin-like growth factor-I receptor in malignancy: an update. Growth Horm IGF Res. 2012;22(6):193-9.
67.Singh I, Amin H, Rah B, Goswami A. Targeting EGFR and IGF 1R: a promising combination therapy for metastatic cancer. Front Biosci (Schol Ed). 2013;5:231-46.
68.Kaklamani VG, Pasche B. Role of TGF-beta in cancer and the potential for therapy and prevention. Expert Rev Anticancer Ther. 2004;4(4):649-61.
69.Wen D, Li S, Ji F, Cao H, Jiang W, Zhu J, et al. miR-133b acts as a tumor suppressor and negatively regulates FGFR1 in gastric cancer. Tumour Biol. 2013;34(2):793-803.
70.Beekman JM, Verhagen LP, Geijsen N, Coffer PJ. Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output. Blood. 2009;114(18):3917-27.
71.Lambaerts K, Van Dyck S, Mortier E, Ivarsson Y, Degeest G, Luyten A, et al. Syntenin, a syndecan adaptor and an Arf6 phosphatidylinositol 4,5-bisphosphate effector, is essential for epiboly and gastrulation cell movements in zebrafish. J Cell Sci. 2012;125(Pt 5):1129-40.
72.McClelland AC, Sheffler-Collins SI, Kayser MS, Dalva MB. Ephrin-B1 and ephrin-B2 mediate EphB-dependent presynaptic development via syntenin-1. Proc Natl Acad Sci U S A. 2009;106(48):20487-92.
73.Jeon HY, Das SK, Dasgupta S, Emdad L, Sarkar D, Kim SH, et al. Expression patterns of MDA-9/syntenin during development of the mouse embryo. J Mol Histol. 2013;44(2):159-66.
74.Yang Y, Hong Q, Shi P, Liu Z, Luo J, Shao Z. Elevated expression of syntenin in breast cancer is correlated with lymph node metastasis and poor patient survival. Breast Cancer Res. 2013;15(3):R50.
75.Hwangbo C, Kim J, Lee JJ, Lee JH. Activation of the integrin effector kinase focal adhesion kinase in cancer cells is regulated by crosstalk between protein kinase Calpha and the PDZ adapter protein mda-9/Syntenin. Cancer Res. 2010;70(4):1645-55.
76.Hwangbo C, Park J, Lee JH. mda-9/Syntenin protein positively regulates the activation of Akt protein by facilitating integrin-linked kinase adaptor function during adhesion to type I collagen. J Biol Chem. 2011;286(38):33601-12.
77.Sarkar D, Boukerche H, Su ZZ, Fisher PB. mda-9/syntenin: recent insights into a novel cell signaling and metastasis-associated gene. Pharmacol Ther. 2004;104(2):101-15.
78.Das SK, Bhutia SK, Azab B, Kegelman TP, Peachy L, Santhekadur PK, et al. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. Cancer Res. 2013;73(2):844-54.
79.Boukerche H, Su ZZ, Emdad L, Sarkar D, Fisher PB. mda-9/Syntenin regulates the metastatic phenotype in human melanoma cells by activating nuclear factor-kappaB. Cancer Res. 2007;67(4):1812-22.
80.Koo TH, Lee JJ, Kim EM, Kim KW, Kim HD, Lee JH. Syntenin is overexpressed and promotes cell migration in metastatic human breast and gastric cancer cell lines. Oncogene. 2002;21(26):4080-8.
81.Kim WY, Jang JY, Jeon YK, Chung DH, Kim YG, Kim CW. Syntenin increases the invasiveness of small cell lung cancer cells by activating p38, AKT, focal adhesion kinase and SP1. Exp Mol Med. 2014;46:e90.
82.Boukerche H, Aissaoui H, Prevost C, Hirbec H, Das SK, Su ZZ, et al. Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB. Oncogene. 2010;29(21):3054-66.
83.Langer EM, Feng Y, Zhaoyuan H, Rauscher FJ, 3rd, Kroll KL, Longmore GD. Ajuba LIM proteins are snail/slug corepressors required for neural crest development in Xenopus. Dev Cell. 2008;14(3):424-36.
84.Montoya-Durango DE, Velu CS, Kazanjian A, Rojas ME, Jay CM, Longmore GD, et al. Ajuba functions as a histone deacetylase-dependent co-repressor for autoregulation of the growth factor-independent-1 transcription factor. J Biol Chem. 2008;283(46):32056-65.
85.Ayyanathan K, Peng H, Hou Z, Fredericks WJ, Goyal RK, Langer EM, et al. The Ajuba LIM domain protein is a corepressor for SNAG domain mediated repression and participates in nucleocytoplasmic Shuttling. Cancer Res. 2007;67(19):9097-106.
86.Chang TH, Tsai MF, Su KY, Wu SG, Huang CP, Yu SL, et al. Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. Am J Respir Crit Care Med. 2011;183(8):1071-9.
87.Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009;27(9):2059-68.
88.Suda K, Tomizawa K, Fujii M, Murakami H, Osada H, Maehara Y, et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J Thorac Oncol. 2011;6(7):1152-61.
89.Zimmermann P, Tomatis D, Rosas M, Grootjans J, Leenaerts I, Degeest G, et al. Characterization of syntenin, a syndecan-binding PDZ protein, as a component of cell adhesion sites and microfilaments. Mol Biol Cell. 2001;12(2):339-50.
90.Gangemi R, Mirisola V, Barisione G, Fabbi M, Brizzolara A, Lanza F, et al. Mda-9/syntenin is expressed in uveal melanoma and correlates with metastatic progression. PLoS One. 2012;7(1):e29989.
91.Lin YY, Hsu YH, Huang HY, Shann YJ, Huang CY, Wei SC, et al. Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and beta-catenin interactions. J Clin Invest. 2012;122(5):1881-94.
92.Okumura F, Yoshida K, Liang F, Hatakeyama S. MDA-9/syntenin interacts with ubiquitin via a novel ubiquitin-binding motif. Mol Cell Biochem. 2011;352(1-2):163-72.
93.Dasgupta S, Menezes ME, Das SK, Emdad L, Janjic A, Bhatia S, et al. Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling. Clin Cancer Res. 2013;19(17):4621-33.

QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
無相關期刊