進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-1805201710285400
論文名稱(中文) 泛素特異性胜肽酶二十四在肺癌生長,惡化與腫瘤相關微環境中所扮演的角色
論文名稱(英文) The role of USP24 in lung cancer proliferation, malignancy, and tumor-associated microenvironment
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 105
學期 2
出版年 106
研究生(中文) 王毅昌
研究生(英文) Yi-Chang Wang
學號 S58011035
學位類別 博士
語文別 英文
論文頁數 186頁
口試委員 指導教授-洪建中
共同指導教授-張文昌
召集委員-蘇五洲
口試委員-王憶卿
口試委員-陳瑞華
口試委員-阮麗蓉
中文關鍵字 肺癌  泛素化  泛素特異性胜肽酶24 
英文關鍵字 lung cancer  ubiquitination  USP24 
學科別分類
中文摘要 泛素化 (ubiquitination) 為可逆的轉譯後修飾機制,可藉由影響蛋白質的穩定性、親和性或細胞內位置而影響細胞的功能。過去的研究多著重在參與泛素化過程的E3泛素連結酶 (E3 ligase),且已證實E3泛素連結酶的變異與癌症發生有關。然而關於移除泛素化的酵素 (deubiquitinating enzyme) 在近幾年才受到重視,因此許多去泛素化酵素與癌症的關聯性仍不明確。本篇研究目的在於釐清泛素特異性胜肽酶24 (ubiquitin specific peptidase 24, USP24) 在肺癌發展中所扮演的角色。首先,我們發現在肺癌早期,上皮生長因子接受器 (epidermal growth factor receptor, EGFR) 路徑活化會導致USP24被磷酸化並降低USP24的表現,進一步導致USP24受質Bax、p300的泛素化增加而被降解,同時減少Ku70的乙醯化 (acetylation) 而抑制癌細胞的細胞凋亡。除了Bax、p300以外,我們也發現USP24的減少會降低USP24的受質E2F4與securin的表現量,並進一步促進細胞週期G1/S的轉化 (G1/S transition) 與分裂週期中的中/後期轉化 (metaphase/anaphase transition), 因此加速癌細胞生長。此外,當USP24表現量降低時,癌細胞可藉由失去E2F4的轉錄抑制作用而過度表現下游調控DNA修復的基因RAD51,或可能藉由增加DNA甲基轉移酵素 (DNA methyltransferase) DNMT1的表現,進一步抑制轉錄因子RBL2/p130的表現而增加RAD54L此調控DNA修復的基因,最終使癌細胞對Camptothecin (CPT) 此抗癌藥物產生抗藥性。在肺癌晚期,我們發現USP24本身的單核甘酸多型性 (single nucleotide polymorphism, SNP) 與RNA編輯 (RNA editing) 可經由增加USP24 RNA穩定度而導致USP24表現增加,穩定MDM2此E3 ligase的蛋白質穩定度,進一步抑制組織蛋白甲基轉移酶Suv39H1所造成的基因靜默 (silencing) 而促進癌細胞轉移。除了在癌細胞本身的研究外,我們也發現與腫瘤相關的巨噬細胞 (tumor-associated macrophages, TAMs) M2分化過程中, USP24表現量的增加可能會經由調控p300促進M2巨噬細胞中NF-B的表現,最後刺激IL-6的表現與分泌,或是藉由減少肺癌細胞本身IL-6啟動子 (promoter) 上的甲基化 (methylation) 修飾而促進IL-6的表現與分泌,進一步加速癌細胞的轉移。根據本篇研究,我們證實在肺癌中USP24不論在促進癌細胞生長、抗藥性的產生、癌細胞轉移與腫瘤相關微環境 (tumor-associated microenvironment) 中都扮演重要的角色,顯示USP24有成為一個診斷與治療標的潛力。
英文摘要 Ubiquitin is a critical modifier that regulates the degradation and function of its target proteins via post-translational modification. Numerous studies have found that E3 ligases, which can join ubiquitin molecules and substrates with covalent bonds, are related with cancer formation; however, the relation between deubiquitinating enzymes and cancer is still unclear. In this study, we elucidated multiple roles of a novel deubiquitinating enzyme, ubiquitin-specific peptidase 24 (USP24), in lung cancer progression. First, we found that activation of EGFR signaling pathway caused USP24 phosphorylation and downregulation, resulting in the degradation of its substrates, Bax and p300, and the decrease of Ku70 acetylation, therefore attenuating cancer cell apoptosis. Second, we found other substrates of USP24, such as E2F4 and securin, were also decreased after USP24 downregulation, resulting in the acceleration of cancer cell proliferation through increasing G1/S transition and metaphase/anaphase transition. Moreover, the downregulated E2F4 led to the upregulation of RAD51, which is a crucial gene for DNA damage repair, and led to CPT resistance. Downregulated USP24-induced DNMT1 (DNA methyltransferases 1) upregulation might also involved in DNA damage repair through increasing RAD54L expression. In the late stage of lung cancer, we found that single nucleotide polymorphism (SNP) and RNA editing of USP24 increased USP24 level by increasing its RNA stability. Upregulated USP24 could promote metastasis through stabilizing E3 ligase MDM2, resulting in the decrease of methyltransferase Suv39h1 and decrease of histone H3 lysine-9 methylation. We also found that USP24 was upregulated when monocyte differentiates into tumor-associated M2 macrophages. Increased USP24 might induce interleukin 6 (IL-6) expressions and secretion in tumor-associated microenvironment through regulating p300 and NF-B expression or IL-6 promoter methylation and promote cancer metastasis. Based on these results, we have proved that USP24 plays important roles in cancer cell apoptosis, proliferation, drug resistance, metastasis, and tumor associated microenvironment. By elucidating these detail mechanisms, we hope we can provide new diagnostic and therapeutic strategies for lung cancer treatment.
論文目次 摘要 I
Abstract III
Acknowledgment V
Contents VI
Figure index IX
Abbreviation XI
Introduction 1
I. Lung cancer 1
A. Epidemiology of lung cancer 1
B. Lung cancer diagnosis and classification 1
C. Molecular profiling and treatments of NSCLC 2
II. Cancer biology 3
A. Apoptosis 3
B. Cell cycle control 4
C. Metastasis 5
D. Drug resistance 6
III. Ubiquitin-proteasome system 7
A. Ubiquitin proteasome pathway 7
B. Ubiquitin-specific peptidase 8
C. Ubiquitin-specific peptidase 24 (USP24) 9
Research aims 11
Materials and methods 12
Materials 12
Methods 19
Results 32
1. EGF-inhibited UPS24 expression induces cancer formation 32
2. USP24 induces apoptosis by stabilizing p300 and Bax 33
3. USP24 inhibits the G1-S transition by increasing the E2F4 level 35
4. The decrease in USP24 during mitosis is crucial for the metaphase-anaphase transition via the declining securin level 37
5. Phosphorylation of USP24 increases its degradation during tumorigenesis and cell cycle progression 39
6. USP24 downregulation induces RAD51 dependent homologous recombination and CPT resistance 41
7. USP24 downregulation promotes RAD51 expression and CPT resistance through decreasing E2F4 expression 43
8. USP24 is highly expressed in late stage lung cancer 46
9. Higher incidence of USP24 SNPs in late stage lung cancer 46
10. Variants of USP24 show better mRNA stability and facilitate lung cancer malignancy 48
11. USP24 stabilizes MDM2, degrading Suv39h1 and affecting H3K9 methylation 49
12. Tumor-infiltrating leukocytes show high USP24 expression level 52
13. USP24 knockdown decreases M2-derived conditioned medium-induced migratory ability and chemotaxic effect on A549 cells 52
14. USP24 knockdown decreases M2 induced lung cancer cells metastasis and angiogenesis in vivo 53
15. USP24 knockdown decreases IL-6 expression and secretion in M2 macrophages and lung cancer cells 54
16. USP24 might regulate IL-6 expression through modulating NF-kB expression in M2 macrophages and IL-6 promoter methylation in A549 cells 55
Discussion 57
1. Whether p130 and TFDP-1 also participate in USP24 downregulation induced DNA damage repair? 57
2. The possible mechanisms of how USP24 regulates p130 and TFDP-1 58
3. Potential enzymes that catalyze USP24 phosphorylation 59
4. Potential enzymes that catalyze USP24 RNA editing 60
5. Multiple roles and multiple ways of USP24 in promoting lung cancer metastasis 61
6. Clinical application 63
Conclusion 64
Reference 65
Publication 156
Curriculum vitae 157
參考文獻 Al Mohammad, B., Brennan, P. C., & Mello-Thoms, C. (2017). A review of lung cancer screening and the role of computer-aided detection. Clin Radiol, 72(6), 433-442. doi: 10.1016/j.crad.2017.01.002
Amsel, A. D., Rathaus, M., Kronman, N., & Cohen, H. Y. (2008). Regulation of the proapoptotic factor Bax by Ku70-dependent deubiquitylation. Proc Natl Acad Sci U S A, 105(13), 5117-5122. doi: 10.1073/pnas.0706700105
Araujo, A., Ribeiro, R., Azevedo, I., Coelho, A., Soares, M., Sousa, B., . . . Scagliotti, G. V. (2007). Genetic polymorphisms of the epidermal growth factor and related receptor in non-small cell lung cancer--a review of the literature. Oncologist, 12(2), 201-210. doi: 10.1634/theoncologist.12-2-201
Asmarinah, A., Paradowska-Dogan, A., Kodariah, R., Tanuhardja, B., Waliszewski, P., Mochtar, C. A., . . . Hinsch, E. (2014). Expression of the Bcl-2 family genes and complexes involved in the mitochondrial transport in prostate cancer cells. Int J Oncol, 45(4), 1489-1496. doi: 10.3892/ijo.2014.2576
Baldys, A., Gooz, M., Morinelli, T. A., Lee, M. H., Raymond, J. R., Jr., Luttrell, L. M., & Raymond, J. R., Sr. (2009). Essential role of c-Cbl in amphiregulin-induced recycling and signaling of the endogenous epidermal growth factor receptor. Biochemistry, 48(7), 1462-1473. doi: 10.1021/bi801771g
Beadsmoore, C. J., & Screaton, N. J. (2003). Classification, staging and prognosis of lung cancer. Eur J Radiol, 45(1), 8-17.
Bezzubova, O., Silbergleit, A., Yamaguchi-Iwai, Y., Takeda, S., & Buerstedde, J. M. (1997). Reduced X-ray resistance and homologous recombination frequencies in a RAD54-/- mutant of the chicken DT40 cell line. Cell, 89(2), 185-193.
Bhattacharya, S., Socinski, M. A., & Burns, T. F. (2015). KRAS mutant lung cancer: progress thus far on an elusive therapeutic target. Clin Transl Med, 4(1), 35. doi: 10.1186/s40169-015-0075-0
Blanc, V., & Davidson, N. O. (2003). C-to-U RNA editing: mechanisms leading to genetic diversity. J Biol Chem, 278(3), 1395-1398. doi: 10.1074/jbc.R200024200
Blanchette, P., Gilchrist, C. A., Baker, R. T., & Gray, D. A. (2001). Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130. Oncogene, 20(39), 5533-5537. doi: 10.1038/sj.onc.1204823
Bochis, O. V., Irimie, A., Pichler, M., & Berindan-Neagoe, I. (2015). The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer. J Gastrointestin Liver Dis, 24(2), 225-234. doi: 10.15403/jgld.2014.1121.242.skp2
Bosch-Presegue, L., Raurell-Vila, H., Marazuela-Duque, A., Kane-Goldsmith, N., Valle, A., Oliver, J., . . . Vaquero, A. (2011). Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol Cell, 42(2), 210-223. doi: 10.1016/j.molcel.2011.02.034
Cai, L., Ma, X., Huang, Y., Zou, Y., & Chen, X. (2014). Aberrant histone methylation and the effect of Suv39H1 siRNA on gastric carcinoma. Oncol Rep, 31(6), 2593-2600. doi: 10.3892/or.2014.3135
Chatziandreou, I., Tsioli, P., Sakellariou, S., Mourkioti, I., Giannopoulou, I., Levidou, G., . . . Saetta, A. A. (2015). Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations. PLoS One, 10(7), e0133859. doi: 10.1371/journal.pone.0133859
Chen, S. H., Habib, G., Yang, C. Y., Gu, Z. W., Lee, B. R., Weng, S. A., . . . et al. (1987). Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science, 238(4825), 363-366.
Chen, Z., Xu, L., Ye, X., Shen, S., Li, Z., Niu, X., & Lu, S. (2013). Polymorphisms of microRNA sequences or binding sites and lung cancer: a meta-analysis and systematic review. PLoS One, 8(4), e61008. doi: 10.1371/journal.pone.0061008
Ciechanover, A., & Brundin, P. (2003). The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron, 40(2), 427-446.
Conway, E. M., Pikor, L. A., Kung, S. H., Hamilton, M. J., Lam, S., Lam, W. L., & Bennewith, K. L. (2016). Macrophages, Inflammation, and Lung Cancer. Am J Respir Crit Care Med, 193(2), 116-130. doi: 10.1164/rccm.201508-1545CI
Daks, A., Petukhov, A., Fedorova, O., Shuvalov, O., Merkulov, V., Vasileva, E., . . . Barlev, N. A. (2016). E3 ubiquitin ligase Pirh2 enhances tumorigenic properties of human non-small cell lung carcinoma cells. Genes Cancer, 7(11-12), 383-393. doi: 10.18632/genesandcancer.123
Das, T. K., Dana, D., Paroly, S. S., Perumal, S. K., Singh, S., Jhun, H., . . . Kumar, S. (2013). Centrosomal kinase Nek2 cooperates with oncogenic pathways to promote metastasis. Oncogenesis, 2, e69. doi: 10.1038/oncsis.2013.34
Dominguez-Brauer, C., Khatun, R., Elia, A. J., Thu, K. L., Ramachandran, P., Baniasadi, S. P., . . . Mak, T. W. (2017). E3 ubiquitin ligase Mule targets beta-catenin under conditions of hyperactive Wnt signaling. Proc Natl Acad Sci U S A, 114(7), E1148-E1157. doi: 10.1073/pnas.1621355114
Eberhard, D. A., Johnson, B. E., Amler, L. C., Goddard, A. D., Heldens, S. L., Herbst, R. S., . . . Hillan, K. J. (2005). Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol, 23(25), 5900-5909. doi: 10.1200/JCO.2005.02.857
Ebert, M. P., Mooney, S. H., Tonnes-Priddy, L., Lograsso, J., Hoffmann, J., Chen, J., . . . Lofton-Day, C. (2005). Hypermethylation of the TPEF/HPP1 gene in primary and metastatic colorectal cancers. Neoplasia, 7(8), 771-778.
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., . . . Wong, K. K. (2008). Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med, 14(12), 1351-1356. doi: 10.1038/nm.1890
Fang, Q. L., Yin, Y. R., Xie, C. R., Zhang, S., Zhao, W. X., Pan, C., . . . Yin, Z. Y. (2015). Mechanistic and biological significance of DNA methyltransferase 1 upregulated by growth factors in human hepatocellular carcinoma. Int J Oncol, 46(2), 782-790. doi: 10.3892/ijo.2014.2776
Gajewski, T. F., Schreiber, H., & Fu, Y. X. (2013). Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol, 14(10), 1014-1022. doi: 10.1038/ni.2703
Garcia, G. A., & Kittendorf, J. D. (2005). Transglycosylation: a mechanism for RNA modification (and editing?). Bioorg Chem, 33(3), 229-251. doi: 10.1016/j.bioorg.2005.01.001
Garon, E. B., Finn, R. S., Hosmer, W., Dering, J., Ginther, C., Adhami, S., . . . Slamon, D. J. (2010). Identification of common predictive markers of in vitro response to the Mek inhibitor selumetinib (AZD6244; ARRY-142886) in human breast cancer and non-small cell lung cancer cell lines. Mol Cancer Ther, 9(7), 1985-1994. doi: 10.1158/1535-7163.MCT-10-0037
Gautschi, O., Huegli, B., Ziegler, A., Gugger, M., Heighway, J., Ratschiller, D., . . . Betticher, D. C. (2007). Origin and prognostic value of circulating KRAS mutations in lung cancer patients. Cancer Lett, 254(2), 265-273. doi: 10.1016/j.canlet.2007.03.008
Giotakis, A. I., Kontos, C. K., Manolopoulos, L. D., Sismanis, A., Konstadoulakis, M. M., & Scorilas, A. (2016). High BAX/BCL2 mRNA ratio predicts favorable prognosis in laryngeal squamous cell carcinoma, particularly in patients with negative lymph nodes at the time of diagnosis. Clin Biochem, 49(12), 890-896. doi: 10.1016/j.clinbiochem.2016.04.010
Giovinazzi, S., Morozov, V. M., Summers, M. K., Reinhold, W. C., & Ishov, A. M. (2013). USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase. Cell Death Differ, 20(5), 721-731. doi: 10.1038/cdd.2012.169
Gottesman, M. M. (2002). Mechanisms of cancer drug resistance. Annu Rev Med, 53, 615-627. doi: 10.1146/annurev.med.53.082901.103929
Gottlieb, T. M., & Jackson, S. P. (1993). The DNA-dependent protein kinase: requirement for DNA ends and association with Ku antigen. Cell, 72(1), 131-142.
Greene, W. C., & Chen, L. F. (2004). Regulation of NF-kappaB action by reversible acetylation. Novartis Found Symp, 259, 208-217; discussion 218-225.
Harb, G., Vasavada, R. C., Cobrinik, D., & Stewart, A. F. (2009). The retinoblastoma protein and its homolog p130 regulate the G1/S transition in pancreatic beta-cells. Diabetes, 58(8), 1852-1862. doi: 10.2337/db08-0759
He, Y., Jin, Y. J., Zhang, Y. H., Meng, H. X., Zhao, B. S., Jiang, Y., . . . Jin, X. M. (2015). Ubiquitin-specific peptidase 22 overexpression may promote cancer progression and poor prognosis in human gastric carcinoma. Transl Res, 165(3), 407-416. doi: 10.1016/j.trsl.2014.09.005
Helleday, T. (2010). Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis, 31(6), 955-960. doi: 10.1093/carcin/bgq064
Hershko, D. D., Robb, B. W., Luo, G., & Hasselgren, P. O. (2002). Multiple transcription factors regulating the IL-6 gene are activated by cAMP in cultured Caco-2 cells. Am J Physiol Regul Integr Comp Physiol, 283(5), R1140-1148. doi: 10.1152/ajpregu.00161.2002
Hu, W., Li, X., Zhang, C., Yang, Y., Jiang, J., & Wu, C. (2016). Tumor-associated macrophages in cancers. Clin Transl Oncol, 18(3), 251-258. doi: 10.1007/s12094-015-1373-0
Hunter, J. C., Gurbani, D., Ficarro, S. B., Carrasco, M. A., Lim, S. M., Choi, H. G., . . . Westover, K. D. (2014). In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. Proc Natl Acad Sci U S A, 111(24), 8895-8900. doi: 10.1073/pnas.1404639111
International Early Lung Cancer Action Program, I., Henschke, C. I., Yankelevitz, D. F., Libby, D. M., Pasmantier, M. W., Smith, J. P., & Miettinen, O. S. (2006). Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med, 355(17), 1763-1771. doi: 10.1056/NEJMoa060476
Ishida, K., Kobayashi, T., Ito, S., Komatsu, Y., Yokoyama, T., Okada, M., . . . Yoshie, H. (2012). Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. J Periodontol, 83(7), 917-925. doi: 10.1902/jop.2011.110356
Jia, L., Yan, F., Cao, W., Chen, Z., Zheng, H., Li, H., . . . Zhou, P. (2017). Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer. J Biol Chem, 292(7), 2966-2978. doi: 10.1074/jbc.M116.765230
Johnson, B. N., Berger, A. K., Cortese, G. P., & Lavoie, M. J. (2012). The ubiquitin E3 ligase parkin regulates the proapoptotic function of Bax. Proc Natl Acad Sci U S A, 109(16), 6283-6288. doi: 10.1073/pnas.1113248109
Jorge, S. E., Kobayashi, S. S., & Costa, D. B. (2014). Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data. Braz J Med Biol Res, 47(11), 929-939.
Kiesslich, T., Pichler, M., & Neureiter, D. (2013). Epigenetic control of epithelial-mesenchymal-transition in human cancer. Mol Clin Oncol, 1(1), 3-11. doi: 10.3892/mco.2012.28
Klein, H. L. (2008). The consequences of Rad51 overexpression for normal and tumor cells. DNA Repair (Amst), 7(5), 686-693. doi: 10.1016/j.dnarep.2007.12.008
Klemm, F., & Joyce, J. A. (2015). Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol, 25(4), 198-213. doi: 10.1016/j.tcb.2014.11.006
Krumm, A., Barckhausen, C., Kucuk, P., Tomaszowski, K. H., Loquai, C., Fahrer, J., . . . Roos, W. P. (2016). Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance. Cancer Res, 76(10), 3067-3077. doi: 10.1158/0008-5472.CAN-15-2680
Lane, D. P., & Hall, P. A. (1997). MDM2--arbiter of p53's destruction. Trends Biochem Sci, 22(10), 372-374.
Lee, B. K., Bhinge, A. A., & Iyer, V. R. (2011). Wide-ranging functions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis. Nucleic Acids Res, 39(9), 3558-3573. doi: 10.1093/nar/gkq1313
Lee, J. G., & Kay, E. P. (2008). Involvement of two distinct ubiquitin E3 ligase systems for p27 degradation in corneal endothelial cells. Invest Ophthalmol Vis Sci, 49(1), 189-196. doi: 10.1167/iovs.07-0855
Legrand-Poels, S., Schoonbroodt, S., & Piette, J. (2000). Regulation of interleukin-6 gene expression by pro-inflammatory cytokines in a colon cancer cell line. Biochem J, 349 Pt 3, 765-773.
Li, L. C., Zhao, H., Nakajima, K., Oh, B. R., Ribeiro Filho, L. A., Carroll, P., & Dahiya, R. (2001). Methylation of the E-cadherin gene promoter correlates with progression of prostate cancer. J Urol, 166(2), 705-709.
Li, S., Wang, L., Zhao, Q., Liu, Y., He, L., Xu, Q., . . . Ke, Y. (2014). SHP2 positively regulates TGFbeta1-induced epithelial-mesenchymal transition modulated by its novel interacting protein Hook1. J Biol Chem, 289(49), 34152-34160. doi: 10.1074/jbc.M113.546077
Li, X., & Heyer, W. D. (2009). RAD54 controls access to the invading 3'-OH end after RAD51-mediated DNA strand invasion in homologous recombination in Saccharomyces cerevisiae. Nucleic Acids Res, 37(2), 638-646. doi: 10.1093/nar/gkn980
Li, Y., Schrodi, S., Rowland, C., Tacey, K., Catanese, J., & Grupe, A. (2006). Genetic evidence for ubiquitin-specific proteases USP24 and USP40 as candidate genes for late-onset Parkinson disease. Hum Mutat, 27(10), 1017-1023. doi: 10.1002/humu.20382
Lin, R. K., & Wang, Y. C. (2014). Dysregulated transcriptional and post-translational control of DNA methyltransferases in cancer. Cell Biosci, 4, 46. doi: 10.1186/2045-3701-4-46
Lin, Z., Yang, H., Tan, C., Li, J., Liu, Z., Quan, Q., . . . Fang, D. (2013). USP10 antagonizes c-Myc transcriptional activation through SIRT6 stabilization to suppress tumor formation. Cell Rep, 5(6), 1639-1649. doi: 10.1016/j.celrep.2013.11.029
Litovchick, L., Sadasivam, S., Florens, L., Zhu, X., Swanson, S. K., Velmurugan, S., . . . DeCaprio, J. A. (2007). Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell, 26(4), 539-551. doi: 10.1016/j.molcel.2007.04.015
Mauer, J., Chaurasia, B., Goldau, J., Vogt, M. C., Ruud, J., Nguyen, K. D., . . . Bruning, J. C. (2014). Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol, 15(5), 423-430. doi: 10.1038/ni.2865
McFarlane, C., Kelvin, A. A., de la Vega, M., Govender, U., Scott, C. J., Burrows, J. F., & Johnston, J. A. (2010). The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1-S progression. Cancer Res, 70(8), 3329-3339. doi: 10.1158/0008-5472.CAN-09-4152
Mehlen, P., & Puisieux, A. (2006). Metastasis: a question of life or death. Nat Rev Cancer, 6(6), 449-458. doi: 10.1038/nrc1886
Mileo, A. M., Mattarocci, S., Matarrese, P., Anticoli, S., Abbruzzese, C., Catone, S., . . . Ruggieri, A. (2015). Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation. J Exp Clin Cancer Res, 34, 140. doi: 10.1186/s13046-015-0255-1
Morrow, J. K., Lin, H. K., Sun, S. C., & Zhang, S. (2015). Targeting ubiquitination for cancer therapies. Future Med Chem, 7(17), 2333-2350. doi: 10.4155/fmc.15.148
Mungamuri, S. K., Qiao, R. F., Yao, S., Manfredi, J. J., Gu, W., & Aaronson, S. A. (2016). USP7 Enforces Heterochromatinization of p53 Target Promoters by Protecting SUV39H1 from MDM2-Mediated Degradation. Cell Rep, 14(11), 2528-2537. doi: 10.1016/j.celrep.2016.02.049
Ndlovu, M. N., Van Lint, C., Van Wesemael, K., Callebert, P., Chalbos, D., Haegeman, G., & Vanden Berghe, W. (2009). Hyperactivated NF-{kappa}B and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells. Mol Cell Biol, 29(20), 5488-5504. doi: 10.1128/MCB.01657-08
Nile, C. J., Read, R. C., Akil, M., Duff, G. W., & Wilson, A. G. (2008). Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum, 58(9), 2686-2693. doi: 10.1002/art.23758
Nishikura, K. (2010). Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem, 79, 321-349. doi: 10.1146/annurev-biochem-060208-105251
Peterson, L. F., Sun, H., Liu, Y., Potu, H., Kandarpa, M., Ermann, M., . . . Donato, N. J. (2015). Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies. Blood, 125(23), 3588-3597. doi: 10.1182/blood-2014-10-605584
Pfleger, C. M., Lee, E., & Kirschner, M. W. (2001). Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex. Genes Dev, 15(18), 2396-2407. doi: 10.1101/gad.918201
Popov, B., Chang, L. S., & Serikov, V. (2005). Cell cycle-related transformation of the E2F4-p130 repressor complex. Biochem Biophys Res Commun, 336(3), 762-769. doi: 10.1016/j.bbrc.2005.08.163
Quail, D. F., & Joyce, J. A. (2013). Microenvironmental regulation of tumor progression and metastasis. Nat Med, 19(11), 1423-1437. doi: 10.1038/nm.3394
Richer, E., Prendergast, C., Zhang, D. E., Qureshi, S. T., Vidal, S. M., & Malo, D. (2010). N-ethyl-N-nitrosourea-induced mutation in ubiquitin-specific peptidase 18 causes hyperactivation of IFN-alphass signaling and suppresses STAT4-induced IFN-gamma production, resulting in increased susceptibility to Salmonella typhimurium. J Immunol, 185(6), 3593-3601. doi: 10.4049/jimmunol.1000890
Robbins, J. A., & Cross, F. R. (2010). Regulated degradation of the APC coactivator Cdc20. Cell Div, 5, 23. doi: 10.1186/1747-1028-5-23
Roszer, T. (2015). Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators Inflamm, 2015, 816460. doi: 10.1155/2015/816460
Salah, Z., Melino, G., & Aqeilan, R. I. (2011). Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity. Cancer Res, 71(5), 2010-2020. doi: 10.1158/0008-5472.CAN-10-3516
Sasaki, H., Okuda, K., Kawano, O., Endo, K., Yukiue, H., Yokoyama, T., . . . Fujii, Y. (2007). Nras and Kras mutation in Japanese lung cancer patients: Genotyping analysis using LightCycler. Oncol Rep, 18(3), 623-628.
Schafer, Z. T., & Brugge, J. S. (2007). IL-6 involvement in epithelial cancers. J Clin Invest, 117(12), 3660-3663. doi: 10.1172/JCI34237
Scime, A., Li, L., Ciavarra, G., & Whyte, P. (2008). Cyclin D1/cdk4 can interact with E2F4/DP1 and disrupts its DNA-binding capacity. J Cell Physiol, 214(3), 568-581. doi: 10.1002/jcp.21243
Sebti, S. M., & Der, C. J. (2003). Opinion: Searching for the elusive targets of farnesyltransferase inhibitors. Nat Rev Cancer, 3(12), 945-951. doi: 10.1038/nrc1234
Sengupta, S., & Henry, R. W. (2015). Regulation of the retinoblastoma-E2F pathway by the ubiquitin-proteasome system. Biochim Biophys Acta, 1849(10), 1289-1297. doi: 10.1016/j.bbagrm.2015.08.008
Sher, T., Dy, G. K., & Adjei, A. A. (2008). Small cell lung cancer. Mayo Clin Proc, 83(3), 355-367. doi: 10.4065/83.3.355
Shigematsu, H., & Gazdar, A. F. (2006). Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer, 118(2), 257-262. doi: 10.1002/ijc.21496
Sidler, C., Woycicki, R., Li, D., Wang, B., Kovalchuk, I., & Kovalchuk, O. (2014). A role for SUV39H1-mediated H3K9 trimethylation in the control of genome stability and senescence in WI38 human diploid lung fibroblasts. Aging (Albany NY), 6(7), 545-563. doi: 10.18632/aging.100678
Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA Cancer J Clin, 66(1), 7-30. doi: 10.3322/caac.21332
Song, L., & Rape, M. (2011). Substrate-specific regulation of ubiquitination by the anaphase-promoting complex. Cell Cycle, 10(1), 52-56. doi: 10.4161/cc.10.1.14387
Takenaka, M., Zehrmann, A., Verbitskiy, D., Hartel, B., & Brennicke, A. (2013). RNA editing in plants and its evolution. Annu Rev Genet, 47, 335-352. doi: 10.1146/annurev-genet-111212-133519
Tang, C. H., Lu, D. Y., Yang, R. S., Tsai, H. Y., Kao, M. C., Fu, W. M., & Chen, Y. F. (2007). Leptin-induced IL-6 production is mediated by leptin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, NF-kappaB, and p300 pathway in microglia. J Immunol, 179(2), 1292-1302.
Tarangelo, A., Lo, N., Teng, R., Kim, E., Le, L., Watson, D., . . . Viatour, P. (2015). Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression. Nat Commun, 6, 10028. doi: 10.1038/ncomms10028
UK., C. R. (2016). Routes to diagnosis of cancer by stage, 2012-2013 workbook.
Vanden Berghe, W., De Bosscher, K., Boone, E., Plaisance, S., & Haegeman, G. (1999). The nuclear factor-kappaB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J Biol Chem, 274(45), 32091-32098.
Villegas, J., Muller, I., Arredondo, J., Pinto, R., & Burzio, L. O. (2002). A putative RNA editing from U to C in a mouse mitochondrial transcript. Nucleic Acids Res, 30(9), 1895-1901.
Vispe, S., Cazaux, C., Lesca, C., & Defais, M. (1998). Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. Nucleic Acids Res, 26(12), 2859-2864.
Wan, J. Y., Edwards, K. L., Hutter, C. M., Mata, I. F., Samii, A., Roberts, J. W., . . . Zabetian, C. P. (2014). Association mapping of the PARK10 region for Parkinson's disease susceptibility genes. Parkinsonism Relat Disord, 20(1), 93-98. doi: 10.1016/j.parkreldis.2013.10.001
Wang, B. Y., Huang, J. Y., Cheng, C. Y., Lin, C. H., Ko, J., & Liaw, Y. P. (2013). Lung cancer and prognosis in taiwan: a population-based cancer registry. J Thorac Oncol, 8(9), 1128-1135. doi: 10.1097/JTO.0b013e31829ceba4
Wang, C., An, J., Zhang, P., Xu, C., Gao, K., Wu, D., . . . Yu, L. (2012). The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation. Biochem J, 444(2), 279-289. doi: 10.1042/BJ20111983
Wang, D., Zhou, J., Liu, X., Lu, D., Shen, C., Du, Y., . . . Zhu, W. G. (2013). Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability. Proc Natl Acad Sci U S A, 110(14), 5516-5521. doi: 10.1073/pnas.1216596110
Wang, K., Liu, S., Wang, J., Wu, Y., Cai, F., & Song, W. (2014). Transcriptional regulation of human USP24 gene expression by NF-kappa B. J Neurochem, 128(6), 818-828. doi: 10.1111/jnc.12626
Wang, S. A., Li, H. Y., Hsu, T. I., Chen, S. H., Wu, C. J., Chang, W. C., & Hung, J. J. (2011). Heat shock protein 90 stabilizes nucleolin to increase mRNA stability in mitosis. J Biol Chem, 286(51), 43816-43829. doi: 10.1074/jbc.M111.310979
Wang, Y., & Shang, Y. (2013). Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res, 319(2), 160-169. doi: 10.1016/j.yexcr.2012.07.019
Whiteside, T. L. (2008). The tumor microenvironment and its role in promoting tumor growth. Oncogene, 27(45), 5904-5912. doi: 10.1038/onc.2008.271
Wirt, S. E., & Sage, J. (2010). p107 in the public eye: an Rb understudy and more. Cell Div, 5, 9. doi: 10.1186/1747-1028-5-9
Wongchana, W., & Palaga, T. (2012). Direct regulation of interleukin-6 expression by Notch signaling in macrophages. Cell Mol Immunol, 9(2), 155-162. doi: 10.1038/cmi.2011.36
Wu, Y. R., Chen, C. M., Chen, Y. C., Chao, C. Y., Ro, L. S., Fung, H. C., . . . Lee-Chen, G. J. (2010). Ubiquitin specific proteases USP24 and USP40 and ubiquitin thiolesterase UCHL1 polymorphisms have synergic effect on the risk of Parkinson's disease among Taiwanese. Clin Chim Acta, 411(13-14), 955-958. doi: 10.1016/j.cca.2010.03.013
Xiao, W., Hodge, D. R., Wang, L., Yang, X., Zhang, X., & Farrar, W. L. (2004). NF-kappaB activates IL-6 expression through cooperation with c-Jun and IL6-AP1 site, but is independent of its IL6-NFkappaB regulatory site in autocrine human multiple myeloma cells. Cancer Biol Ther, 3(10), 1007-1017.
Yanagisawa, T., Kiribuchi-Otobe, C., Hirano, H., Suzuki, Y., & Fujita, M. (2003). Detection of single nucleotide polymorphism (SNP) controlling the waxy character in wheat by using a derived cleaved amplified polymorphic sequence (dCAPS) marker. Theor Appl Genet, 107(1), 84-88. doi: 10.1007/s00122-003-1235-y
Yuan, Y., Li, X. F., Chen, J. Q., Dong, C. X., Weng, S. S., & Huang, J. J. (2014). Critical appraisal of the role of gefitinib in the management of locally advanced or metastatic non-small cell lung cancer. Onco Targets Ther, 7, 841-852. doi: 10.2147/OTT.S34124
Yuan, Z., Zeng, X., Yang, D., Wang, W., & Liu, Z. (2013). Effects of common polymorphism rs11614913 in Hsa-miR-196a2 on lung cancer risk. PLoS One, 8(4), e61047. doi: 10.1371/journal.pone.0061047
Zhang, L., Lubin, A., Chen, H., Sun, Z., & Gong, F. (2012). The deubiquitinating protein USP24 interacts with DDB2 and regulates DDB2 stability. Cell Cycle, 11(23), 4378-4384. doi: 10.4161/cc.22688
Zhang, L., Nemzow, L., Chen, H., Lubin, A., Rong, X., Sun, Z., . . . Gong, F. (2015). The deubiquitinating enzyme USP24 is a regulator of the UV damage response. Cell Rep, 10(2), 140-147. doi: 10.1016/j.celrep.2014.12.024
Zhao, B., Song, W., Chen, Y. P., Huang, R., Chen, K., Cao, B., . . . Shang, H. F. (2012). Association analysis of single-nucleotide polymorphisms of USP24 and USP40 with Parkinson's disease in the Han Chinese population. Eur Neurol, 68(3), 181-184. doi: 10.1159/000339641
Zhao, Z., Cheng, X., Wang, Y., Han, R., Li, L., Xiang, T., . . . He, Y. (2014). Metformin inhibits the IL-6-induced epithelial-mesenchymal transition and lung adenocarcinoma growth and metastasis. PLoS One, 9(4), e95884. doi: 10.1371/journal.pone.0095884
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2022-01-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2022-01-01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