NSC 74859通过抑制STAT3的表达可以增加Cetuximab对肝癌细胞的生长抑制作用
|
摘要
背景
肝癌的早期诊断相当困难,并且缺乏有效的治疗方法,因而多数患者预后不佳。西妥昔单抗(Cetuximab,一种表皮生长因子受体抑制剂)是一种在其他癌症治疗中非常有效的药物,如直肠癌。但是在肝癌患者的临床试验中却疗效欠佳。信号转导与转录激活子(Signal transducers and activators of transcription,简称Stat)家族是一组重要的调控细胞增殖和生长,侵袭,转移和血管生成的细胞因子,尤其是其中的Stat3。先前的研究已经表明,肝癌组织中Stat3的表达较正常肝脏组织高,可作为肝癌化疗药物的敏感性决定因素。而关于Cetuximab在肝癌患者中耐药机理的研究至今未见报道。
材料和方法
本实验选用Hep G2和SK-HEP 1两种肝癌细胞株,通过MTT法比较二者对于Cetuximab的耐受程度。同时采用NSC 74859作为Stat3通路的特异性阻断剂,研究阻断或不阻断Stat3通路下两种细胞株对于Cetuximab的耐药情况。采用SiRNA转染使细胞株丧失或获得Stat3的表达,通过RT-PCR和Western blot检测EGFR, Stat3和p-Stat3在不同用药组的表达水平。
结果
我们在研究中发现,Hep G2细胞株比SK-HEP 1细胞株对单独使用Cetuximab更敏感。p-Stat3蛋白在SK-HEP 1中的表达明显高于在Hep G2中的表达。用NSC74859或者Stat3的SiRNA阻断p-Stat3的表达可明显提高Cetuximab对两种细胞株的生长抑制作用,尤其是SK-HEP 1.而转染了Stat3基因的Hep G2细胞株较对照组则丧失了对Cetuximab敏感性。
结论
我们的研究首次发现,通过NSC 74859抑制p-Stat3的表达可以增强肝癌细胞株对于Cetuximab的敏感性,这表明将NSC 74859与Cetuximab联合应用将可能是未来一种有效的肝癌治疗方法。
Background
HCC is a troublesome tumor with a poor prognosis due to late diagnoses and a lack of effective treatment options. Cetuximab(an Epidermal growth factor receptor inhibitor) is an effective drug in other cancers such as rectal cancer which shown only modest efficacy in clinical trials of HCC. Signal transducers and activators of transcription (STAT) family of transcriptional factors were originally identified as the critical mediators of cytokine responses and subsequently implicated in diverse external stimuli-initiated cellular signaling. Stat3 is a member of STAT family which has been considered as an oncogene based on its ability to transactivate a number of genes whose products are involved in cell proliferation and survival, invasion, metastasis and angiogenesis. Previous studies have shown that the level of Stat3 in hepatic tumor tissue was higher than in normal tissue and expression of Stat3 may be as a determinant of sensitivity of HCC to antitumor drugs. But the relationship of Stat3 and the mechanism of resistance to Cetuximab in liver cancer patients has not been reported.
Materials and Methods
We compared the tolerance for Cetuximab between two HCC cell lines, Hep G2 and SK-HEP 1 by MTT. We used the Stat3 pathway specific blocker NSC 74859 to block the Stat3 pathway. And we compared the percentage of resistance to Cetuximab of the two cell lines with or without NSC 74859. Hep G2 and SK-HEP 1 cells were transfected with Nagative SiRNA, Stat3 SiRNA and wild type stat3. EGFR, Stat3, and p-Stat3 expression in different levels of treatment group were estimated by RT-PCR and Western blot.
Result
In our study, we found that Hep G2 was more sensitive to cetuximab than Sk-Hep-1. We also found that the expression of p-stat3 in Sk-Hep-1 cell line was higher than that in Hep G2 cell line. Blocking p-stat3 using NSC 74859 or an small interfere RNA(stat3 SiRNA) boost the cetuximab's effect in both cell lines especially in Sk-Hep-1 while transfection stat3 cDNA plasmid into Hep G2 lost the sensitivity to cetuximab compared to control Hep G2.
Conclusion
Our study first found that p-stat3 inhibition by NSC74859 mediate sensitivity to cetuximab, suggesting that the combined NSC74859 with cetuximab would be an effective therapy for HCC.
肝癌的早期诊断相当困难,并且缺乏有效的治疗方法,因而多数患者预后不佳。西妥昔单抗(Cetuximab,一种表皮生长因子受体抑制剂)是一种在其他癌症治疗中非常有效的药物,如直肠癌。但是在肝癌患者的临床试验中却疗效欠佳。信号转导与转录激活子(Signal transducers and activators of transcription,简称Stat)家族是一组重要的调控细胞增殖和生长,侵袭,转移和血管生成的细胞因子,尤其是其中的Stat3。先前的研究已经表明,肝癌组织中Stat3的表达较正常肝脏组织高,可作为肝癌化疗药物的敏感性决定因素。而关于Cetuximab在肝癌患者中耐药机理的研究至今未见报道。
材料和方法
本实验选用Hep G2和SK-HEP 1两种肝癌细胞株,通过MTT法比较二者对于Cetuximab的耐受程度。同时采用NSC 74859作为Stat3通路的特异性阻断剂,研究阻断或不阻断Stat3通路下两种细胞株对于Cetuximab的耐药情况。采用SiRNA转染使细胞株丧失或获得Stat3的表达,通过RT-PCR和Western blot检测EGFR, Stat3和p-Stat3在不同用药组的表达水平。
结果
我们在研究中发现,Hep G2细胞株比SK-HEP 1细胞株对单独使用Cetuximab更敏感。p-Stat3蛋白在SK-HEP 1中的表达明显高于在Hep G2中的表达。用NSC74859或者Stat3的SiRNA阻断p-Stat3的表达可明显提高Cetuximab对两种细胞株的生长抑制作用,尤其是SK-HEP 1.而转染了Stat3基因的Hep G2细胞株较对照组则丧失了对Cetuximab敏感性。
结论
我们的研究首次发现,通过NSC 74859抑制p-Stat3的表达可以增强肝癌细胞株对于Cetuximab的敏感性,这表明将NSC 74859与Cetuximab联合应用将可能是未来一种有效的肝癌治疗方法。
Background
HCC is a troublesome tumor with a poor prognosis due to late diagnoses and a lack of effective treatment options. Cetuximab(an Epidermal growth factor receptor inhibitor) is an effective drug in other cancers such as rectal cancer which shown only modest efficacy in clinical trials of HCC. Signal transducers and activators of transcription (STAT) family of transcriptional factors were originally identified as the critical mediators of cytokine responses and subsequently implicated in diverse external stimuli-initiated cellular signaling. Stat3 is a member of STAT family which has been considered as an oncogene based on its ability to transactivate a number of genes whose products are involved in cell proliferation and survival, invasion, metastasis and angiogenesis. Previous studies have shown that the level of Stat3 in hepatic tumor tissue was higher than in normal tissue and expression of Stat3 may be as a determinant of sensitivity of HCC to antitumor drugs. But the relationship of Stat3 and the mechanism of resistance to Cetuximab in liver cancer patients has not been reported.
Materials and Methods
We compared the tolerance for Cetuximab between two HCC cell lines, Hep G2 and SK-HEP 1 by MTT. We used the Stat3 pathway specific blocker NSC 74859 to block the Stat3 pathway. And we compared the percentage of resistance to Cetuximab of the two cell lines with or without NSC 74859. Hep G2 and SK-HEP 1 cells were transfected with Nagative SiRNA, Stat3 SiRNA and wild type stat3. EGFR, Stat3, and p-Stat3 expression in different levels of treatment group were estimated by RT-PCR and Western blot.
Result
In our study, we found that Hep G2 was more sensitive to cetuximab than Sk-Hep-1. We also found that the expression of p-stat3 in Sk-Hep-1 cell line was higher than that in Hep G2 cell line. Blocking p-stat3 using NSC 74859 or an small interfere RNA(stat3 SiRNA) boost the cetuximab's effect in both cell lines especially in Sk-Hep-1 while transfection stat3 cDNA plasmid into Hep G2 lost the sensitivity to cetuximab compared to control Hep G2.
Conclusion
Our study first found that p-stat3 inhibition by NSC74859 mediate sensitivity to cetuximab, suggesting that the combined NSC74859 with cetuximab would be an effective therapy for HCC.
引文
1、 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,2002. CA Cancer J Clin2005;55:74-108.
2、 Tang ZY,Ye SL, Liu YK, eta 1. A decade's studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130:187-96.
3、 Zhu AX. Systemic therapy of advanced hepatocellular carcinoma:how hopeful should we be? Oncologist 2006; 11:790-800.
4、 Ciardiello F, Tortora G A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958-70.
5、 Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787-99.
6、 Harari PM. Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer 2004; 11:689-708.
7、 Daveau M, Scotte M, Francois A, Coulouarn C, Ros G, Tallet Y, et al. Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog 2003;36:130-41.
8、 Zhao YN, Cao J, Wu FX, Ou C, Yuan WP, Mo QG, et al. Expression and significance of EGF mRNA and EGFR mRNA in hepatocellular carcinoma. Ai Zheng 2004;23:762-6.
9、 Ito Y, Takeda T, Sakon M, Tsujimoto M, Higashiyama S, Noda K, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 2001;84:1377-83.
10、 Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23:6657-63.
11、 Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007; 110:1059-67.
12、 Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110:581-9.
13、 Yu H, Jove R. The STATS of cancerLnew molecular targets come of age.Nat Rev Cancer 2004;4:97-105.
14、 Tannapfel A, Anhalt K,Hausermann P, et al. Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol 2003; 201:238-49.
15、 Lin L, Amin R, Gallicano GI, Glasgow E, Jogunoori W, Jessup JM, et al. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling. Oncogene.2009 Feb 19;28(7):961-72.
16、 Gariboldi MB, Ravizza R, Molteni R, Osella D, Gabano E, et al. Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line. Cancer Lett.2007 Dec 18;258(2):181-8. Epub 2007 Oct 24.
17、 Fan Z, Lu Y, Wu XP, Mendelsohn J. Antibody-induced epidermal growth-factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma-cells. J Biol Chem 1994;269:27595-602.
18、 Prewett M, Rockwell P, Rockwell RF, Giorgio NA, Mendelsohn J, Scher HI, et al. The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J Immunother 1996;19:419-27.
19、 Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H. EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol.2005 Nov 25;70(11):1568-78. Epub 2005 Oct 13.
20、 Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002;62:200-7.
21、 Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, et al. Impact of IGF-IR/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 2006; 119:2557-66.
22、 Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res.2008 Apr 1;68(7):2391-9.
23、 Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000; 19:2474-88.
24、 Silva CM. Oncogene.2004 Oct 18;23(48):8017-23. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis.
25、 Berclaz G, Altermatt HJ, Rohrbach V, et al. EGFR dependent expression of Stat3 (but not STAT1) in breast cancer. Int J Oncol 2001;19:1155-60.
26、 Campbell CL, Jiang Z, Savarese DM, et al. Increased expression of the interleukin-11 receptor and evidence of Stat3 activation in prostate carcinoma. Am J Pathol 2001;158:25-32.
27、 Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR et al. (2007). Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 104:7391-7396.
1 Thiery JP:Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002,2:442-454.
2 Thiery JP:Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003,15:740-746.
3 Gru " nert S, Jechlinger M, Beug H:Diverse cellular and molecular mechanisms contribute to epithelial plasticity andmetastasis. Nat Rev Mol Cell Biol 2003, 4:657-665.
4 Kalluri R, Neilson EG:Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003,112:1776-1784.
5 Nawshad A, LaGamba D, Hay ED:Transforming growth factor b (TGFb) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 2004,49:675-689.
6 Balkwill F:Cancer and the chemokine network. Nat Rev Cancer 2004,4:540-550.
7 Eger A, Mikulits W:Models of epithelial-mesenchymal transition. Drug Discovery Today:Disease Models.2005.
8 Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL:Activation of the Erk pathway is required for TGF-bl-induced EMT in vitro. Neoplasia 2004, 6:603-610.
9 Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, Brugge JS:Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 2004,101:1257-1262.
10 Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL:Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem 2004,279:24505-24513.
11 Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J:Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 2003,100:8430-8435.
12 Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J:The transcriptional response to Raf activation is almost completely dependent on mitogen-activated protein kinase kinase activity and shows a major autocrine component. Mol Biol Cell 2004,15:3450-3463.
13 PollakMN, Schernhammer ES, Hankinson SE:Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004,4:505-518.
14 Jechlinger M, Grunert S, Tamir IH, Janda E, Ludemann S, Waerner T, Seither P, Weith A, Beug H, Kraut N:Expression profiling of epithelial plasticity in tumor progression. Oncogene 2003,22:7155-7169.
15 Nelson WJ, Nusse R:Convergence of Wnt, b-catenin, and cadherin pathways. Science 2004,303:1483-1487.
16 Liebner S, Cattelino A, Gallini R, Rudini N, Iurlaro M, Piccolo S, Dejana E: b-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 2004,166:359-367.
17 Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J, Aranda S, Palomo S, McCormick F, Izpisua-Belmonte JC et al.:Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 2004,18:99-115.
18 Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP:Integration of TGF-b/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 2004,23:1155-1165.
19 Pasca di Magliano M, Hebrok M:Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003,3:903-911.
20 Karhadkar SS, BovaGS, Abdallah N, Dhara S,Gardner D,Maitra A, Isaacs JT, Berman DM, Beachy PA:Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004,431:707-712.
21 Mullor JL, Dahmane N, Sun T, Ruiz i Altaba A:Wnt signals are targets and mediators of Gli function. Curr Biol 2001,11:769-773.
22 Kang Y, Massague J:Epithelial-mesenchymal transitions:twist in development and metastasis. Cell 2004,118:277-279.
23 Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T:NF-kB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004, 114:569-581.
24 Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM:Glycogen synthase kinase-3 is an endogenous inhibitor ofSnail transcription:implications for the epithelial-mesenchymal transition. J Cell Biol 2005,168:29-33.
25 Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC:Dual regulation of Snail by GSK-3b-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004,6:931-940.
26 Yu H, Jove R:The STATS of cancer - new molecular targets come of age. Nat Rev Cancer 2004,4:97-105.
27 Yeatman TJ:A renaissance for SRC. Nat Rev Cancer 2004,4:470-480.
28 Yamashita S, Miyagi C, Fukada T, Kagara N, Che YS, Hirano T:Zinc transporter LIVI controls epithelial-mesenchymaltransition in zebrafish gastrula organizer. Nature 2004,429:298-302.
29 Taylor KM, Nicholson RI:The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim Biophys Acta 2003,1611:16-30.
30 Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA:MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 2003,113:207-219.
31 Humbert P, Russell S, Richardson H:Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays 2003,25:542-553.
32 Pagliarini RA, Xu T:A genetic screen in Drosophila for metastatic behavior. Science 2003,302:1227-1231.
33 Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL: Regulation of the polarity protein Par6 by TGFb receptors controls epithelial cell plasticity. Science 2005,307:1603-1609.
34 Pantel K, Brakenhoff RH:Dissecting the metastatic cascade. Nat Rev Cancer 2004,4:448-456.
35 Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA:Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117:927-939.
36 Yingling JM, Blanchard KL, Sawyer JS:Development of TGF-bsignalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004,3:1011-1022.
37 Condeelis J, Segall JE:Intravital imaging of cell movement in tumours. Nat Rev Cancer 2003,3:921-930.
38 Gschwind A, Fischer OM, Ullrich A:The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004,4:361-370.
39 Downward J:Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003,3:11-22.
40 Karin M, Yamamoto Y, Wang QM:The IKK NF-kB system:a treasure trove for drug development. Nat Rev Drug Discov 2004,3:17-26.
41 Bilder D:Epithelial polarity and proliferation control:links from the Drosophila neoplastic tumor suppressors.Genes Dev 2004,18:1909-1925.
42 Besson A, Assoian RK, Roberts JM:Regulation of the cytoskeleton:an oncogenic function for CDK inhibitors? Nat Rev Cancer 2004,4:948-955.
2、 Tang ZY,Ye SL, Liu YK, eta 1. A decade's studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130:187-96.
3、 Zhu AX. Systemic therapy of advanced hepatocellular carcinoma:how hopeful should we be? Oncologist 2006; 11:790-800.
4、 Ciardiello F, Tortora G A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958-70.
5、 Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003;21:2787-99.
6、 Harari PM. Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer 2004; 11:689-708.
7、 Daveau M, Scotte M, Francois A, Coulouarn C, Ros G, Tallet Y, et al. Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog 2003;36:130-41.
8、 Zhao YN, Cao J, Wu FX, Ou C, Yuan WP, Mo QG, et al. Expression and significance of EGF mRNA and EGFR mRNA in hepatocellular carcinoma. Ai Zheng 2004;23:762-6.
9、 Ito Y, Takeda T, Sakon M, Tsujimoto M, Higashiyama S, Noda K, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 2001;84:1377-83.
10、 Philip PA, Mahoney MR, Allmer C, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23:6657-63.
11、 Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007; 110:1059-67.
12、 Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110:581-9.
13、 Yu H, Jove R. The STATS of cancerLnew molecular targets come of age.Nat Rev Cancer 2004;4:97-105.
14、 Tannapfel A, Anhalt K,Hausermann P, et al. Identification of novel proteins associated with hepatocellular carcinomas using protein microarrays. J Pathol 2003; 201:238-49.
15、 Lin L, Amin R, Gallicano GI, Glasgow E, Jogunoori W, Jessup JM, et al. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling. Oncogene.2009 Feb 19;28(7):961-72.
16、 Gariboldi MB, Ravizza R, Molteni R, Osella D, Gabano E, et al. Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line. Cancer Lett.2007 Dec 18;258(2):181-8. Epub 2007 Oct 24.
17、 Fan Z, Lu Y, Wu XP, Mendelsohn J. Antibody-induced epidermal growth-factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma-cells. J Biol Chem 1994;269:27595-602.
18、 Prewett M, Rockwell P, Rockwell RF, Giorgio NA, Mendelsohn J, Scher HI, et al. The biologic effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate carcinoma. J Immunother 1996;19:419-27.
19、 Huether A, Hopfner M, Baradari V, Schuppan D, Scherubl H. EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol.2005 Nov 25;70(11):1568-78. Epub 2005 Oct 13.
20、 Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002;62:200-7.
21、 Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, et al. Impact of IGF-IR/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 2006; 119:2557-66.
22、 Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res.2008 Apr 1;68(7):2391-9.
23、 Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000; 19:2474-88.
24、 Silva CM. Oncogene.2004 Oct 18;23(48):8017-23. Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis.
25、 Berclaz G, Altermatt HJ, Rohrbach V, et al. EGFR dependent expression of Stat3 (but not STAT1) in breast cancer. Int J Oncol 2001;19:1155-60.
26、 Campbell CL, Jiang Z, Savarese DM, et al. Increased expression of the interleukin-11 receptor and evidence of Stat3 activation in prostate carcinoma. Am J Pathol 2001;158:25-32.
27、 Siddiquee K, Zhang S, Guida WC, Blaskovich MA, Greedy B, Lawrence HR et al. (2007). Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci USA 104:7391-7396.
1 Thiery JP:Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002,2:442-454.
2 Thiery JP:Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003,15:740-746.
3 Gru " nert S, Jechlinger M, Beug H:Diverse cellular and molecular mechanisms contribute to epithelial plasticity andmetastasis. Nat Rev Mol Cell Biol 2003, 4:657-665.
4 Kalluri R, Neilson EG:Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003,112:1776-1784.
5 Nawshad A, LaGamba D, Hay ED:Transforming growth factor b (TGFb) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 2004,49:675-689.
6 Balkwill F:Cancer and the chemokine network. Nat Rev Cancer 2004,4:540-550.
7 Eger A, Mikulits W:Models of epithelial-mesenchymal transition. Drug Discovery Today:Disease Models.2005.
8 Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL:Activation of the Erk pathway is required for TGF-bl-induced EMT in vitro. Neoplasia 2004, 6:603-610.
9 Seton-Rogers SE, Lu Y, Hines LM, Koundinya M, LaBaer J, Muthuswamy SK, Brugge JS:Cooperation of the ErbB2 receptor and transforming growth factor beta in induction of migration and invasion in mammary epithelial cells. Proc Natl Acad Sci USA 2004,101:1257-1262.
10 Ueda Y, Wang S, Dumont N, Yi JY, Koh Y, Arteaga CL:Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. J Biol Chem 2004,279:24505-24513.
11 Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J:Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci USA 2003,100:8430-8435.
12 Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J:The transcriptional response to Raf activation is almost completely dependent on mitogen-activated protein kinase kinase activity and shows a major autocrine component. Mol Biol Cell 2004,15:3450-3463.
13 PollakMN, Schernhammer ES, Hankinson SE:Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004,4:505-518.
14 Jechlinger M, Grunert S, Tamir IH, Janda E, Ludemann S, Waerner T, Seither P, Weith A, Beug H, Kraut N:Expression profiling of epithelial plasticity in tumor progression. Oncogene 2003,22:7155-7169.
15 Nelson WJ, Nusse R:Convergence of Wnt, b-catenin, and cadherin pathways. Science 2004,303:1483-1487.
16 Liebner S, Cattelino A, Gallini R, Rudini N, Iurlaro M, Piccolo S, Dejana E: b-catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 2004,166:359-367.
17 Timmerman LA, Grego-Bessa J, Raya A, Bertran E, Perez-Pomares JM, Diez J, Aranda S, Palomo S, McCormick F, Izpisua-Belmonte JC et al.:Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 2004,18:99-115.
18 Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP:Integration of TGF-b/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 2004,23:1155-1165.
19 Pasca di Magliano M, Hebrok M:Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003,3:903-911.
20 Karhadkar SS, BovaGS, Abdallah N, Dhara S,Gardner D,Maitra A, Isaacs JT, Berman DM, Beachy PA:Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 2004,431:707-712.
21 Mullor JL, Dahmane N, Sun T, Ruiz i Altaba A:Wnt signals are targets and mediators of Gli function. Curr Biol 2001,11:769-773.
22 Kang Y, Massague J:Epithelial-mesenchymal transitions:twist in development and metastasis. Cell 2004,118:277-279.
23 Huber MA, Azoitei N, Baumann B, Grunert S, Sommer A, Pehamberger H, Kraut N, Beug H, Wirth T:NF-kB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004, 114:569-581.
24 Bachelder RE, Yoon SO, Franci C, de Herreros AG, Mercurio AM:Glycogen synthase kinase-3 is an endogenous inhibitor ofSnail transcription:implications for the epithelial-mesenchymal transition. J Cell Biol 2005,168:29-33.
25 Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC:Dual regulation of Snail by GSK-3b-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004,6:931-940.
26 Yu H, Jove R:The STATS of cancer - new molecular targets come of age. Nat Rev Cancer 2004,4:97-105.
27 Yeatman TJ:A renaissance for SRC. Nat Rev Cancer 2004,4:470-480.
28 Yamashita S, Miyagi C, Fukada T, Kagara N, Che YS, Hirano T:Zinc transporter LIVI controls epithelial-mesenchymaltransition in zebrafish gastrula organizer. Nature 2004,429:298-302.
29 Taylor KM, Nicholson RI:The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim Biophys Acta 2003,1611:16-30.
30 Fujita N, Jaye DL, Kajita M, Geigerman C, Moreno CS, Wade PA:MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell 2003,113:207-219.
31 Humbert P, Russell S, Richardson H:Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer. Bioessays 2003,25:542-553.
32 Pagliarini RA, Xu T:A genetic screen in Drosophila for metastatic behavior. Science 2003,302:1227-1231.
33 Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL: Regulation of the polarity protein Par6 by TGFb receptors controls epithelial cell plasticity. Science 2005,307:1603-1609.
34 Pantel K, Brakenhoff RH:Dissecting the metastatic cascade. Nat Rev Cancer 2004,4:448-456.
35 Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA:Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117:927-939.
36 Yingling JM, Blanchard KL, Sawyer JS:Development of TGF-bsignalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004,3:1011-1022.
37 Condeelis J, Segall JE:Intravital imaging of cell movement in tumours. Nat Rev Cancer 2003,3:921-930.
38 Gschwind A, Fischer OM, Ullrich A:The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004,4:361-370.
39 Downward J:Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003,3:11-22.
40 Karin M, Yamamoto Y, Wang QM:The IKK NF-kB system:a treasure trove for drug development. Nat Rev Drug Discov 2004,3:17-26.
41 Bilder D:Epithelial polarity and proliferation control:links from the Drosophila neoplastic tumor suppressors.Genes Dev 2004,18:1909-1925.
42 Besson A, Assoian RK, Roberts JM:Regulation of the cytoskeleton:an oncogenic function for CDK inhibitors? Nat Rev Cancer 2004,4:948-955.