成功大學博碩士論文系統

簡易檢索 / 詳目顯示

回結果列表

研究生：	吳嘉恩 Wu, Jia-En
論文名稱：	DNA 甲基化維持 CLDN1-EPHB6-SLUG 軸而增強化療的療效並抑制肺癌的進展 Maintenance of the CLDN1-EPHB6-SLUG axis by DNA methylation enhances chemotherapy and inhibits lung cancer progression
指導教授：	洪澤民 Hong, Tse-Ming
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	142
中文關鍵詞：	DNA 甲基化、CLDN1-EPHB6-SLUG 、RUNX3 、癌幹細胞、抗藥性、癌轉移
外文關鍵詞：	DNA methylation, CLDN1-EPHB6-SLUG, RUNX3, cancer stem-like cells, drug resistance, metastasis
相關次數：	點閱：91 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

癌細胞是否喪失細胞間連結並從原位的腫瘤環境逃離將取決癌症轉移與否。我們之前的研究顯示緊密連結蛋白 claudin-1 (CLDN1) 在肺腺癌中可作為肺癌轉移的抑制因子，然而其中的分子機制尚未被詳細研究。本篇研究顯示 CLDN1 可藉由 CLDN1-EPHB6-SLUG 的回饋路徑抑制癌轉移與減少抗藥性和癌幹細胞的生成。大量表達 CLDN1 蛋白可促進 EPHB6 蛋白的表現，並藉由 EPHB6 路徑抑制 ERK1/2 的磷酸化來抑制 SLUG 蛋白表現。有趣的是，在癌轉移能力較低的細胞中 CLDN1 基因啟動子上的 DNA 甲基化非但沒有抑制 CLDN1 基因的表現反而抑制 SLUG 蛋白的結合，進而維持 CLDN1 基因的轉錄能力，其中 RUNX3 作為 CLDN1 的轉錄活化因子。另一方面，在癌轉移能力較高的細胞中，組織蛋白去乙醯酶抑制劑 trichostatin A 或 vorinostat 可藉由促進 CLDN1 蛋白重新表達而增加化療藥物的效果。當癌細胞合併處理 cisplatin 與 trichostatin A 或 vorinostat 時，對癌細胞的毒殺效果具協同作用。重要的是，我們找到的基因特徵 RUNX3highCLDN1highSLUGlow 和 RUNX3lowCLDN1lowSLUGhigh 可在病人的總生存率上分成顯著的兩群。由於 CLDN1 蛋白表現可加強化療藥物的療效，所以 CLDN1 不只是病人生存率的預後指標，同時 CLDN1 也許也可以作為預測病人是否對化療藥物有較好反應的分子標誌；另一方面，在 CLDN1 表現量低的肺腺癌中，利用組織蛋白去乙醯酶抑制劑重新表達 CLDN1 蛋白並合併處理化療藥物，也許是一新的治療方針。

Cancer cells lose the tight junctions between cells, and escape from the primary tumor environment would result in cancer metastasis. Our previous study has demonstrated that claudin-1 (CLDN1), one essential protein of tight junctions, can act as a suppressor of lung cancer metastasis. Still, its molecular mechanism has not been studied in detail. We showed that CLDN1 could inhibit cancer metastasis and reduce drug resistance and the formation of cancer stem-like cells through the feedback pathway of the CLDN1-EPHB6-SLUG axis. Overexpression of CLDN1 protein could promote EPHB6 protein expression and interact with EPHB6 at the tight junctions and inhibit the phosphorylation of ERK1/2; therefore, resulting in repressing SLUG protein expression. Interestingly, DNA methylation on the promoter of the CLDN1 gene in cells with low cancer metastasis ability not only did not repress the expression of the CLDN1 gene but block the binding of SLUG protein, thereby maintaining the CLDN1 gene transcription which activated by a transcriptional activator, RUNX3 protein. In contrast, in cells with higher cancer metastasis ability, the histone deacetylase inhibitor trichostatin A or vorinostat could enhance the effect of chemotherapy drugs by promoting the CLDN1 expression. When cancer cells were treated with cisplatin and trichostatin A or vorinostat, the two-drug combination had a synergistic effect on the cytotoxicity of cancer cells. Importantly, three-gene signature, RUNX3highCLDN1highSLUGlow and RUNX3lowCLDN1lowSLUGhigh could classify the lung adenocarcinoma patients into two groups with a significant difference in overall survival. Because the expression of CLDN1 protein could enhance the efficacy of chemotherapy drugs, CLDN1 was not only a prognostic indicator of patient survival rate, but CLDN1 might also be used as a biomarker to predict whether a patient would respond well to chemotherapy drugs. Forced CLDN1 expression by histone deacetylase inhibitors in low CLDN1-expressing lung adenocarcinoma would increase the chemotherapy response, therefore combined treatment of histone deacetylase inhibitors and chemotherapeutic drugs may provide a novel therapeutic strategy.

Abstract in Chinese	I
Abstract	III
Acknowledgement	V
Contents	VI
Table contents	IX
Figure contents	X
Abbreviations	XV
Chapter 1 Introduction	1
1 Cancer metastasis	1
2 Transcriptional repressor, SLUG	2
3 Epigenetics regulates gene expression	3
4 Tight junction protein, CLDN1	3
5 Ephrin and Ephrin receptor family	4
Chapter 2. Motivation and objectives of this study	6
Chapter 3. Materials and Methods	8
1 Cell lines and Antibodies	8
2 Reagents	9
3 Plasmid construction	9
4 Bisulfite sequencing assay	10
5 Methylation-specific PCR assay	10
6 Quantification of methylation level among CpG regions by pyrosequencing	11
7 RNA extraction and reverse-transcription quantitative PCR (RT-qPCR) assay	12
8 Co-immunoprecipitation assay	12
9 Chromatin immunoprecipitation (ChIP) assay	13
10 Production of lentivirus harboring shRNA sequence and infection of cells with lentivirus	14
11 Immunoblotting	16
12 Migration assay	17
13 Sphere assay	17
14 Immunofluorescence (IF) by confocal microscopy	18
15 Luciferase reporter assay	18
16 Immunohistochemistry	19
17 Cytotoxicity	19
18 The detection of CD133, the determination of apoptosis, and the analysis of cell-cycle stages were performed by Flow cytometry.	20
19 Aldefluor assay for CSCs determination	21
20 Soft-agar colony formation assay	21
21 Animal experiments	22
22 Statistics and reproducibility	24
23 Availability of data	24
Chapter 4. Results	26
1 CLDN1 suppresses metastasis by inhibiting SLUG expression via the ERK1/2 signaling pathway.	26
2 CLDN1 upregulates and interacts with EPHB6 to suppress the ERK1/2 signaling pathway and cell migration.	29
3 CLDN1 sensitizes lung adenocarcinoma cells to chemotherapy drugs by suppressing the CSC properties.	31
4 CLDN1 inhibits tumorigenesis and cancer stemness and sensitizes lung adenocarcinoma cells to cisplatin in vivo.	34
5 DNA hypermethylation of the CLDN1 promoter is required to its transcription by blocking SLUG-mediated suppression.	37
6 TSA can induce CLDN1 transcription by histone modification when DNA hypomethylation.	39
7 RUNX3 upregulates CLDN1 transcription and represses SLUG transcription.	40
8 High levels of CLDN1 and RUNX3 predict a positive chemotherapeutic efficacy and a good clinical outcome for patients.	43
9 Cisplatin and histone deacetylase inhibitors had a synergistic effect on cell death for CLDN1low cancer cells.	44
Chapter 5. Discussion	48
1 To induce EMT processes should consider the epigenetic status of the epithelial genes	48
2 The relationship between CLDN1 and SLUG possesses the reciprocal feedback loop.	48
3 The differential compartment localization of CLDN1 confers the paradoxical phenomenon in the cancer metastasis.	49
4 Restoration of RUNX3 might be another strategy to upregulate the CLDN1 expression	51
5 The expression level of CLDN1 in lung cancer might be a predictive biomarker for the combination treatment of cisplatin and vorinostat.	51
Chapter 6. Conclusions	54
Chapter 7. Future work and Perspective	55
References	58
Tables	65
Figures	71
Curriculum Vitae	140
                                    

1. Leung CT, Brugge JS. Outgrowth of single oncogene-expressing cells from suppressive epithelial environments. Nature. 2012; 482: 410-3.
2. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423-37.
3. Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003; 116: 1959-67.
4. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009; 9: 265-73.
5. Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol. 2003; 4: 225-36.
6. Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016; 166: 21-45.
7. Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017; 14: 611-29.
8. Cao J, Zhao M, Liu J, Zhang X, Pei Y, Wang J, et al. RACK1 promotes self-renewal and chemoresistance of cancer stem cells in human hepatocellular carcinoma through stabilizing nanog. Theranostics. 2019; 9: 811-28.
9. Cole AJ, Fayomi AP, Anyaeche VI, Bai S, Buckanovich RJ. An evolving paradigm of cancer stem cell hierarchies: therapeutic implications. Theranostics. 2020; 10: 3083-98.
10. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013; 19: 1438-49.
11. Chen Y, Wang K, Qian CN, Leach R. DNA methylation is associated with transcription of Snail and Slug genes. Biochem Biophys Res Commun. 2013; 430: 1083-90.
12. Stemmler MP, Eccles RL, Brabletz S, Brabletz T. Non-redundant functions of EMT transcription factors. Nat Cell Biol. 2019; 21: 102-12.
13. Zhou W, Gross KM, Kuperwasser C. Molecular regulation of Snai2 in development and disease. J Cell Sci. 2019; 132.
14. Luanpitpong S, Li J, Manke A, Brundage K, Ellis E, McLaughlin SL, et al. SLUG is required for SOX9 stabilization and functions to promote cancer stem cells and metastasis in human lung carcinoma. Oncogene. 2016; 35: 2824-33.
15. 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: 2059-68.
16. Sun Q, Lesperance J, Wettersten H, Luterstein E, DeRose YS, Welm A, et al. Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis. J Clin Invest. 2018; 128: 531-44.
17. Asiedu MK, Ingle JN, Behrens MD, Radisky DC, Knutson KL. TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res. 2011; 71: 4707-19.
18. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010; 12: R68.
19. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002; 3: 662-73.
20. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3: 415-28.
21. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009; 10: 295-304.
22. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006; 439: 871-4.
23. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006; 125: 315-26.
24. Gampenrieder SP, Rinnerthaler G, Hackl H, Pulverer W, Weinhaeusel A, Ilic S, et al. DNA methylation signatures predicting bevacizumab efficacy in metastatic breast cancer. Theranostics. 2018; 8: 2278-88.
25. Teng H, Xue M, Liang J, Wang X, Wang L, Wei W, et al. Inter- and intratumor DNA methylation heterogeneity associated with lymph node metastasis and prognosis of esophageal squamous cell carcinoma. Theranostics. 2020; 10: 3035-48.
26. Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE. Tight junction proteins. Prog Biophys Mol Biol. 2003; 81: 1-44.
27. Bauer H, Zweimueller-Mayer J, Steinbacher P, Lametschwandtner A, Bauer HC. The dual role of zonula occludens (ZO) proteins. J Biomed Biotechnol. 2010; 2010: 402593.
28. Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res. 2005; 65: 9603-6.
29. Chao YC, Pan SH, Yang SC, Yu SL, Che TF, Lin CW, et al. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med. 2009; 179: 123-33.
30. Chang TL, Ito K, Ko TK, Liu Q, Salto-Tellez M, Yeoh KG, et al. Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells. Gastroenterology. 2010; 138: 255-65.
31. Tokes AM, Kulka J, Paku S, Szik A, Paska C, Novak PK, et al. Claudin-1, -3 and -4 proteins and mRNA expression in benign and malignant breast lesions: a research study. Breast Cancer Res. 2005; 7: R296-305.
32. Leotlela PD, Wade MS, Duray PH, Rhode MJ, Brown HF, Rosenthal DT, et al. Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility. Oncogene. 2007; 26: 3846-56.
33. Resnick MB, Konkin T, Routhier J, Sabo E, Pricolo VE. Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study. Mod Pathol. 2005; 18: 511-8.
34. Turksen K. Claudins and cancer stem cells. Stem Cell Rev Rep. 2011; 7: 797-8.
35. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010; 10: 165-80.
36. Clevers H, Batlle E. EphB/EphrinB receptors and Wnt signaling in colorectal cancer. Cancer Res. 2006; 66: 2-5.
37. Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol. 2011; 13: 1100-7.
38. Yu J, Bulk E, Ji P, Hascher A, Tang M, Metzger R, et al. The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer. Clin Cancer Res. 2010; 16: 2275-83.
39. Fox BP, Kandpal RP. EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. Oncogene. 2009; 28: 1706-13.
40. Truitt L, Freywald T, DeCoteau J, Sharfe N, Freywald A. The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer Res. 2010; 70: 1141-53.
41. Fox BP, Kandpal RP. DNA-based assay for EPHB6 expression in breast carcinoma cells as a potential diagnostic test for detecting tumor cells in circulation. Cancer Genomics Proteomics. 2010; 7: 9-16.
42. Holmberg J, Genander M, Halford MM, Anneren C, Sondell M, Chumley MJ, et al. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell. 2006; 125: 1151-63.
43. Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol. 2001; 3: 527-30.
44. Martinez-Estrada OM, Culleres A, Soriano FX, Peinado H, Bolos V, Martinez FO, et al. The transcription factors Slug and Snail act as repressors of Claudin-1 expression in epithelial cells. Biochem J. 2006; 394: 449-57.
45. Savagner P, Kusewitt DF, Carver EA, Magnino F, Choi C, Gridley T, et al. Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol. 2005; 202: 858-66.
46. Olea-Flores M, Zuniga-Eulogio MD, Mendoza-Catalan MA, Rodriguez-Ruiz HA, Castaneda-Saucedo E, Ortuno-Pineda C, et al. Extracellular-signal regulated kinase: a central molecule driving epithelial-mesenchymal transition in cancer. Int J Mol Sci. 2019; 20.
47. Lin CW, Wang LK, Wang SP, Chang YL, Wu YY, Chen HY, et al. Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1alpha/HDAC1/Slug axis. Nat Commun. 2016; 7: 13867.
48. Lee Y, Lee M, Kim S. Gas6 induces cancer cell migration and epithelial-mesenchymal transition through upregulation of MAPK and Slug. Biochem Biophys Res Commun. 2013; 434: 8-14.
49. Muller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwable J, et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res. 2005; 65: 1778-82.
50. Malta TM, Sokolov A, Gentles AJ, Burzykowski T, Poisson L, Weinstein JN, et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell. 2018; 173: 338-54 e15.
51. Alamgeer M, Ganju V, Szczepny A, Russell PA, Prodanovic Z, Kumar B, et al. The prognostic significance of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 expression in early stage non-small cell lung cancer. Thorax. 2013; 68: 1095-104.
52. Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, et al. Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Res. 2010; 70: 9937-48.
53. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008; 15: 504-14.
54. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010; 29: 4741-51.
55. Kim S, Yao J, Suyama K, Qian X, Qian BZ, Bandyopadhyay S, et al. Slug promotes survival during metastasis through suppression of Puma-mediated apoptosis. Cancer Res. 2014; 74: 3695-706.
56. Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell. 2005; 123: 641-53.
57. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012; 31: 1869-83.
58. Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011; 32: 1299-304.
59. Valencia AM, Kadoch C. Chromatin regulatory mechanisms and therapeutic opportunities in cancer. Nat Cell Biol. 2019; 21: 152-61.
60. Tabaries S, Siegel PM. The role of claudins in cancer metastasis. Oncogene. 2017; 36: 1176-90.
61. Shiozaki A, Bai XH, Shen-Tu G, Moodley S, Takeshita H, Fung SY, et al. Claudin 1 mediates TNFalpha-induced gene expression and cell migration in human lung carcinoma cells. PLoS One. 2012; 7: e38049.
62. French AD, Fiori JL, Camilli TC, Leotlela PD, O'Connell MP, Frank BP, et al. PKC and PKA phosphorylation affect the subcellular localization of claudin-1 in melanoma cells. Int J Med Sci. 2009; 6: 93-101.
63. Hoevel T, Macek R, Swisshelm K, Kubbies M. Reexpression of the TJ protein CLDN1 induces apoptosis in breast tumor spheroids. Int J Cancer. 2004; 108: 374-83.
64. Matsuoka H, Obama H, Kelly ML, Matsui T, Nakamoto M. Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration. J Biol Chem. 2005; 280: 29355-63.
65. Yu J, Bulk E, Ji P, Hascher A, Koschmieder S, Berdel WE, et al. The kinase defective EPHB6 receptor tyrosine kinase activates MAP kinase signaling in lung adenocarcinoma. Int J Oncol. 2009; 35: 175-9.
66. Guo H, Huang ZL, Wang W, Zhang SX, Li J, Cheng K, et al. iTRAQ-based proteomics suggests Ephb6 as a potential regulator of the ERK pathway in the prefrontal cortex of chronic social defeat stress model mice. Proteomics Clin Appl. 2017; 11.
67. Tanaka M, Kamata R, Sakai R. Phosphorylation of ephrin-B1 via the interaction with claudin following cell-cell contact formation. EMBO J. 2005; 24: 3700-11.
68. Jin YH, Jeon EJ, Li QL, Lee YH, Choi JK, Kim WJ, et al. Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J Biol Chem. 2004; 279: 29409-17.
69. Kim HJ, Bae SC. Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res. 2011; 3: 166-79.
70. Li QL, Ito K, Sakakura C, Fukamachi H, Inoue K, Chi XZ, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002; 109: 113-24.
71. Lee YS, Lee JW, Jang JW, Chi XZ, Kim JH, Li YH, et al. Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell. 2013; 24: 603-16.
72. Kramer F, White K, Kubbies M, Swisshelm K, Weber BH. Genomic organization of claudin-1 and its assessment in hereditary and sporadic breast cancer. Hum Genet. 2000; 107: 249-56.
73. Traynor AM, Dubey S, Eickhoff JC, Kolesar JM, Schell K, Huie MS, et al. Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study. J Thorac Oncol. 2009; 4: 522-6.
74. Ramalingam SS, Parise RA, Ramanathan RK, Lagattuta TF, Musguire LA, Stoller RG, et al. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res. 2007; 13: 3605-10.
75. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, et al. Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol. 2010; 28: 56-62.
76. Kitai H, Ebi H, Tomida S, Floros KV, Kotani H, Adachi Y, et al. Epithelial-to-Mesenchymal Transition defines feedback activation of receptor tyrosine kinase signaling induced by MEK inhibition in KRAS-mutant lung cancer. Cancer Discov. 2016; 6: 754-69.
77. Ambrogio C, Kohler J, Zhou ZW, Wang H, Paranal R, Li J, et al. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell. 2018; 172: 857-68 e15.
78. Kidger AM, Sipthorp J, Cook SJ. ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway. Pharmacol Ther. 2018; 187: 45-60.
79. Hayes TK, Neel NF, Hu C, Gautam P, Chenard M, Long B, et al. Long-term ERK inhibition in KRAS-mutant pancreatic cancer is associated with MYC degradation and senescence-like growth suppression. Cancer Cell. 2016; 29: 75-89.

校內：2025-08-28公開
校外：2025-08-28公開

簡易檢索 / 詳目顯示

相關論文