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系統識別號 U0026-0106201214353600
論文名稱(中文) 研究ERβ與Stat3間的互動關係以及ERβ對Stat3所調控之基因表現與細胞生物行為的影響
論文名稱(英文) To study the interaction between ERβ and Stat3 and its impact on Stat3-mediated gene regulation and cellular biology
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 100
學期 2
出版年 101
研究生(中文) 王昊宸
研究生(英文) Hao-Chen Wang
學號 s58931269
學位類別 博士
語文別 英文
論文頁數 81頁
口試委員 指導教授-蘇五洲
口試委員-賴明德
召集委員-張文粲
口試委員-蔡美玲
口試委員-洪文俊
口試委員-劉柯俊
中文關鍵字 乙型雌激素受體  訊息傳遞與轉錄因子3  肺癌  表皮生長因子受體突變 
英文關鍵字 ERβ  Stat3  lung cancer  EGFR mutation 
學科別分類
中文摘要 雌激素對於女性肺癌的作用影響主要透過乙型雌激素受體(ERβ),不過乙型雌激素受體在肺癌細胞中如何受到調控則仍屬未知。在先前的實驗裏,我們已觀察到在PC14PE6/AS2肺癌細胞中訊息傳遞與轉錄因子3(Stat3)的活化會導致乙型雌激素受體的表現增加,因此我們想進一步確認乙型雌激素受體的表現是否受訊息傳遞與轉錄因子3所調控。本研究中我們發現介白素6(IL-6)會刺激肺癌細胞使乙型雌激素受體的mRNA與蛋白質表現增加,此一效應可被Jak2抑制劑AG490、dominant-negative的訊息傳遞與轉錄因子3和訊息傳遞與轉錄因子3的 siRNA所抑制。Luciferase reporter assay及ChIP assay的結果確認經介白素6活化的訊息傳遞與轉錄因子3會結合至乙型雌激素受體的啟動子上。乙型雌激素受體的表現除了可透過活化Jak2/Stat3路徑來增加外,尚可經由MEK/Erk路徑所控制,然而PI3K/Akt則沒有參與。進一步我們也發現表皮生長因子(EGF)的刺激或是表皮生長因子受體(EGFR)突變也同樣能造成訊息傳遞與轉錄因子3的活化以及乙型雌激素受體的表現增加。利用藥物或siRNA抑制訊息傳遞與轉錄因子3的活性可有效減少表皮生長因子的刺激或表皮生長因子受體突變所引起乙型雌激素受體的表現增加,此一結果表示訊息傳遞與轉錄因子3的活化在表皮生長因子刺激或表皮生長因子受體突變所引起乙型雌激素受體的增加過程中佔有必要的角色,而利用乙型雌激素受體的siRNA降低乙型雌激素受體的蛋白表現則可抑制表皮生長因子受體突變造成的細胞增生現象。除此之外,我們也發現介白素6或表皮生長因子刺激可促進乙型雌激素受體與訊息傳遞與轉錄因子3之間的蛋白質結合,此一結合可能發生在細胞核或粒線體中,至於詳細機轉則需更多實驗證實。總結我們的研究發現介白素6、表皮生長因子及表皮生長因子受體突變所導致乙型雌激素受體的增加必須依靠訊息傳遞與轉錄因子3的活化,此一結果提供肺癌治療可針對的標靶,特別是有表皮生長因子受體突變的患者。
英文摘要 Estrogens contribute to the pathogenesis of female lung cancer and function mainly through ERβ. However, the way in which ERβ expression is regulated in lung cancer cells remains to be explored. We have found that Stat3 activation up-regulates ERβ expression in PC14PE6/AS2 lung cancer cells in a preliminary Affymetrix oligonucleotide array study, and we sought to confirm the findings. In this study, we show that IL-6 induced ERβ mRNA and protein expression in lung cancer cells. The induction of ERβ in response to IL-6 was abolished by Jak2 inhibitor-AG490, dominant-negative mutant of Stat3, and Stat3-targeting siRNA. The luciferase reporter assay and ChIP assay confirmed that IL-6-activated Stat3 binds to ERβ promoter. Besides the Jak2/Stat3 pathway, the MEK/Erk pathway contributes to ERβ up-regulation induced by IL-6; however, the PI3K/Akt pathway does not. We also found that EGF stimulation or L858R mutation in EGFR induced Stat3 activation as well as ERβ expression in lung cancer cells. Inhibiting Stat3 activity by pharmacological or genetic approaches reduced EGF- and L858R mutant EGFR-induced ERβ expression, indicating that Stat3 activation is required for EGFR signaling-mediated ERβ up-regulation. Silencing ERβ decreased cell proliferation in lung cancer cells that overexpress L858R mutant EGFR. On the other hand, we found a protein-protein interaction between Stat3 and ERβ in lung cancer cells, which was enhanced by IL-6 and EGF stimulation. Both IL-6 and EGF increased the translocation of Stat3 and ERβ to nuclei and mitochondria. However, further investigation is required for clarifying the location of the Stat3-ERβ interaction. In conclusion, we have identified that Stat3 activation is essential for ERβ induction by IL-6, EGF, and the presence of EGFR mutation. The findings shed light on new therapeutic targets for female lung cancer, especially for those with EGFR mutations.
論文目次 中文摘要..............................................................................I
Abstract..............................................................................III
致謝.................................................................................V
Contents...................................................................................VI
Abbreviation list.....................................................................X
Chapter 1: Introduction..........................................................................................1
1-1 Lung cancer....................................................................................................2
1-2 Sex difference in risk of lung cancer..............................................................2
1-3 Estrogen receptor............................................................................................3
1-4 Estrogen signaling pathways in normal lung development and lung cancer............................................................................................................5
1-5 Signal transducers and activators of transcription.........................................6
1-6 Stat3 signaling pathway in lung cancer..........................................................7
1-7 Epidermal growth factor receptor..................................................................9
1-8 EGFR signaling pathway in lung cancer......................................................10
1-9 Rationales.....................................................................................................12
1-10 Specific aims..............................................................................................14
Chapter 2: Materials and Methods.......................................................................15
2-1 Materials.......................................................................................................16
2-1-1 Drugs and reagents.............................................................................16
2-1-2 Antibodies...........................................................................................16
2-1-3 Cell lines ............................................................................................18
2-2 Methods........................................................................................................19
2-2-1 Cell culture conditions........................................................................19
2-2-2 RNA preparation and RT–PCR...........................................................19
2-2-3 Cell lysis and Western blot analysis....................................................20
2-2-4 siRNAs and transient transfection......................................................21
2-2-5 Reporter plasmids and luciferase assays.............................................21
2-2-6 Chromatin immunoprecipitation assays.............................................22
2-2-7 Co-immunoprecipitation and immunoprecipitation...........................22
2-2-8 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays..................................................................................................23
2-2-9 Immunofluorescence and confocal microscopy..................................23
2-2-10 Preparation of nuclear and cytosolic extracts...................................24
2-2-11 Preparation of mitochondrial and cytosolic extracts.........................24
2-2-12 Statistical analysis.............................................................................25
Chapter 3: Results..................................................................................................26
3-1 IL-6 induces Stat3 activation and ERβ expression in lung cancer cells......27
3-2 IL-6 increases transcription and stability of ERβ mRNA and protein in lung cancer cells...................................................................................................27
3-3 Up-regulation of ERβ by IL-6 is mediated through the Jak2/Stat3 and the MEK/Erk but not the PI3K/Akt pathways...................................................28
3-4 Stat3 activation is directly involved in the regulation of ERβ expressio.29
3-5 Stat3 and ERβ interact with each other to regulate estrogen-dependent lung cancer cell growth........................................................................................31
3-6 EGF activates Stat3 and up-regulates ERβ expression in lung cancer cells.............................................................................................................32
3-7 The L858R mutant EGFR up-regulates ERβ expression via Stat3 activation....................................................................................................33
3-8 ERβ contributes to the cell proliferation in lung cancer cells harboring the L858R EGFR mutation................................................................................33
3-9 ERβ interacts with Stat3...............................................................................34
3-10 IL-6 or EGF changes the subcellular distribution of ERβ.........................35
Chapter 4: Discussion and Conclusion.................................................................37
References...............................................................................................................44
Tables and Figures..................................................................................................54
Table 1. The oligonucleotide primers used in this study....................................54
Figure 1. IL-6 up-regulates ERβ protein expression dose-dependently in lung cancer cells.........................................................................................55
Figure 2. IL-6 up-regulates ERβ protein expression in a time course manner in lung cancer cells.................................................................................56
Figure 3. IL-6 up-regulates ERβ mRNA expression in a time course manner in lung cancer cells.................................................................................57
Figure 4. IL-6 increases ERβ mRNA stability in lung cancer cells...................58
Figure 5. IL-6 increases ER protein stability in lung cancer cells...................59
Figure 6. Jak2/Stat3 and MEK/Erk as downstream signaling pathways of IL-6 contribute to the regulation of ERβ expression..................................60
Figure 7. ERβ expression is regulated by Stat3.................................................62
Figure 8. Stat3 specifically binds to ERβ promoter...........................................64
Figure 9. Effects of ERβ activation on Stat3 expression....................................66
Figure 10. The interaction between Stat3 and ERβ contributes to estrogen- dependent cell growth......................................................................67
Figure 11. EGF up-regulates ERβ protein expression in a time course manner in lung cancer cells................................................................................68
Figure 12. Stat3 activation is involved in EGF-induced ERβ expression in lung cancer cells........................................................................................69
Figure 13. ERβ expression is up-regulated by L858R mutant EGFR via Stat3 activation..........................................................................................71
Figure 14. ERβ contributes to L858R mutant EGFR-induced cell growth..........................................................................................72
Figure 15. The combination of DPN and EGF further enhanced cell growth............................................................................................74
Figure 16. IL-6 or EGF enhances the protein-protein interaction between ERβ and Stat3 in lung cancer cells...........................................................75
Figure 17. The translocation of Stat3 and ERβ to the nucleus is promoted by both IL-6 and EGF...........................................................................76
Figure 18. The translocation of ERβ to mitochondria is induced by both IL-6 and EGF............................................................................................78
Figure 19. The DPN-induced Stat3 phosphorylation can be blocked by rotenone..........................................................................................79
Figure 20. The expression levels of ERα and ERβ in various lung cancer cell lines..................................................................................................80
作者簡歷..................................................................................................................81
參考文獻 Akira, S. (1999). "Functional roles of STAT family proteins: lessons from knockout mice." Stem Cells 17(3): 138-146.
Akira, S., Y. Nishio, et al. (1994). "Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway." Cell 77(1): 63-71.
Alvarez, J. V., H. Greulich, et al. (2006). "Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor." Cancer Res 66(6): 3162-3168.
Baselga, J. (2002). "Why the epidermal growth factor receptor? The rationale for cancer therapy." Oncologist 7 Suppl 4: 2-8.
Bjornstrom, L. and M. Sjoberg (2002). "Signal transducers and activators of transcription as downstream targets of nongenomic estrogen receptor actions." Mol Endocrinol 16(10): 2202-2214.
Bjornstrom, L. and M. Sjoberg (2005). "Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes." Mol Endocrinol 19(4): 833-842.
Bowman, T., R. Garcia, et al. (2000). "STATs in oncogenesis." Oncogene 19(21): 2474-2488.
Brambilla, E., W. D. Travis, et al. (2001). "The new World Health Organization classification of lung tumours." Eur Respir J 18(6): 1059-1068.
Brandenberger, A. W., M. K. Tee, et al. (1997). "Tissue distribution of estrogen receptors alpha (ER-alpha) and beta (ER-beta) mRNA in the midgestational human fetus." J Clin Endocrinol Metab 82(10): 3509-3512.
Bromberg, J. F., C. M. Horvath, et al. (1998). "Stat3 activation is required for cellular transformation by v-src." Mol Cell Biol 18(5): 2553-2558.
Bromberg, J. F., M. H. Wrzeszczynska, et al. (1999). "Stat3 as an oncogene." Cell 98(3): 295-303.
Bunone, G., P. A. Briand, et al. (1996). "Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation." EMBO J 15(9): 2174-2183.
Carballo, M., M. Conde, et al. (1999). "Oxidative stress triggers STAT3 tyrosine phosphorylation and nuclear translocation in human lymphocytes." J Biol Chem 274(25): 17580-17586.
Chapman, R. S., P. C. Lourenco, et al. (1999). "Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3." Genes Dev 13(19): 2604-2616.
Chen, J. Q., M. Delannoy, et al. (2004). "Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells." Am J Physiol Endocrinol Metab 286(6): E1011-1022.
Chen, Y. R., Y. N. Fu, et al. (2006). "Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants." Oncogene 25(8): 1205-1215.
Choi, J. H., K. T. Lee, et al. (2011). "Estrogen receptor alpha pathway is involved in leptin-induced ovarian cancer cell growth." Carcinogenesis 32(4): 589-596.
Ciana, P., S. Ghisletti, et al. (2003). "Estrogen receptor alpha, a molecular switch converting transforming growth factor-alpha-mediated proliferation into differentiation in neuroblastoma cells." J Biol Chem 278(34): 31737-31744.
Ciardiello, F. and G. Tortora (2001). "A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor." Clin Cancer Res 7(10): 2958-2970.
Ciardiello, F. and G. Tortora (2003). "Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs." Eur J Cancer 39(10): 1348-1354.
da Cunha Santos, G., F. A. Shepherd, et al. (2011). "EGFR mutations and lung cancer." Annu Rev Pathol 6: 49-69.
Darnell, J. E., Jr., I. M. Kerr, et al. (1994). "Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins." Science 264(5164): 1415-1421.
Downward, J., P. Parker, et al. (1984). "Autophosphorylation sites on the epidermal growth factor receptor." Nature 311(5985): 483-485.
Enmark, E., M. Pelto-Huikko, et al. (1997). "Human estrogen receptor beta-gene structure, chromosomal localization, and expression pattern." J Clin Endocrinol Metab 82(12): 4258-4265.
Felty, Q., W. C. Xiong, et al. (2005). "Estrogen-induced mitochondrial reactive oxygen species as signal-transducing messengers." Biochemistry 44(18): 6900-6909.
Ferguson, M. K., J. Wang, et al. (2000). "Sex-associated differences in survival of patients undergoing resection for lung cancer." Ann Thorac Surg 69(1): 245-249; discussion 249-250.
Frasor, J., K. Park, et al. (2001). "Differential roles for signal transducers and activators of transcription 5a and 5b in PRL stimulation of ERalpha and ERbeta transcription." Mol Endocrinol 15(12): 2172-2181.
Fukuoka, M., S. Yano, et al. (2003). "Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]." J Clin Oncol 21(12): 2237-2246.
Gao, Q. and T. L. Horvath (2008). "Cross-talk between estrogen and leptin signaling in the hypothalamus." Am J Physiol Endocrinol Metab 294(5): E817-826.
Gao, S. P., K. G. Mark, et al. (2007). "Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas." J Clin Invest 117(12): 3846-3856.
Garcia, R. and R. Jove (1998). "Activation of STAT transcription factors in oncogenic tyrosine kinase signaling." J Biomed Sci 5(2): 79-85.
Gazdar, A. F., H. Shigematsu, et al. (2004). "Mutations and addiction to EGFR: the Achilles 'heal' of lung cancers?" Trends Mol Med 10(10): 481-486.
Giddabasappa, A., M. Bauler, et al. (2010). "17-beta estradiol protects ARPE-19 cells from oxidative stress through estrogen receptor-beta." Invest Ophthalmol Vis Sci 51(10): 5278-5287.
Greenlee, R. T., M. B. Hill-Harmon, et al. (2001). "Cancer statistics, 2001." CA Cancer J Clin 51(1): 15-36.
Gross, I., C. M. Wilson, et al. (1979). "The influence of hormones on the biochemical development of fetal rat lung in organ culture. I. Estrogen." Biochim Biophys Acta 575(3): 375-383.
Guinee, D. G., Jr., W. D. Travis, et al. (1995). "Gender comparisons in human lung cancer: analysis of p53 mutations, anti-p53 serum antibodies and C-erbB-2 expression." Carcinogenesis 16(5): 993-1002.
Hatae, J., N. Takami, et al. (2009). "17beta-Estradiol-induced enhancement of estrogen receptor biosynthesis via MAPK pathway in mouse skeletal muscle myoblasts." J Physiol Sci 59(3): 181-190.
Haura, E. B., Z. Zheng, et al. (2005). "Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer." Clin Cancer Res 11(23): 8288-8294.
Hershberger, P. A., A. C. Vasquez, et al. (2005). "Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands." Cancer Res 65(4): 1598-1605.
Hirsch, F. R., M. Varella-Garcia, et al. (2003). "Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis." J Clin Oncol 21(20): 3798-3807.
Hodge, D. R., E. M. Hurt, et al. (2005). "The role of IL-6 and STAT3 in inflammation and cancer." Eur J Cancer 41(16): 2502-2512.
Hokuto, I., M. Ikegami, et al. (2004). "Stat-3 is required for pulmonary homeostasis during hyperoxia." J Clin Invest 113(1): 28-37.
Hung, M. J., W. J. Cherng, et al. (2010). "Interleukin-6 inhibits endothelial nitric oxide synthase activation and increases endothelial nitric oxide synthase binding to stabilized caveolin-1 in human vascular endothelial cells." J Hypertens 28(5): 940-951.
Hynes, N. E., K. Horsch, et al. (2001). "The ErbB receptor tyrosine family as signal integrators." Endocr Relat Cancer 8(3): 151-159.
Hynes, N. E. and H. A. Lane (2005). "ERBB receptors and cancer: the complexity of targeted inhibitors." Nat Rev Cancer 5(5): 341-354.
Janne, P. A., S. Gurubhagavatula, et al. (2004). "Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, "Iressa") on an expanded access study." Lung Cancer 44(2): 221-230.
Ji, H., D. Li, et al. (2006). "The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies." Cancer Cell 9(6): 485-495.
Kato, S., H. Endoh, et al. (1995). "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase." Science 270(5241): 1491-1494.
Kawai, H., A. Ishii, et al. (2005). "Estrogen receptor alpha and beta are prognostic factors in non-small cell lung cancer." Clin Cancer Res 11(14): 5084-5089.
Kris, M. G., R. B. Natale, et al. (2003). "Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial." JAMA 290(16): 2149-2158.
Kuiper, G. G., B. Carlsson, et al. (1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta." Endocrinology 138(3): 863-870.
Kuiper, G. G., E. Enmark, et al. (1996). "Cloning of a novel receptor expressed in rat prostate and ovary." Proc Natl Acad Sci U S A 93(12): 5925-5930.
Kure, E. H., D. Ryberg, et al. (1996). "p53 mutations in lung tumours: relationship to gender and lung DNA adduct levels." Carcinogenesis 17(10): 2201-2205.
Lam, W. K. (2005). "Lung cancer in Asian women-the environment and genes." Respirology 10(4): 408-417.
Lee, S. M. (2006). "Is EGFR expression important in non-small cell lung cancer?" Thorax 61(2): 98-99.
Levy, D. E. and J. E. Darnell, Jr. (2002). "Stats: transcriptional control and biological impact." Nat Rev Mol Cell Biol 3(9): 651-662.
Li, Y., H. Du, et al. (2007). "Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung." Cancer Res 67(18): 8494-8503.
Liaw, Y. P., Y. C. Huang, et al. (2005). "Patterns of lung cancer mortality in 23 countries: application of the age-period-cohort model." BMC Public Health 5: 22.
Lim, C. P. and X. Cao (2006). "Structure, function, and regulation of STAT proteins." Mol Biosyst 2(11): 536-550.
Liu, Y., M. Inoue, et al. (2005). "Reproductive factors, hormone use and the risk of lung cancer among middle-aged never-smoking Japanese women: a large-scale population-based cohort study." Int J Cancer 117(4): 662-666.
Lutticken, C., U. M. Wegenka, et al. (1994). "Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130." Science 263(5143): 89-92.
Lynch, T. J., D. W. Bell, et al. (2004). "Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib." N Engl J Med 350(21): 2129-2139.
Marquez-Garban, D. C., H. W. Chen, et al. (2007). "Estrogen receptor signaling pathways in human non-small cell lung cancer." Steroids 72(2): 135-143.
Maziere, C., G. Alimardani, et al. (1999). "Oxidized LDL activates STAT1 and STAT3 transcription factors: possible involvement of reactive oxygen species." FEBS Lett 448(1): 49-52.
McDonnell, D. P. and J. D. Norris (2002). "Connections and regulation of the human estrogen receptor." Science 296(5573): 1642-1644.
Mendelsohn, J. (2000). "Blockade of receptors for growth factors: an anticancer therapy--the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture." Clin Cancer Res 6(3): 747-753.
Mendelsohn, J. (2002). "Targeting the epidermal growth factor receptor for cancer therapy." J Clin Oncol 20(18 Suppl): 1S-13S.
Miller, V. A., M. G. Kris, et al. (2004). "Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer." J Clin Oncol 22(6): 1103-1109.
Mollerup, S., K. Jorgensen, et al. (2002). "Expression of estrogen receptors alpha and beta in human lung tissue and cell lines." Lung Cancer 37(2): 153-159.
Monroe, D. G., B. J. Getz, et al. (2003). "Estrogen receptor isoform-specific regulation of endogenous gene expression in human osteoblastic cell lines expressing either ERalpha or ERbeta." J Cell Biochem 90(2): 315-326.
Morani, A., R. P. Barros, et al. (2006). "Lung dysfunction causes systemic hypoxia in estrogen receptor beta knockout (ERbeta-/-) mice." Proc Natl Acad Sci U S A 103(18): 7165-7169.
Mostertz, W., M. Stevenson, et al. (2010). "Age- and sex-specific genomic profiles in non-small cell lung cancer." JAMA 303(6): 535-543.
Nakamura, H., N. Kawasaki, et al. (2006). "Survival impact of epidermal growth factor receptor overexpression in patients with non-small cell lung cancer: a meta-analysis." Thorax 61(2): 140-145.
Nicholson, R. I., J. M. Gee, et al. (2001). "EGFR and cancer prognosis." Eur J Cancer 37 Suppl 4: S9-15.
Nilsson, S., S. Makela, et al. (2001). "Mechanisms of estrogen action." Physiol Rev 81(4): 1535-1565.
Normanno, N., A. De Luca, et al. (2006). "Epidermal growth factor receptor (EGFR) signaling in cancer." Gene 366(1): 2-16.
Nose, N., K. Sugio, et al. (2009). "Association between estrogen receptor-beta expression and epidermal growth factor receptor mutation in the postoperative prognosis of adenocarcinoma of the lung." J Clin Oncol 27(3): 411-417.
Nose, N., H. Uramoto, et al. (2011). "Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung." Lung Cancer 71(3): 350-355.
Oh, A. S., L. A. Lorant, et al. (2001). "Hyperactivation of MAPK induces loss of ERalpha expression in breast cancer cells." Mol Endocrinol 15(8): 1344-1359.
Okoh, V., A. Deoraj, et al. (2011). "Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer." Biochim Biophys Acta 1815(1): 115-133.
Olayioye, M. A., R. M. Neve, et al. (2000). "The ErbB signaling network: receptor heterodimerization in development and cancer." EMBO J 19(13): 3159-3167.
Omoto, Y., Y. Kobayashi, et al. (2001). "Expression, function, and clinical implications of the estrogen receptor beta in human lung cancers." Biochem Biophys Res Commun 285(2): 340-347.
Paez, J. G., P. A. Janne, et al. (2004). "EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy." Science 304(5676): 1497-1500.
Pao, W. and V. A. Miller (2005). "Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions." J Clin Oncol 23(11): 2556-2568.
Parkin, D. M., F. Bray, et al. (2005). "Global cancer statistics, 2002." CA Cancer J Clin 55(2): 74-108.
Patrone, C., T. N. Cassel, et al. (2003). "Regulation of postnatal lung development and homeostasis by estrogen receptor beta." Mol Cell Biol 23(23): 8542-8552.
Politi, K., M. F. Zakowski, et al. (2006). "Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors." Genes Dev 20(11): 1496-1510.
Ross, J. S., D. P. Schenkein, et al. (2004). "Targeted therapies for cancer 2004." Am J Clin Pathol 122(4): 598-609.
Sano, S., S. Itami, et al. (1999). "Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis." EMBO J 18(17): 4657-4668.
Scagliotti, G. V., G. Selvaggi, et al. (2004). "The biology of epidermal growth factor receptor in lung cancer." Clin Cancer Res 10(12 Pt 2): 4227s-4232s.
Schindler, C., D. E. Levy, et al. (2007). "JAK-STAT signaling: from interferons to cytokines." J Biol Chem 282(28): 20059-20063.
Schindler, C. and C. Plumlee (2008). "Inteferons pen the JAK-STAT pathway." Semin Cell Dev Biol 19(4): 311-318.
Schwartz, A. G., G. M. Prysak, et al. (2005). "Nuclear estrogen receptor beta in lung cancer: expression and survival differences by sex." Clin Cancer Res 11(20): 7280-7287.
Seki, Y., N. Suzuki, et al. (2004). "STAT3 and MAPK in human lung cancer tissues and suppression of oncogenic growth by JAB and dominant negative STAT3." Int J Oncol 24(4): 931-934.
Shao, H., H. Y. Cheng, et al. (2003). "Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor." Cancer Res 63(14): 3923-3930.
Shen, H., Y. Yuan, et al. (2010). "Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects." Biomed Pharmacother 64(2): 88-92.
Shepherd, F. A., J. Rodrigues Pereira, et al. (2005). "Erlotinib in previously treated non-small-cell lung cancer." N Engl J Med 353(2): 123-132.
Siddiquee, K., S. Zhang, et al. (2007). "Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity." Proc Natl Acad Sci U S A 104(18): 7391-7396.
Siegfried, J. M. (2001). "Women and lung cancer: does oestrogen play a role?" Lancet Oncol 2(8): 506-513.
Smith, C. L. (1998). "Cross-talk between peptide growth factor and estrogen receptor signaling pathways." Biol Reprod 58(3): 627-632.
Solakidi, S., A. M. Psarra, et al. (2005). "Differential subcellular distribution of estrogen receptor isoforms: localization of ERalpha in the nucleoli and ERbeta in the mitochondria of human osteosarcoma SaOS-2 and hepatocarcinoma HepG2 cell lines." Biochim Biophys Acta 1745(3): 382-392.
Song, L., J. Turkson, et al. (2003). "Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells." Oncogene 22(27): 4150-4165.
Sordella, R., D. W. Bell, et al. (2004). "Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways." Science 305(5687): 1163-1167.
Spiotto, M. T. and T. D. Chung (2000). "STAT3 mediates IL-6-induced growth inhibition in the human prostate cancer cell line LNCaP." Prostate 42(2): 88-98.
Stabile, L. P., S. Dacic, et al. (2011). "Combined analysis of estrogen receptor {beta}-1 and progesterone receptor expression identifies lung cancer patients with poor outcome." Clin Cancer Res 17(1): 154-164.
Stabile, L. P., A. L. Davis, et al. (2002). "Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen." Cancer Res 62(7): 2141-2150.
Stabile, L. P., J. S. Lyker, et al. (2005). "Combined targeting of the estrogen receptor and the epidermal growth factor receptor in non-small cell lung cancer shows enhanced antiproliferative effects." Cancer Res 65(4): 1459-1470.
Su, H. W., H. H. Yeh, et al. (2007). "Cell confluence-induced activation of signal transducer and activator of transcription-3 (Stat3) triggers epithelial dome formation via augmentation of sodium hydrogen exchanger-3 (NHE3) expression." J Biol Chem 282(13): 9883-9894.
Su, Y. W., T. X. Xie, et al. (2011). "IL-6 stabilizes Twist and enhances tumor cell motility in head and neck cancer cells through activation of casein kinase 2." PLoS One 6(4): e19412.
Subramanian, J. and R. Govindan (2007). "Lung cancer in never smokers: a review." J Clin Oncol 25(5): 561-570.
Sun, S., J. H. Schiller, et al. (2007). "Lung cancer in never smokers--a different disease." Nat Rev Cancer 7(10): 778-790.
Taioli, E. and E. L. Wynder (1994). "Re: Endocrine factors and adenocarcinoma of the lung in women." J Natl Cancer Inst 86(11): 869-870.
Takeda, K., T. Kaisho, et al. (1998). "Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice." J Immunol 161(9): 4652-4660.
Thomas, R. K., H. Greulich, et al. (2005). "Detection of oncogenic mutations in the EGFR gene in lung adenocarcinoma with differential sensitivity to EGFR tyrosine kinase inhibitors." Cold Spring Harb Symp Quant Biol 70: 73-81.
Thuresson-Klein, A., A. H. Moawad, et al. (1985). "Estrogen stimulates formation of lamellar bodies and release of surfactant in the rat fetal lung." Am J Obstet Gynecol 151(4): 506-514.
Toh, C. K., B. Ahmad, et al. (2010). "Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas." J Thorac Oncol 5(1): 17-22.
Tolon, R. M., A. I. Castillo, et al. (2000). "Association with Ets-1 causes ligand- and AF2-independent activation of nuclear receptors." Mol Cell Biol 20(23): 8793-8802.
Tremblay, A., G. B. Tremblay, et al. (1999). "Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1." Mol Cell 3(4): 513-519.
Turkson, J., T. Bowman, et al. (1998). "Stat3 activation by Src induces specific gene regulation and is required for cell transformation." Mol Cell Biol 18(5): 2545-2552.
Walter, P., S. Green, et al. (1985). "Cloning of the human estrogen receptor cDNA." Proc Natl Acad Sci U S A 82(23): 7889-7893.
Weigert, C., M. Dufer, et al. (2007). "Upregulation of IL-6 mRNA by IL-6 in skeletal muscle cells: role of IL-6 mRNA stabilization and Ca2+-dependent mechanisms." Am J Physiol Cell Physiol 293(3): C1139-1147.
Weinberg, O. K., D. C. Marquez-Garban, et al. (2005). "Aromatase inhibitors in human lung cancer therapy." Cancer Res 65(24): 11287-11291.
Wu, C. T., Y. L. Chang, et al. (2005). "The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers." J Thorac Cardiovasc Surg 130(4): 979-986.
Yamamoto, T., T. Matsuda, et al. (2000). "Cross-talk between signal transducer and activator of transcription 3 and estrogen receptor signaling." FEBS Lett 486(2): 143-148.
Yang, S. H., R. Liu, et al. (2004). "Mitochondrial localization of estrogen receptor beta." Proc Natl Acad Sci U S A 101(12): 4130-4135.
Yang, S. H., S. N. Sarkar, et al. (2009). "Estrogen receptor beta as a mitochondrial vulnerability factor." J Biol Chem 284(14): 9540-9548.
Yeh, H. H., W. W. Lai, et al. (2006). "Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion." Oncogene 25(31): 4300-4309.
Youlden, D. R., S. M. Cramb, et al. (2008). "The International Epidemiology of Lung Cancer: geographical distribution and secular trends." J Thorac Oncol 3(8): 819-831.
Yu, H. and R. Jove (2004). "The STATs of cancer--new molecular targets come of age." Nat Rev Cancer 4(2): 97-105.
Zhang, G., X. Liu, et al. (2009). "Estrogen receptor beta functions through nongenomic mechanisms in lung cancer cells." Mol Endocrinol 23(2): 146-156.
Zhang, G., N. Yanamala, et al. (2010). "Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells." Mol Endocrinol 24(9): 1737-1747.
Zhao, C., K. Dahlman-Wright, et al. (2008). "Estrogen receptor beta: an overview and update." Nucl Recept Signal 6: e003.
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