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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 俞松良(Sung-Liang Yu) | |
| dc.contributor.author | Hsiao-Chun Wang | en |
| dc.contributor.author | 王筱珺 | zh_TW |
| dc.date.accessioned | 2021-06-16T06:48:46Z | - |
| dc.date.available | 2024-08-01 | |
| dc.date.copyright | 2014-10-09 | |
| dc.date.issued | 2014 | |
| dc.date.submitted | 2014-07-24 | |
| dc.identifier.citation | 1. Siegel, R., et al., Cancer statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29.
2. Roy S. Herbst, M.D., Ph.D., John V. Heymach, M.D., Ph.D., and Scott M. Lippman, M.D., Lung Cancer.pdf. N Engl J Med 2008. 3. Kenfield, S.A., et al., Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control, 2008. 17(3): p. 198-204. 4. Hynes, N.E. and H.A. Lane, ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer, 2005. 5(5): p. 341-54. 5. Gazdar, A.F., Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev, 2010. 29(1): p. 37-48. 6. Nurwidya, F., et al., Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Respiratory Investigation, 2014. 52(2): p. 82-91. 7. Zhang, Z., et al., Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis, 2010. 31(4): p. 577-86. 8. Kobayashi, S., et al., Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling. Cancer Res, 2006. 66(23): p. 11389-98. 9. Moncho-Amor, V., et al., DUSP1/MKP1 promotes angiogenesis, invasion and metastasis in non-small-cell lung cancer. Oncogene, 2011. 30(6): p. 668-78. 10. Wang, Q., et al., Retaining MKP1 expression and attenuating JNK-mediated apoptosis by RIP1 for cisplatin resistance through miR-940 inhibition. Oncotarget, 2014. 5(5): p. 1304-14. 11. Suda, K., et al., Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny. Cancer Metastasis Rev, 2012. 31(3-4): p. 807-14. 12. Tabara, K., et al., Loss of activating EGFR mutant gene contributes to acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer cells. PLoS One, 2012. 7(7): p. e41017. 13. Tebbutt, N., M.W. Pedersen, and T.G. Johns, Targeting the ERBB family in cancer: couples therapy. Nat Rev Cancer, 2013. 13(9): p. 663-73. 14. Kobayashi, S., et al., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 2005. 352(8): p. 786-92. 15. Ohashi, K., et al., Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol, 2013. 31(8): p. 1070-80. 16. Silva, J.M., et al., Second-generation shRNA libraries covering the mouse and human genomes. Nat Genet, 2005. 37(11): p. 1281-8. 17. Silva, J.M., et al., Profiling essential genes in human mammary cells by multiplex RNAi screening. Science, 2008. 319(5863): p. 617-20. 18. Schlabach, M.R., et al., Cancer proliferation gene discovery through functional genomics. Science, 2008. 319(5863): p. 620-4. 19. Imai, H., et al., High throughput RNAi screening identifies ID1 as a synthetic sick/lethal gene interacting with the common TP53 mutation R175H. Oncol Rep, 2014. 31(3): p. 1043-50. 20. Tank, J., et al., Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts. J Mol Cell Cardiol, 2014. 66: p. 141-56. 21. Li, G.M., et al., RNAi screening with shRNAs against histone methylation-related genes reveals determinants of sorafenib sensitivity in hepatocellular carcinoma cells. Int J Clin Exp Pathol, 2014. 7(3): p. 1085-92. 22. Andersen, J.N., et al., A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J, 2004. 18(1): p. 8-30. 23. Jeffrey, K.L., et al., Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov, 2007. 6(5): p. 391-403.x 24. Alonso, A., et al., Protein tyrosine phosphatases in the human genome. Cell, 2004. 117(6): p. 699-711. 25. Keyse, S.M., Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev, 2008. 27(2): p. 253-61. 26. Patterson, K.I., et al., Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J, 2009. 418(3): p. 475-89. 27. Farooq, A. and M.M. Zhou, Structure and regulation of MAPK phosphatases. Cell Signal, 2004. 16(7): p. 769-79. 28. Huang, C.Y. and T.H. Tan, DUSPs, to MAP kinases and beyond. Cell Biosci, 2012. 2(1): p. 24. 29. Jeffrey, K.L., et al., Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol, 2006. 7(3): p. 274-83. 30. Li, M., et al., The Phosphatase MKP1 Is a Transcriptional Target of p53 Involved in Cell Cycle Regulation. Journal of Biological Chemistry, 2003. 278(42): p. 41059-41068. 31. Shen, W.H., et al., Mitogen-activated protein kinase phosphatase 2: a novel transcription target of p53 in apoptosis. Cancer Res, 2006. 66(12): p. 6033-9. 32. Ueda, K., H. Arakawa, and Y. Nakamura, Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target of tumor suppressor p53. Oncogene, 2003. 22(36): p. 5586-91. 33. Reth, M. and T. Brummer, Feedback regulation of lymphocyte signalling. Nat Rev Immunol, 2004. 4(4): p. 269-77. 34. Cheung, P.C., et al., Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha. EMBO J, 2003. 22(21): p. 5793-805. 35. Brondello, J.M., J. Pouyssegur, and F.R. McKenzie, Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science, 1999. 286(5449): p. 2514-7. 36. Masuda, K., et al., MKP-7, a novel mitogen-activated protein kinase phosphatase, functions as a shuttle protein. J Biol Chem, 2001. 276(42): p. 39002-11. 37. Karlsson, M., et al., Both Nuclear-Cytoplasmic Shuttling of the Dual Specificity Phosphatase MKP-3 and Its Ability to Anchor MAP Kinase in the Cytoplasm Are Mediated by a Conserved Nuclear Export Signal. Journal of Biological Chemistry, 2004. 279(40): p. 41882-41891. 38. Park, J., et al., Positive regulation of apoptosis signal-regulating kinase 1 by dual-specificity phosphatase 13A. Cellular and Molecular Life Sciences, 2010. 67(15): p. 2619-2629. 39. Nakamura, K., et al., Molecular cloning and characterization of a novel dual-specificity protein phosphatase possibly involved in spermatogenesis. Biochem J, 1999. 344 Pt 3: p. 819-25. 40. Katagiri, C., et al., DUSP13B/TMDP inhibits stress-activated MAPKs and suppresses AP-1-dependent gene expression. Molecular and Cellular Biochemistry, 2011. 352(1): p. 155-162. 41. Arnau, J., et al., Current strategies for the use of affinity tags and tag removal for the purification of recombinant proteins. Protein Expr Purif, 2006. 48(1): p. 1-13. 42. Terpe, K., Overview of tag protein fusions: from molecular and biochemical fundamentals to commercial systems. Appl Microbiol Biotechnol, 2003. 60(5): p. 523-33. 43. Lichty, J.J., et al., Comparison of affinity tags for protein purification. Protein Expr Purif, 2005. 41(1): p. 98-105. 44. Derewenda, Z.S., The use of recombinant methods and molecular engineering in protein crystallization. Methods, 2004. 34(3): p. 354-363. 45. Hochuli, E., H. Dobeli, and A. Schacher, New metal chelate adsorbent selective for proteins and peptides containing neighbouring histidine residues. Journal of Chromatography A, 1987. 411(0): p. 177-184. 46. Hefti, M.H., et al., A Novel Purification Method for Histidine-Tagged Proteins Containing a Thrombin Cleavage Site. Analytical Biochemistry, 2001. 295(2): p. 180-185. 47. Block, H., et al., Chapter 27 Immobilized-Metal Affinity Chromatography (IMAC): A Review, in Methods in Enzymology, R.B. Richard and P.D. Murray, Editors. 2009, Academic Press. p. 439-473. 48. Ayyar, B.V., et al., Affinity chromatography as a tool for antibody purification. Methods, 2012. 56(2): p. 116-129. 49. Janknecht, R., et al., Rapid and efficient purification of native histidine-tagged protein expressed by recombinant vaccinia virus. Proc Natl Acad Sci U S A, 1991. 88(20): p. 8972-6. 50. Chen, B.P.C. and T. Hai, Expression vectors for affinity purification and radiolabeling of proteins using Escherichia coli as host. Gene, 1994. 139(1): p. 73-75. 51. Rank, K.B., et al., [W206R]-Procaspase 3: An Inactivatable Substrate for Caspase 8. Protein Expression and Purification, 2001. 22(2): p. 258-266. 52. Lazo, J.S., et al., Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. J Med Chem, 2001. 44(24): p. 4042-9. 53. Denu, J.M., et al., Form and function in protein dephosphorylation. Cell, 1996. 87(3): p. 361-4. 54. Brisson, M., et al., Redox Regulation of Cdc25B by Cell-Active Quinolinediones. Molecular Pharmacology, 2005. 68(6): p. 1810-1820. 55. Lee, I.-S., A. Ju, and S. Cho, Inhibition of DUSP13B Activity by NSC 663284. 2012. 33: p. 3505-3507. 56. Chang, T.-H., et al., Slug Confers Resistance to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. American Journal of Respiratory and Critical Care Medicine, 2011. 183(8): p. 1071-1079. 57. Lee, J.Y., et al., Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: the versatile adjuvant for gefitinib therapy. PLoS One, 2011. 6(8): p. e23756. 58. Li, M., et al., The phosphatase MKP1 is a transcriptional target of p53 involved in cell cycle regulation. J Biol Chem, 2003. 278(42): p. 41059-68. 59. Keyse, S.M. and E.A. Emslie, Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature, 1992. 359(6396): p. 644-7. 60. Haagenson, K.K., et al., Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity. Oncotarget, 2014. 5(4): p. 1101-10. 61. Small, G.W., et al., Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance. Cancer Res, 2007. 67(9): p. 4459-66. 62. Sanchez-Perez, I., et al., CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin. Oncogene, 2000. 19(45): p. 5142-52. 63. Wang, Z., et al., Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance. Cancer Res, 2006. 66(17): p. 8870-7. 64. Wang, J., J.Y. Zhou, and G.S. Wu, ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells. Cancer Res, 2007. 67(24): p. 11933-41. 65. Balko, J.M., et al., Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat Med, 2012. 18(7): p. 1052-9. 66. Huang, M.H., et al., MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib. Mol Oncol, 2013. 7(1): p. 112-20. 67. Pu, L., et al., Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 6-chloro-7-[corrected](2-morpholin-4-ylethylamino)-quinoline-5,8-dione. J Biol Chem, 2002. 277(49): p. 46877-85. 68. Akgul, C., D.A. Moulding, and S.W. Edwards, Alternative splicing of Bcl-2-related genes: functional consequences and potential therapeutic applications. Cell Mol Life Sci, 2004. 61(17): p. 2189-99. 69. Eberle, J. and A.M. Hossini, Expression and function of bcl-2 proteins in melanoma. Curr Genomics, 2008. 9(6): p. 409-19. 70. Savkur, R.S., A.V. Philips, and T.A. Cooper, Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet, 2001. 29(1): p. 40-7. 71. Kosaki, A. and N.J. Webster, Effect of dexamethasone on the alternative splicing of the insulin receptor mRNA and insulin action in HepG2 hepatoma cells. J Biol Chem, 1993. 268(29): p. 21990-6. 72. Kosaki, A., et al., The B isoform of the insulin receptor signals more efficiently than the A isoform in HepG2 cells. J Biol Chem, 1995. 270(35): p. 20816-23. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57499 | - |
| dc.description.abstract | 針對具有表皮生長因子受體(epidermal growth factor receptor, EGFR)突變的非小細胞肺癌中，目前最常使用的抗癌藥物為表皮生長因子受體酪胺酸激酶抑制劑-吉非替尼 (Gefitinib)，儘管此抑制劑具有顯著的治療效果，約30~40%病人在長期服用藥物的情況下，逐漸產生內生性抗藥性導致癌症的復發，目前在吉非替尼藥物引發的抗藥機制尚不完全清楚。
在實驗室先前的研究中，我們利用包含16,000條小髮夾核醣核酸(short hairpin RNA, shRNA)之干擾核醣核酸庫，針對激酶、磷酸酶、轉錄因子與去泛素酵素等多達3,000個基因挑出一個可能參與此獲得性吉非替尼抗藥性機制的候選基因 dual-specificity phosphatase 13 (DUSP13)，此基因會轉譯出兩個不同功能性的蛋白質：DUSP13A與DUSP13B。先前報導指出DUSP13A為新穎的apoptosis signal-regulating kinase 1 (ASK1)調控者；DUSP13B具有去磷酸酶之活性並且抑制下游mitogen-activated protein kinase (MAPK )訊息傳遞路徑的活化。目前為止，此二種蛋白質皆未被報導與肺癌抗藥性有關聯性。 為了了解DUSP13在獲得性吉非替尼抗藥性扮演的角色，專一性偵測DUSP13A與DUAP13B蛋白質表現為必須的步驟。由於目前市面上沒有合適的DUSP13A與DUSP13B之專一性抗體，我們透過免疫紐西蘭大白兔建立DUSP13A與DUSP13B之專ㄧ性抗體，希望能藉此更加了解何種DUSP13在抗藥性機制中扮演主要調控的角色。另一方面，我們利用活體外細胞聚落形成實驗 (in vitro colony forming assay) 觀察到給予吉非替尼作用時，剔除DUSP13基因的抗藥性細胞株形成聚落之能力明顯下降。接著分別利用西方墨點法與流式細胞儀觀察細胞凋亡標記poly ADP-ribose polymerase (PARP)、caspase3 與subG1 phase在給予吉非替尼作用的環境中表現量明顯上升。實驗室先前的研究發現當活體外剔除DUSP13基因的細胞株能夠明顯地回復對藥物之敏感性。另外，在活體動物皮下腫瘤接種實驗(in vivo mouse subcutaneous injection assay)中也觀察到剔除DUSP13基因之腫瘤在給予低濃度吉非替尼(10 mg/kg/day)治療後，其腫瘤生長明顯地受到抑制。 根據文獻指出，NRAS基因的突變可能促進ERK基因之表現，使抗藥性PC9/gef細胞株產生獲得性吉非替尼抗藥性。另一篇研究指出DUSP13B 蛋白質抑制MAPK 的活化。我們推測DUSP13B蛋白質可能參與調控MAPK路徑，藉此在獲得性吉非替尼抗藥性的PC9細胞中扮演一個重要的角色。 | zh_TW |
| dc.description.abstract | Gefitinib is an EGFR-tyrosine kinase inhibitor that has excellent antitumor activity in the advanced non-small-cell lung cancer (NSCLC) with EGFR-activating mutations. Despite the dramatic response to such inhibitors, 30-40% of patients seem to have intrinsic resistance and ultimately get a rapid relapse. However, the underlying mechanisms of such resistance to gefitinib are not completely understood.
In our previous study, we used a pooled-based RNAi library screening which contains 16,000 shRNAs targeting all of known human kinases, phosphatases, and deubiquitinase to discover new candidates that confer acquired resistance to gefitinib. We identified a novel gene, dual-specificity phosphatase 13 (DUSP13), may be involved in the mechanism of acquired-gefitinib resistance. DUSP13 encodes two different functional proteins: DUSP13A and DUSP13B. Previous studies showed that DUSP13A functions as a novel regulator of apoptosis signal-regulating kinase 1 (ASK1) and DUSP13B has phosphatase activity that inactivates mitogen-activated protein kinase (MAPK) activation, but both of them have not been reported to involve in drug resistance of lung cancer. To investigate the role of DUSP13 in acquired-gefitinib resistance, detecting the protein expression of DUSP13A and DUSP13B specifically is necessary. Due to there is neither commercially available anti-DUSP13A nor anti-DUSP13B antibody, we generated two specific antibodies that specifically react DUSP13A and DUSP13B proteins by New Zealand white rabbit immunization, and try to elucidate which protein plays the important role conferring acquired resistance to gefitinib. On the other hand, the in vitro colony formation assay showed that knockdown of DUSP13 inhibited colony forming ability in gefitinib treated gefitinib-resistance cells PC9. Two increased apoptosis markers, cleaved poly ADP-ribose polymerase (PARP) and cleaved caspase 3, assayed by Western blot and increase of subG1 phase assayed by flow cytometry are observed in the DUSP13 silenced gefitinib-resistance cells in presence of gefitinib. The previous study in our laboratory found that knockdown of DUSP13 not only restored gefitinib sensitivity in vitro but also decreased in vivo tumor growth in low dose gefitinib (10 mg/kg/day) in the xenograft mouse model. Previous study indicated that the mechanism of acquired resistance to gefitinib in PC9/gef cells may be due to activating ERK pathway induced by NRAS mutation. Another study reported that DUSP13B inactivates MAPK activation. We suppose that DUSP13B may play an important role in MAPK pathway activation in the acquired gefitinib-resistance PC9 cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T06:48:46Z (GMT). No. of bitstreams: 1 ntu-103-R01424020-1.pdf: 2734367 bytes, checksum: 88faee789904f82906465e1e0ccd2433 (MD5) Previous issue date: 2014 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
致謝 II 中文摘要 III Abstract V 1. Introduction 1 1.1 Lung adenocarcinoma 2 1.2 The mechanism of gefitinib resistance. 3 1.3 RNAi library screening 4 1.4 Protein tyrosine phosphatases (PTPs) family 5 1.5 Dual-specificity phosphatases 13 (DUSP13) 7 1.6 Preparation of target proteins for rabbit immunization 8 1.7 NSC663284, an inhibitor of dual-specificity phosphatase 13B 9 1.8 The previous investigation in laboratory 10 1.9 Specific aim 11 2. Materials and Methods 12 2.1 Cell lines and cell culture 13 2.2 High content RNAi screening in PC9 and PC9/gef cells. 13 2.3 Lentivirus production and transduction 14 2.4 Cell viability assay 14 2.5 Drug treatment 15 2.6 Cell cycle analysis 15 2.7 Dependent and independent colony formation 16 2.8 Plasmid construction 16 2.9 Quantitative real-time PCR 17 2.10 Competent cell preparation 18 2.11 IPTG induction 18 2.12 Protein purification 19 2.13 Coomassie Blue stain 19 2.14 Protein dialysis 20 2.15 Rabbit immunization 20 2.16 Specific antibody purification 21 2.17 Immunoblot 21 3. Results 23 3.1 DUSP13A/DUSP13B protein induction and recombinant protein purification. 24 3.2 Unpurified DUSP13B serum successfully recognizes the overexpressed DUSP13B protein in Escherichia coli cells. 26 3.3 Unpurified DUSP13A and DUSP13B serum successfully recognize the overexpressed DUSP13 in human cell lines. 28 3.4 Comparison of DUSP13A and DUSP13B mRNA expressions. 30 3.5 Knockdown of DUSP13 in PC9/gef-shLacZ cells can restore the gefitinib sensitivity. 31 3.6 Knockdown of DUSP13 in PC9/gef cells inhibits in vitro anchorage-independent and anchorage-dependent cell growth. 31 3.7 Cell sensitivity to NSC663284, a DUSP13B inhibitor, in PC9 and PC9/gef cells. 32 4. Discussion 34 5. Figures 41 Figure 1. DUSP13 isoforms. 42 Figure 2. Expression of DUSP13A and DUSP13B proteins by IPTG induction. 44 Figure 3. Purification of DUSP13A and DUSP13B proteins. 45 Figure 4. Optimization of DUSP13A protein purification. 46 Figure 5. DUSP13B protein quantification for New Zealand white rabbits immunization. 49 Figure 6. Specificity of first immunized DUSP13B serum from Rabbit-H with E. coli BL21 expressing DUSP13B protein. 50 Figure 7. Specificity of first immunized DUSP13B serum from Rabbit-L with E. coli BL21 expressing DUSP13B protein. 51 Figure 8. The detect limitation of forth immunized DUSP13B serum of Rabbit-H and Rabbit-L with E. coli BL21 expressing DUSP13B protein. 52 Figure 9. Anti-DUSP13B antibody successfully recognizes different DUSP13 isoforms but not DUSP13A. 53 Figure 10. Unpurified anti-DUSP13A antiserum recognizes DUSP13A. 56 Figure 11. The expression of DUSP13A and DUSP13B in PC9 and PC9/gef cells. 59 Figure 12. Knockdown of DUSP13 resensitize the gefitinib susceptibility in PC9/gef cells. 61 Figure 13. Knockdown of DUSP13 inhibits anchorage-dependent and anchorage-independent cell growth in PC9/gef cells. 64 Figure 14. NSC663284 sensitivity in PC9 and PC9/gef cell lines. 65 Figure 15. Drug sensitivity of NSC663284 and gefitinib in PC9 and PC9/gef cells. 66 6. References 67 | |
| dc.language.iso | en | |
| dc.subject | 表皮生長因子受體突變 | zh_TW |
| dc.subject | 表皮生長因子受體 | zh_TW |
| dc.subject | MAPK 訊息傳遞路徑 | zh_TW |
| dc.subject | 表皮生長因子受體酪胺酸激?抑制劑 | zh_TW |
| dc.subject | EGFR | en |
| dc.subject | EGFR-activating mutation | en |
| dc.subject | EGFR-tyrosine kinase inhibitor | en |
| dc.subject | MAPK pathway | en |
| dc.title | 製備DUSP13抗體以探討具獲得性Gefitinib抗藥性之肺腺癌 | zh_TW |
| dc.title | Development of Anti-DUSP13 Antibody for Acquired Gefitinib Resistance in Lung Adenocarcinoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 102-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李財坤,詹迺立,張正琪,蘇剛毅 | |
| dc.subject.keyword | 表皮生長因子受體,表皮生長因子受體突變,表皮生長因子受體酪胺酸激?抑制劑,MAPK 訊息傳遞路徑, | zh_TW |
| dc.subject.keyword | EGFR,EGFR-activating mutation,EGFR-tyrosine kinase inhibitor,MAPK pathway, | en |
| dc.relation.page | 77 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2014-07-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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