STAT3信号通路对大肠癌肿瘤血管生成的影响及其作用机理的初步研究
|
摘要
目的
(1)探讨大肠癌组织中STAT3表达,并研究STAT3表达与肿瘤血管生成的相关性。
(2)观察STAT3基因沉默对大肠癌HT-29细胞的增殖能力及细胞周期变化的影响。
(3)观察STAT3基因沉默对大肠癌HT-29细胞裸鼠皮下种植瘤生长的影响。
(4)在裸鼠体内观察STAT3信号对肿瘤血管生成的影响,并初步探讨其作用机理。
方法
(1)取临床大肠癌石蜡标本,免疫组化检测STAT3、CD34的表达情况,通过CD34的表达情况计数MVD,应用统计学方法分析STAT3表达与MVD的相关性。
(2)设计合成3对靶向STAT3基因的siRNA序列,通过筛选获得最佳siRNA序列,构建shRNA表达序列并连接到慢病毒载体pRNAT-U6.2/Lenti中,获得pRNAT-shSTAT3重组慢病毒质粒,经酶切和测序鉴定正确后,进行包装产生病毒液,测定其滴度。将包装获得的病毒液感染大肠癌HT-29细胞,筛选扩增获得阳性细胞株HT-29-shSTAT3。同法,用慢病毒空质粒包装后产生的病毒液感染大肠癌HT-29细胞,筛选获得阳性克隆细胞株HT-29-GFP。Real-time PCR和Western blot检测shRNA对STAT3基因的沉默效率,MTT法检测细胞生长情况,流式细胞仪检测细胞周期变化。
(3)分别将HT-29、HT-29-GFP、HT-29-shSTAT3细胞注射入裸鼠皮下成瘤,定期测量各组肿瘤体积变化。
(4) 30天后处死裸鼠,取各组瘤组织通过免疫组化检测STAT3和CD34的表达情况,并计数MVD。血管生成基因芯片检测肿瘤组织内血管生成和抑制因子的表达情况。
结果
(1)临床大肠癌组织中STAT3蛋白表达阳性率为63.6%,显著高于正常大肠组织;大肠癌组织中MVD为47.55±12.15,而正常大肠组织中MVD为11.67±1.08,两者相比具有显著差异(P<0.01);大肠癌组织中STAT3的表达和MVD与肿瘤的恶性程度、Duke’s分期及淋巴结转移有关(P<0.05)。相关分析表明STAT3表达与MVD呈显著正相关(r=0.788)。
(2)酶切鉴定和测序结果证实STAT3shRNA核苷酸序列插入正确,成功包装后产生病毒悬液的滴度为2×107TU/ml。病毒感染大肠癌HT-29细胞,经G418筛选获得稳定细胞株,Real-time PCR和Western blot分别显示HT-29-shSTAT3细胞STAT3 mRNA的表达和蛋白明显减弱,表达量分别为16.9±2.1%、18.8±2.4%(P<0.01)。MTT结果显示STAT3基因沉默后的大肠癌HT-29细胞生长明显减慢,G0/G1期细胞占68.73±2.88%,S期细胞占22.93±1.10%,与对照组相比差异显著(P<0.01)。
(3)各组裸鼠在接种肿瘤细胞后均成瘤,至接种后第15天,HT-29-shSTAT3细胞接种组肿瘤体积明显小于HT-29和HT-29-GFP细胞接种组(P<0.05);至接种后第30天差异更为显著(P<0.01),肿瘤生长抑制率为57.46%。
(4)取肿瘤组织行免疫组化检查,见HT-29和HT-29-GFP组肿瘤内有多量的微血管分布,MVD分别为28.73±5.11,27.60±4.27,两者无显著差异(P>0.05);而HT-29-shSTAT3组微血管明显减少,MVD为9.80±3.02,与前两组相比,差异显著(P<0.01)。
(5)血管生成基因芯片结果提示在HT-29-shSTAT3裸鼠组大肠癌组织中,表达下调的基因有15条,上调的基因有7条。
结论
(1)临床大肠癌组织中存在STAT3的高表达,STAT3的表达可能在大肠癌的病程发展及转移过程中发挥重要的作用。大肠癌的发生过程中STAT3信号与肿瘤血管的生成密切相关。
(2) STAT3信号通路对于大肠癌HT-29细胞生长起着重要的作用,沉默STAT3基因表达的大肠癌HT-29细胞生长速度明显减慢,细胞阻滞于G0/G1期。
(3)抑制STAT3信号可以抑制大肠癌HT-29细胞裸鼠皮下种植瘤的生长。
(4)在大肠癌组织中,STAT3信号可以促进肿瘤血管生成。
(5)在大肠癌肿瘤血管生成过程中,STAT3信号可能通过调控VEGF-A、MMP-2、ECGF1、EPHB4、IGF1、NRP1、NRP2、STAB1、TNF、VEGFR-1、BAI1的表达来促进新生血管的生成。
Objective
(1) To explore the expressing of STAT3 in human colorectal carcinoma and study the impact on angiogenesis.
(2) To observe the impact of STAT3 gene silencing on HT-29 cell growth and cell cycle distribution.
(3) To observe the effect of STAT3 signal on tumor growth of human colorectal carcinoma in nude mice.
(4) To investigate the effect of STAT3 signaling pathway on tumor angiogenesis of human colorectal carcinoma in nude mice, and probe the primary mechanism.
Methods
(1) STAT3 and CD34 expressing in the clinical colorectal carcinomas were studied by the way of immunohistochemistry. MVD were counted according to CD34 expression in tumor tissues. The correlation between the expression of STAT3 and MVD was statistically analyzed.
(2) Three different siRNAs of STAT3 were designed and synthesized. After being screened, the most effective siRNA was found. According to this sequence, the short hairpin DNA of STAT3 was constructed. The shRNA duplex was ligated into the recombinant vector pRNAT-U6.2/Lenti. The recombinant vector was conformed by the restriction map and DNA sequencing. The correct recombinant lentiviral vectors were packaged in 293T cells. Viruses in the supernatant were collected and the titer was measured. HT-29 cells transfected with viruses were selected by G418 and transfected cells were gained and harvested. Real-time PCR and Western blot were used to detect the interference effects. Cell growth was assessed by MTT assay and cell cycle distribution was detected by flow cytometry.
(3) HT-29, HT-29-GFP and HT-29-shSTAT3 cells were respectively injected subcutaneously into the back of the nude mice of each group. During the tumor growth, the appearance and size of each tumor were examined.
(4) On 30th day all mice were killed. Tumor tissues were removed for histopatho- logical and CD34 immunohistochemical analysis and taken to extract total RNA for angiogenesis superarray assay.
Results
(1) The positive rate of STAT3 expressing in colorectal carcinomas was 63.6%, which was significantly higher than that in the normal group(P<0.01). MVD in colorectal carcinoma tissus was 47.55±12.15, which was significantly higher than that in the normal group(P<0.01). In colorectal carcinoma, the positive rate of STAT3 expression and MVD were closely related to malignancy degree、Duke’s stage and lymph node metastasis (P<0.05), and MVD was closely correlated to the expression of STAT3(r=0.788).
(2) The restriction map and DNA sequencing demonstrated that the recombinant lentiviral vector of RNA interference of STAT3 gene was constructed successfully. Virus particles were packaged in 293T cells, and the title of viruses was 2×107 TU/ml. In HT-29 cells transfected with viruses effectively, the expressing level of STAT3 was down-regulated as Real-time PCR and Western blot analyses demonasrated. In transfected group, MTT assay showed the growth of HT-29 cells was suppressed and FCM assay indicated the proportion of cells at G0/G1 and S phase was 68.73±2.88% and 22.93±1.10% respectively, which was great different from that of the control group (P<0.01).
(3) A tumor was formed in every nude mouse. On day 15 after inoculating, tumor volums of the HT-29-shSTAT3 group were less than those of HT-29 group and HT-29-GFP group (P<0.05). On day 30 after inoculating, the difference was more obvious (P<0.01), the inhibitory rate of tumor growth was 57.46%.
(4) MVD in the HT-29-shSTAT3 group was less than that in the other two groups (P<0.01).
(5) The result of angiogenesis superarray indicated that there were 15 down- regulated genes and 7 up-regulated genes in tumor tissues of the HT-29-shSTAT3 mice group.
Conclusions
(1) STAT3 expressing in colorectal carcinoma is significantly higher. It may play an important role in the development and metastasis of colorectal carcinoma. It is suggested that angiogenesis is closely correlated to STAT3 signaling pathway in colorectal carcinoma.
(2) STAT3 singnaling pathway plays an important role in HT-29 cells growth. STAT3 targeting shRNA can silence the STAT3 gene remarkably, induce HT-29 cell growth inhibition and block cell cycle at G0/G1 phase.
(3) In nude mice, STAT3 singnal is important to the growth of human colorectal carcinoma.
(4) In human colorectal carcinoma, STAT3 signal can promote angiogenesis.
(5) In human colorectal carcinoma, STAT3 singnal may participate in regulating angiogenesis through modulating expression of VEGF-A, MMP-2, ECGF1, EPHB4, IGF1, NRP1, NRP2, STAB1, TNF,VEGFR-1 and BAI1.
(1)探讨大肠癌组织中STAT3表达,并研究STAT3表达与肿瘤血管生成的相关性。
(2)观察STAT3基因沉默对大肠癌HT-29细胞的增殖能力及细胞周期变化的影响。
(3)观察STAT3基因沉默对大肠癌HT-29细胞裸鼠皮下种植瘤生长的影响。
(4)在裸鼠体内观察STAT3信号对肿瘤血管生成的影响,并初步探讨其作用机理。
方法
(1)取临床大肠癌石蜡标本,免疫组化检测STAT3、CD34的表达情况,通过CD34的表达情况计数MVD,应用统计学方法分析STAT3表达与MVD的相关性。
(2)设计合成3对靶向STAT3基因的siRNA序列,通过筛选获得最佳siRNA序列,构建shRNA表达序列并连接到慢病毒载体pRNAT-U6.2/Lenti中,获得pRNAT-shSTAT3重组慢病毒质粒,经酶切和测序鉴定正确后,进行包装产生病毒液,测定其滴度。将包装获得的病毒液感染大肠癌HT-29细胞,筛选扩增获得阳性细胞株HT-29-shSTAT3。同法,用慢病毒空质粒包装后产生的病毒液感染大肠癌HT-29细胞,筛选获得阳性克隆细胞株HT-29-GFP。Real-time PCR和Western blot检测shRNA对STAT3基因的沉默效率,MTT法检测细胞生长情况,流式细胞仪检测细胞周期变化。
(3)分别将HT-29、HT-29-GFP、HT-29-shSTAT3细胞注射入裸鼠皮下成瘤,定期测量各组肿瘤体积变化。
(4) 30天后处死裸鼠,取各组瘤组织通过免疫组化检测STAT3和CD34的表达情况,并计数MVD。血管生成基因芯片检测肿瘤组织内血管生成和抑制因子的表达情况。
结果
(1)临床大肠癌组织中STAT3蛋白表达阳性率为63.6%,显著高于正常大肠组织;大肠癌组织中MVD为47.55±12.15,而正常大肠组织中MVD为11.67±1.08,两者相比具有显著差异(P<0.01);大肠癌组织中STAT3的表达和MVD与肿瘤的恶性程度、Duke’s分期及淋巴结转移有关(P<0.05)。相关分析表明STAT3表达与MVD呈显著正相关(r=0.788)。
(2)酶切鉴定和测序结果证实STAT3shRNA核苷酸序列插入正确,成功包装后产生病毒悬液的滴度为2×107TU/ml。病毒感染大肠癌HT-29细胞,经G418筛选获得稳定细胞株,Real-time PCR和Western blot分别显示HT-29-shSTAT3细胞STAT3 mRNA的表达和蛋白明显减弱,表达量分别为16.9±2.1%、18.8±2.4%(P<0.01)。MTT结果显示STAT3基因沉默后的大肠癌HT-29细胞生长明显减慢,G0/G1期细胞占68.73±2.88%,S期细胞占22.93±1.10%,与对照组相比差异显著(P<0.01)。
(3)各组裸鼠在接种肿瘤细胞后均成瘤,至接种后第15天,HT-29-shSTAT3细胞接种组肿瘤体积明显小于HT-29和HT-29-GFP细胞接种组(P<0.05);至接种后第30天差异更为显著(P<0.01),肿瘤生长抑制率为57.46%。
(4)取肿瘤组织行免疫组化检查,见HT-29和HT-29-GFP组肿瘤内有多量的微血管分布,MVD分别为28.73±5.11,27.60±4.27,两者无显著差异(P>0.05);而HT-29-shSTAT3组微血管明显减少,MVD为9.80±3.02,与前两组相比,差异显著(P<0.01)。
(5)血管生成基因芯片结果提示在HT-29-shSTAT3裸鼠组大肠癌组织中,表达下调的基因有15条,上调的基因有7条。
结论
(1)临床大肠癌组织中存在STAT3的高表达,STAT3的表达可能在大肠癌的病程发展及转移过程中发挥重要的作用。大肠癌的发生过程中STAT3信号与肿瘤血管的生成密切相关。
(2) STAT3信号通路对于大肠癌HT-29细胞生长起着重要的作用,沉默STAT3基因表达的大肠癌HT-29细胞生长速度明显减慢,细胞阻滞于G0/G1期。
(3)抑制STAT3信号可以抑制大肠癌HT-29细胞裸鼠皮下种植瘤的生长。
(4)在大肠癌组织中,STAT3信号可以促进肿瘤血管生成。
(5)在大肠癌肿瘤血管生成过程中,STAT3信号可能通过调控VEGF-A、MMP-2、ECGF1、EPHB4、IGF1、NRP1、NRP2、STAB1、TNF、VEGFR-1、BAI1的表达来促进新生血管的生成。
Objective
(1) To explore the expressing of STAT3 in human colorectal carcinoma and study the impact on angiogenesis.
(2) To observe the impact of STAT3 gene silencing on HT-29 cell growth and cell cycle distribution.
(3) To observe the effect of STAT3 signal on tumor growth of human colorectal carcinoma in nude mice.
(4) To investigate the effect of STAT3 signaling pathway on tumor angiogenesis of human colorectal carcinoma in nude mice, and probe the primary mechanism.
Methods
(1) STAT3 and CD34 expressing in the clinical colorectal carcinomas were studied by the way of immunohistochemistry. MVD were counted according to CD34 expression in tumor tissues. The correlation between the expression of STAT3 and MVD was statistically analyzed.
(2) Three different siRNAs of STAT3 were designed and synthesized. After being screened, the most effective siRNA was found. According to this sequence, the short hairpin DNA of STAT3 was constructed. The shRNA duplex was ligated into the recombinant vector pRNAT-U6.2/Lenti. The recombinant vector was conformed by the restriction map and DNA sequencing. The correct recombinant lentiviral vectors were packaged in 293T cells. Viruses in the supernatant were collected and the titer was measured. HT-29 cells transfected with viruses were selected by G418 and transfected cells were gained and harvested. Real-time PCR and Western blot were used to detect the interference effects. Cell growth was assessed by MTT assay and cell cycle distribution was detected by flow cytometry.
(3) HT-29, HT-29-GFP and HT-29-shSTAT3 cells were respectively injected subcutaneously into the back of the nude mice of each group. During the tumor growth, the appearance and size of each tumor were examined.
(4) On 30th day all mice were killed. Tumor tissues were removed for histopatho- logical and CD34 immunohistochemical analysis and taken to extract total RNA for angiogenesis superarray assay.
Results
(1) The positive rate of STAT3 expressing in colorectal carcinomas was 63.6%, which was significantly higher than that in the normal group(P<0.01). MVD in colorectal carcinoma tissus was 47.55±12.15, which was significantly higher than that in the normal group(P<0.01). In colorectal carcinoma, the positive rate of STAT3 expression and MVD were closely related to malignancy degree、Duke’s stage and lymph node metastasis (P<0.05), and MVD was closely correlated to the expression of STAT3(r=0.788).
(2) The restriction map and DNA sequencing demonstrated that the recombinant lentiviral vector of RNA interference of STAT3 gene was constructed successfully. Virus particles were packaged in 293T cells, and the title of viruses was 2×107 TU/ml. In HT-29 cells transfected with viruses effectively, the expressing level of STAT3 was down-regulated as Real-time PCR and Western blot analyses demonasrated. In transfected group, MTT assay showed the growth of HT-29 cells was suppressed and FCM assay indicated the proportion of cells at G0/G1 and S phase was 68.73±2.88% and 22.93±1.10% respectively, which was great different from that of the control group (P<0.01).
(3) A tumor was formed in every nude mouse. On day 15 after inoculating, tumor volums of the HT-29-shSTAT3 group were less than those of HT-29 group and HT-29-GFP group (P<0.05). On day 30 after inoculating, the difference was more obvious (P<0.01), the inhibitory rate of tumor growth was 57.46%.
(4) MVD in the HT-29-shSTAT3 group was less than that in the other two groups (P<0.01).
(5) The result of angiogenesis superarray indicated that there were 15 down- regulated genes and 7 up-regulated genes in tumor tissues of the HT-29-shSTAT3 mice group.
Conclusions
(1) STAT3 expressing in colorectal carcinoma is significantly higher. It may play an important role in the development and metastasis of colorectal carcinoma. It is suggested that angiogenesis is closely correlated to STAT3 signaling pathway in colorectal carcinoma.
(2) STAT3 singnaling pathway plays an important role in HT-29 cells growth. STAT3 targeting shRNA can silence the STAT3 gene remarkably, induce HT-29 cell growth inhibition and block cell cycle at G0/G1 phase.
(3) In nude mice, STAT3 singnal is important to the growth of human colorectal carcinoma.
(4) In human colorectal carcinoma, STAT3 signal can promote angiogenesis.
(5) In human colorectal carcinoma, STAT3 singnal may participate in regulating angiogenesis through modulating expression of VEGF-A, MMP-2, ECGF1, EPHB4, IGF1, NRP1, NRP2, STAB1, TNF,VEGFR-1 and BAI1.
引文
1. Jemal A, Murray T, Samuels A, et a1. Cancer statistics, 2003. CA Cancer J Clin, 2003 53(1): 5-26.
2. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biolo- gical responses. Cytokine Growth Factor Rev, 2000, 11(3): l99-207.
3. Wegenka UM, Lutticken C, Buschmann J, et a1. The interleukin-6-activated acute- phase response factor is antigenically and functionally related to member of the signal transducer and activate of transcription(STAT) family. Mol Cell Bio, 1994, 14(5): 3186 -3196.
4. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a Stat family member activated by yrosine phos- phorrylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155): 95-98.
5. Chung J, Uchida E, Grammer TC, et a1. STAT3 serine phosphorylation by ERK -dependent and -independent pathways negatively modulates its tyrosine phosphor- rylation. Mol Cel1 Biol, 1997, 17(11): 6508-6516.
6. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 2002, 3(9): 651-662.
7. Haura EB. SRC and STAT Pathways. J Thorac Oncol, 2006, l(5): 403-405.
8. Murray PJ. The JAK-STAT signaling Pathway: input and output integration.J Immunol, 2007, 178(5): 2623-2629.
9. Wang LH, Yang XY, Zhang X, et a1. Nuclear receptors as negative modulators of STAT3 in muhiple myeloma. Cell Cycle, 2005, 4(2): 242-245.
10. Han Y, Amin HM, Franko B, et a1. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large cell lymphoma. Blood, 2006, 108(8): 2796-2803.
11. Yang SF, Wang SN, Wu CF, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Cli Pathol, 2007, 60(6): 642-648.
12. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in andangiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005; 11(4): 1386-13 93.
13. Achcar Rde O, Cagle PT, Jagirdar J.Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-1360.
14. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16(6): 601-607.
15. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
16. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
17. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
18. Cheng F, Wang HW, Cuenca A, et a1.A critical role for Stat3 signaling in immune tolerance. Immunity, 2003, l9(3): 425-436.
19. Wang T, Niu G, Kortylewski M, et a1. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med, 2004, 10(1): 48-54.
20. Nefedova Y, Huang M, Kusmartsev, et a1. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J lmmunol, 2004, 172(1): 464- 474.
21. Kortylewski M, Kujawski M, Wang T, et a1. Inhibiting Stat3 signaling in the hemato- poietic system elicits multicomponent antitumor immunity. Nat Med, 2005, 11(12): 1314-1321.
22. Giordano FJ, Johnson RS. Angiogenesis:the role of the microenvronment in flipping the switch.Curr Opin Genet Dev, 2001, 11(1): 35-40.
23. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 2003, 3(6): 401-410.
24. Lu J, Zhang K, Nam S, et al. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling.Carcinogenesis, 2010, 31(3):481- 488.
25. Kim JY, Bae YH, Bae MK, et al. Visfatin through STAT3 activation enhances IL-6 expression that promotes endothelial angiogenesis. Biochim Biophys Acta, 2009, 1793 (11): 1759-67.
26. Shinriki S, Jono H, Ota K,et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res, 2009, 15(17): 5426-5434.
27. van Cruijsen H, Ruiz MG, van der Valk P, et al. Tissue microarray analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer, 2009, 9: 180.
28. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5(1): 13-17.
29. Zhu BH, Zhan WH, Li ZR, et al. (-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis. World J Gastroenterol, 2007, 13(8): 1162-1169.
30. Tran PT, Felsher DW. The current STATe of biomarkers to predict the response to anti-angiogenic therapies.Cancer Biol Ther, 2008, 7(12): 2004-2006.
31. Chen SH, Murphy DA, Lassoued W, et al. Activated STAT3 is a mediator and biomark- er of VEGF endothelial activation. Cancer Biol Ther, 2008, 7(12): 1994-2003.
32. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J Inves Dermatol, 2004, 123(6): 1169- 1175.
33. Loeffler S, Fayard B, Weis J, et al. Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int J Cancer, 2005, 115(2): 202-213.
34. Srivastava K, Kundumani-Sridharan V, Zhang B, et al. 15(S)-hydroxyleicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. Cancer Res, 2007, 67(9): 4328-4336.
35. Zhu BH, Zhan WH, He YL, et al. [Epigallocatechin-3-gallate inhibits growth and angiogenesis of gastric cancer and its molecular mechanism].Zhonghua Wei Chang WaiKe Za Zhi, 2009, 12(1): 82-85.
36. Jung JE, Lee HG, Cho IH, et a1. STAT3 is a potential modulator of HIF-l-mediated VEGF expression in human renal carcinoma cells. FASEB J, 2005, 19(10): 1296- 1298.
37. Wang M, Tan J, Coffey A, et al. Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha-induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg, 2009,138(1):163-171.
38. Huang W, Yu LF, Zhong J, et al. STAT3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci, 2009, 54(10): 2056-2062.
39. Lang SA, Schachtschneider P, Moser C, et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther, 2008, 7(11): 3509-3518.
40. Choi JH, Ahn MJ, Park CK, et al. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS, 2006, 114(9): 619-625.
41. Xie TX, Huang FJ, Aldape KD, et al. Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
42. Tsareva SA, Moriggl R, Corvinus FM, et al. Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia, 2007, 9(4): 279-291.
43. Kusaba T, Nakayama T, Yamazuni K. et a1. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rcp. 2006, 15(6): 1445-1451.
44. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorec- tal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol, 2005, 58(8): 833-838.
45. Ma XT, Wang S, Ye YJ, et al. Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. World J Gastroenterol, 2004, 10(11): 1569-1573.
46. Mello CC, Conte D Jr. Revealing the world of RNA interference. Nature, 2004, 431(7006): 338-342.
47. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 2l-and 22- nucleotide RNAs. Genes Dev, 200l, l5(2): l88-200.
48. Hannon GJ. RNA interference. Nature, 2002, 418(6894): 244-251.
49. Scherr M, Morgan MA, Eder M. Gene siliencing mediated by small interfering RNAs in Mammalian cells . Curr Med Chem, 2003, 10(3): 245-256.
50. Lee SS, Lee RY, Fraser AG, et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans lonevity . Nat Genet, 2003, 33(1): 40-48.
51. Brummelkamp TR, Bernards R, Agami R. A system for stable expressing of short interfering RNAs in mammalian cells . Science, 2002, 296(5567): 550-553.
1. Lu J, Zhang K, Nam S, et al. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis, 2010, 31(3): 481- 488.
2. Kim JY, Bae YH, Bae MK,et al. Visfatin through STAT3 activation enhances IL-6 expression that promotes endothelial angiogenesis. Biochim Biophys Acta, 2009, 1793 (11): 1759-67.
3. Shinriki S, Jono H, Ota K,et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res, 2009, 15(17): 5426-5434.
4. van Cruijsen H, Ruiz MG, van der Valk P, et al. Tissue microarray analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer, 2009, 9: 180.
5. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5 (1): 13-17.
6. Zhu BH, Zhan WH, Li ZR, et al. (-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis. World J Gastroenterol, 2007, 13(8): 1162-1169.
7. Tran PT, Felsher DW. The current STATe of biomarkers to predict the response to anti-angiogenic therapies.Cancer Biol Ther, 2008, 7(12): 2004-2006.
8. Chen SH, Murphy DA, Lassoued W, et al. Activated STAT3 is a mediator and biomark- er of VEGF endothelial activation. Cancer Biol Ther, 2008, 7(12): 1994-2003.
9. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J Inves Dermatol, 2004, 123(6): 1169-1175.
10. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of STAT3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
11. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
12. Saito H, Tsujitani S, Oka S, et al. The expressing of thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using floyouracil derivatives in advanced gastric carcinoma. Br J Cancer, 1998, 81(3):484-489.
13. Giordano FJ, Johnson RS. Angiogenesis:the role of the microenvronment in flipping the switch.Curr Opin Genet Dev, 2001, 11(1): 35-40.
14. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 2003, 3(6): 401-410.
15. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5(1): 13-17.
16. Weidner N, Cady B, Goodson WH 3rd, et al. Pathologic prognostic factors for patients with breast carcinoma. Which factors are important. Surg-Oncol-Clin-N-Am, 1997, 6(3): 415-462.
17. Chung YS, Maeda K, Sowa M. Prognostic value of angiogenesis in gastro-intedtinal tumors. Eur-J-Cancer, 1996, 32(14): 2501-2505.
18. Tanigawa N, Amaya H, Matsumura M, et al. Tumor angiogenesis and mode ofmetastasis in patients with colorectal cancer. Cancer Res, 1997, 57(6): 1043-1046.
19. Wegenka UM, Lutticken C, Buschmann J, et a1. The interleukin-6-activated acute phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription(STAT)family. Mol Cell Biol, 1994, 14(5): 3186-3196.
20. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by yrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155): 95-98.
21. Chung J, Uchidae E, Grammertc TC, et a1. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation . Mol Cell Biol, 1997, 17(11): 6508-6516.
22. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 2002, 3(9): 651-662.
23. Haura EB. SRC and Stat Pathways. J Thorac Oncol, 2006, l(5): 403-405.
24. Murray PJ. The Jak-Stat Signaling Pathway:input and output integration.J Immunol, 2007, 178(5): 2623-2629.
25. Wang LH, Yang XY, Zhang X, et a1. Nuclear receptors as negative modulators of STAT3 in muhiple myeloma. Cell Cycle, 2005; 4(2): 242-245.
26. Han Y, Amin HM, Franko B, et a1. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large cell lymphoma. Blood, 2006, 108(8): 2796-2803.
27. Yang SF, Wang SN, Wu CF, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Cli Pathol, 2007, 60(6): 642-648.
28. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005; 11(4): 1386-13 93.
29. Achcar Rde O, Cagle PT, Jagirdar J.Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and
44 malignant mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-60.
30. Jing N, Tweardy DJ. Targeting STAT3 in cancer therapy. Anticancer Drugs, 2005, 16 (6): 601-607.
31. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
32. Wei D, Le X, Zheng L, et al. STAT3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3): 319-329.
33. Jung JE, Lee HG, Cho IH, et a1. STAT3 is a potential modulator of HIF-l-mediated VEGF expression in human renal carcinoma cells. FASEB J, 2005, 19(10): 1296- 1298.
34. Wang M, Tan J, Coffey A,et al. Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha-induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg, 2009, 138(1): 163-171.
35. Huang W, Yu LF, Zhong J,et al. STAT3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci, 2009, 54(10): 2056-2062.
36. Lang SA, Schachtschneider P, Moser C,et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther, 2008, 7(11): 3509-3518.
37. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, Kim IS. Phospho-STAT3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS, 2006, 114(9): 619-625.
38. Xie TX, Huang FJ, Aldape KD, et al. Activation of STAT3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
39. Ma XT, Wang S, Ye YJ, et al. Constitutive activation of STAT3 signaling pathway in human colorectal carcinoma. World J Gastroenterol, 2004,10(11): 1569-1573.
40. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors.J Clin Pathol, 2005, 58(8): 833-838.
41. Kusaba T, Nakayama T, Yamazuni K. et a1. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rcp, 2006, 15(6): 1445-1451.
1. Kunnumakkara AB, Nair AS, Sung B, et al. Boswellic acid blocks signal transducers and activetors of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res, 2009, 7(1): 118- 128.
2. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16(6): 601-607.
3. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
4. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
5. Gao L, Zhang L, Hu J, et al. Down-regulation of signal transducer and activator of trans- cription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res, 2005, 11(17): 6333-6341.
6. Wang CG, Sun M, Zhao XJ, et al. Effect of Stat3 siRNA- induced inhibition of Stat3 gene expression on the growth and apoptosis of lewis lung cancer cells. Chin J clin oncology, 2006, 3(6): 392-399.
7. Kunigal S, Lakka SS, Sodadasu PK, et al. Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer. Int J Oncol, 2009, 34(5):1209-1220.
8. Chen H, Qin ZJ, Li HM, et al. The inhibitory effects of siRNA expression vector on STAT3 expression of human pancreatic cancer. Chin J Pancreatol, 2006, 6(4): 226-229.
9. Wang HR, Li XM, Lu XY. [Silencing of signal transducer and activator of transcription
3 gene expression using RNAi enhances the efficacy of radiotherapy for laryngeal carcinoma in vivo].Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2009, 44(7): 591-5 96.
10. Li J, Piao YF, Jiang Z, et al. Silencing of signal transducer and activator of transcrip- tion 3 expression by RNA interference suppresses growth of human hepato-cellular carcinoma in tumor-bearing nude mice.World J Gastroenterol, 2009, 15(21): 2602-2608.
11. Li GH, Wei H, Chen ZT, et al. STAT3 silencing with lentivirus inhibits growth andinduces apoptosis and differentiation of U251 cells. J Neurooncol, 2009, 91(2): 165- 174.
12. Qiu Z, Huang C, Sun J, et al. RNA interference-mediated signal transducers and active- teors of transcription 3 gene silencing inhibits invasion and metastasis of human pancr- eatic cancer cells. Cancer Sci, 2007, 98(7): 106-109.
13. Konnikova L, Kotecki M, Kruger M, et al. Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer. 2003, 3: 23.
14. Ma XT, Wang S, Ye YJ, et al. Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. World J Gastroenterol, 2004, 10(11): 1569-1573.
15. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol, 2005, 58(8): 833-838.
16. Kusaba T, Nakayama T, Yamazuni K. et a1. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rcp, 2006, 15(6): 1445-1451.
17. Tsareva SA, Moriggl R,Corvinus FM, et al. Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia, 2007, 9(4): 279-291.
18. Meister G, Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature, 2004, 431(7006): 343-349.
19. Mello CC, Conte D Jr. Revealing the world of RNA interference. Nature, 2004; 431(7006): 338-342.
20. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 2l-and 22- nucleotide RNAs. Genes Dev, 200l, l5(2): l88-200.
21. Hannon GJ. RNA interference. Nature, 2002, 418(6894): 244-251.
22. Scherr M, Morgan MA, Eder M. Gene silencing mediated by small interfering RNAs in Mammalian cells .Curr Med Chem, 2003, 10(3): 245-256.
23. Lee SS, Lee RY, Fraser AG, et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans lonevity . Nat Genet, 2003, 33(1): 40-48.
24. Brummelkamp TR, Bernards R, Agami R, et al. A system for stable expressing of short interfering RNAs in mammalian cells . Science, 2002, 296(5567):550-553.
25. Singer O, Marr R A, Rockenstein E, et a1. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci, 2005, 8(10):1343-1349.
26. Haura EB, Turkson J, Jove R. Mechanisms of disease:Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol, 2005, 2(6): 3l5-324.
27. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
1. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
2. Kunnumakkara AB, Nair AS, Sung B, et al. Boswellic acid blocks signal transducers and activetors of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res, 2009, 7(1): 118-128.
3. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16(6): 601-607.
4. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
5. Srivastava K, Kundumani-Sridharan V, Zhang B, et al. 15(S)-hydroxyleicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. Cancer Res, 2007, 67(9): 4328-4336.
6. Kong HL, Crystal RG. Gene therapy stratetegies for tumor antiagiogenesis. J Natl Cancer 1nst, 1998, 90(4): 270-271.
7. Nesbit M. Abrogation of tumor vasculature using gene therapy. Cancer Mestastasis Rev, 2000, 19(1-2): 45-49.
8. Weidner N, Cady B, Goodson WH 3rd, et al. Pathologic prognostic factors for patients with breast carcinoma. Which factors are important. Surg-Oncol-Clin-N-Am, 1997, 6 (3): 415-462.
9. Chung YS, Maeda K, Sowa M. Prognostic value of angiogenesis in gastro-intedtinal tumors. Eur-J-Cancer, 1996, 32(14): 2501-2503.
10. Tanigawa N, Amaya H, Matsumura M, et al. Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res, 1997, 57(6): 1043-1046.
11. Offersen BV, Borre M, Overgaard J. Quantification of angiogenesis as a prognostic marker in human carcinomas: a critical evalution of histopathological methods for estimation of vascular desity. Eur J Cancer, 2003, 39(7): 881-890.
12. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell, 1999, 98(3): 295-303.
13. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
14. Yang SF, Wang SN, Wu CF, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Cli Pathol, 2007, 60(6): 642-648.
15. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005; 11(4): 1386-13 93.
16. Achcar Rde O, Cagle PT, Jagirdar J.Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-1360.
17. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16 (6): 601-607.
18. Gao L, Zhang L, Hu J, et al. Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res, 2005, 11(17): 6333-6341.
19. Zhu BH. Zhan WH. Li ZR. et al. (-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis. World J Gastroenterol, 2007, 13(8): 1162-1169.
20. Jung JE,Lee HG,Cho IH,et a1.STAT3 is a potential modulator of HIF-l- mediated VEGF expression in human renal carcinoma cells.FASEB J, 2005, 19(10): 1296- 1298.
21. Wang M, Tan J, Coffey A,et al. Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha- induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg, 2009, 138(1): 163-171.
22. Huang W, Yu LF, Zhong J,et al. STAT3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci, 2009, 54(10): 2056-2062.
23. Lang SA, Schachtschneider P, Moser C,et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther, 2008, 7(11): 3509-3518.
24. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, Kim IS. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS, 2006, 114(9): 619-625.
25. Xie TX, Huang FJ, Aldape KD, et al. Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
26. Holash J, Maispnpierre PC, Compton D, et a1. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science, 1999, 284: 1994-1998.
27. Holash J, Wiegand SJ, Yaneopoulos GD. New model of tumor arngiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene, 1999, 18: 5356-5362.
28. Ahmad SA, Liu W, Jung YD, et al. Differential expression of angiopoietin-1 and angiopoietin-2 in colon carcinoma. A possible mechanism for the initiation of angiogenesis. Cancer, 2001, 92: 1138-1143.
29. Lobov IB, Brooks PC, Lang RA. Angiopoielin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA, 2002, 99: 11205-11210.
30. Yonemura Y, Endo Y, Tabata K, et al. Role of VEGF-C VEGF-D in lymphangiogenesis in gastric cancer. Int J Clin Oncol, 2005, 10(5): 318-327.
31. Pellet-Many C, Frankel P, Jia H, et a1. Neuropilins: structure, function and role in dise- ase. Biochem J, 2008, 411(2): 211-226.
1. Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264(5164): 1415-1421.
2. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev, 2000, 11(3): l99-207.
3. Bowman T, Garcia R, Turkson J, et a1. STATs in oncogenesis, Oncogene, 2000, 19(21): 2474-2488.
4. Wegenka UM, Lutticken C, Buschmann J, et a1. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to member of the signal transducer and activate of transcription(STAT)family. Mol Cell Bio, 1994, 14(5): 3186- 3196.
5. Zhong Z, Wen Z, Darnell JE Jr. STAT3:a Stat family member activated by yrosine phos- phorrylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155): 95-98.
6. Chung J, Uchida E, Grammer TC, et a1.STAT3 serine phosphorylation by ERK -dependent and -independent pathways negatively modulates its tyrosine phosphor- rylation. Mol Cel1 Biol, 1997, 17(11): 6508-6516.
7. Levy DE, Darnell JE Jr. Stats:transcriptional control and biological impact. Nat RevMol Cell Biol, 2002, 3(9): 651-662.
8. Haura EB. SRC and STAT Pathways. J Thorac Oncol, 2006, l(5): 403-405.
9. Murray PJ. The JAK-STAT signaling Pathway: input and output integration.J Immunol, 2007, 178(5): 2623-2629.
10. Wang LH, Yang XY, Zhang X, et a1. Nuclear receptors as negative modulators of STAT3 in muhiple myeloma. Cell Cycle, 2005, 4(2):242-245.
11. Han Y, Amin HM, Franko B, et a1. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large cell lymphoma. Blood, 2006, 108(8): 2796-2803.
12. Chakraborty A, Dyer KF, Cascio M, et a1. Identification of a nove1 STAT3 recruit- ment and activation motif within the granulocyte colony-stimulating factor receptor. Blood, 1999, 93(1): 15-24.
13. Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer, 2004, 4(2): 97–105.
14. Bromberg J. Stat proteins and oncogenesis. J Clin Invest, 2002, 109(9): 1139-1142.
15. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell, 1999, 99(2):295-303.
16. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity, 1999, 10(1): 105-115.
17. Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest, 2001, 107(3): 351-362.
18. Ivanov VN, Bhoumik A, Krasilnikov M, et al. Cooperation between STAT3 and c-jun suppresses Fas transcription. Mol Cell, 2001, 7(3): 517-528.
19. Haura EB, Turkson J, Jove R. Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol, 2005, 2(6): 3l5-324.
20. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3 regulated genes in human breast cancer . Biochem Biophys Res Commun, 2005, 335(2): 292-299.
21. Nadiminty N, Lou W, Lee SO, et al. STAT3 activation of NF-{kappa}B p100 process- ing involves CBP/p300-mediated acetylation. Proc Natl Acad Sci USA, 2006, 103(19):7264-7269.
22. Niu G, Wright KL, Ma Y, et al. Role of STAT3 in regulating p53 expression and function. Mol Cell Biol, 2005, 25(17): 7432–7440.
23. Kusaba T, Nakayama T, Yamazumi K, et a1. Expression of p-STAT3 in human colore- ctal adenocarcinoma and adenoma;correlation with clinicopathological factors. J Clin Pathol, 2005, 58(8): 833-838.
24. Wei D, Le X, Zheng L, et a1. STAT3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3): 319-329.
25. Jung JE, Lee HG, Cho IH, et a1. STAT3 is a potential modulator of HIF-l-mediated VEGF expression in human renal carcinoma cells. FASEB J, 2005, 19(10): 1296-1298.
26. Gray MJ, Zhang J, Ellis LM, et a1. HIF-l alpha,STAT3,CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia- induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene, 2005, 24(19): 3110-3120.
27. Xu Q, Briggs J, Park S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene, 2005, 24(36): 5552-5560.
28. Xie TX, Huang FJ, Aldape KD, et al. Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
29. Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 2004, 23(20): 3550-3560.
30. Itoh M, Murata T, Suzuki T, et al. Requirement of STAT3 activation for maximal collagenase-1(MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene, 2006, 25(8): 1195–1204.
31. Dechow TN, Pedranzini L, Leitch A, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA, 2004, 101(29): 10602–10607.
32. Cheng F, Wang HW, Cuenca A, et a1. A critical role for Stat3 signaling in immune tolerance. Immunity, 2003, l9(3): 425-436.
33. Nefedova Y, Huang M, Kusmartsev, et al. Hyperactivation of STAT3 is involved inabnormal differentiation ofdendritic cells in cancer. J lmmunol, 2004, 172(1): 464- 474.
34. Wang T, Niu G, Kortylewski M, et a1. Regulation of the innate and adaptive immune responses by STAT3 signaling in tumor cells. Nat Med, 2004, 10(1): 48-54.
35. Kortylewski M, Kujawski M, Wang T.Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med, 2005, 11(12): 1314- 1321.
36. Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene, 2002, 21(13): 2000-2008.
37. Wang FF, Chen HZ, Xie X, et a1. Phosphorylation of Stat3 induced by vascular endot- helial growth factor in ovarian carcinoma cell line in vitro. Zhong hua Fu Chan Ke Za Zhi, 2004, 39(6): 385-389.
38. Deo DD, Axelrad TW, Robert EG, et al. Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet- activating factor, JAK-2, and Src in human umbilical vein endothelial cells. Evidence for a dual kinase mechanism. J Biol Chem, 2002, 277(24): 21237–21245.
39. Bartoli M, Platt D, Lemtalsi T, et al. VEGF differentially activates STAT3 in micro- vascular endothelial cells. FASEB J, 2003, 17(11): 1562-1564.
40. Schaefer LK, Ren Z, Fuller GN, et al. Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene, 2002, 21(13): 2058-2065.
2. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biolo- gical responses. Cytokine Growth Factor Rev, 2000, 11(3): l99-207.
3. Wegenka UM, Lutticken C, Buschmann J, et a1. The interleukin-6-activated acute- phase response factor is antigenically and functionally related to member of the signal transducer and activate of transcription(STAT) family. Mol Cell Bio, 1994, 14(5): 3186 -3196.
4. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a Stat family member activated by yrosine phos- phorrylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155): 95-98.
5. Chung J, Uchida E, Grammer TC, et a1. STAT3 serine phosphorylation by ERK -dependent and -independent pathways negatively modulates its tyrosine phosphor- rylation. Mol Cel1 Biol, 1997, 17(11): 6508-6516.
6. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 2002, 3(9): 651-662.
7. Haura EB. SRC and STAT Pathways. J Thorac Oncol, 2006, l(5): 403-405.
8. Murray PJ. The JAK-STAT signaling Pathway: input and output integration.J Immunol, 2007, 178(5): 2623-2629.
9. Wang LH, Yang XY, Zhang X, et a1. Nuclear receptors as negative modulators of STAT3 in muhiple myeloma. Cell Cycle, 2005, 4(2): 242-245.
10. Han Y, Amin HM, Franko B, et a1. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large cell lymphoma. Blood, 2006, 108(8): 2796-2803.
11. Yang SF, Wang SN, Wu CF, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Cli Pathol, 2007, 60(6): 642-648.
12. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in andangiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005; 11(4): 1386-13 93.
13. Achcar Rde O, Cagle PT, Jagirdar J.Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-1360.
14. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16(6): 601-607.
15. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
16. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
17. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
18. Cheng F, Wang HW, Cuenca A, et a1.A critical role for Stat3 signaling in immune tolerance. Immunity, 2003, l9(3): 425-436.
19. Wang T, Niu G, Kortylewski M, et a1. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med, 2004, 10(1): 48-54.
20. Nefedova Y, Huang M, Kusmartsev, et a1. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J lmmunol, 2004, 172(1): 464- 474.
21. Kortylewski M, Kujawski M, Wang T, et a1. Inhibiting Stat3 signaling in the hemato- poietic system elicits multicomponent antitumor immunity. Nat Med, 2005, 11(12): 1314-1321.
22. Giordano FJ, Johnson RS. Angiogenesis:the role of the microenvronment in flipping the switch.Curr Opin Genet Dev, 2001, 11(1): 35-40.
23. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 2003, 3(6): 401-410.
24. Lu J, Zhang K, Nam S, et al. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling.Carcinogenesis, 2010, 31(3):481- 488.
25. Kim JY, Bae YH, Bae MK, et al. Visfatin through STAT3 activation enhances IL-6 expression that promotes endothelial angiogenesis. Biochim Biophys Acta, 2009, 1793 (11): 1759-67.
26. Shinriki S, Jono H, Ota K,et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res, 2009, 15(17): 5426-5434.
27. van Cruijsen H, Ruiz MG, van der Valk P, et al. Tissue microarray analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer, 2009, 9: 180.
28. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5(1): 13-17.
29. Zhu BH, Zhan WH, Li ZR, et al. (-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis. World J Gastroenterol, 2007, 13(8): 1162-1169.
30. Tran PT, Felsher DW. The current STATe of biomarkers to predict the response to anti-angiogenic therapies.Cancer Biol Ther, 2008, 7(12): 2004-2006.
31. Chen SH, Murphy DA, Lassoued W, et al. Activated STAT3 is a mediator and biomark- er of VEGF endothelial activation. Cancer Biol Ther, 2008, 7(12): 1994-2003.
32. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J Inves Dermatol, 2004, 123(6): 1169- 1175.
33. Loeffler S, Fayard B, Weis J, et al. Interleukin-6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1. Int J Cancer, 2005, 115(2): 202-213.
34. Srivastava K, Kundumani-Sridharan V, Zhang B, et al. 15(S)-hydroxyleicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. Cancer Res, 2007, 67(9): 4328-4336.
35. Zhu BH, Zhan WH, He YL, et al. [Epigallocatechin-3-gallate inhibits growth and angiogenesis of gastric cancer and its molecular mechanism].Zhonghua Wei Chang WaiKe Za Zhi, 2009, 12(1): 82-85.
36. Jung JE, Lee HG, Cho IH, et a1. STAT3 is a potential modulator of HIF-l-mediated VEGF expression in human renal carcinoma cells. FASEB J, 2005, 19(10): 1296- 1298.
37. Wang M, Tan J, Coffey A, et al. Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha-induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg, 2009,138(1):163-171.
38. Huang W, Yu LF, Zhong J, et al. STAT3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci, 2009, 54(10): 2056-2062.
39. Lang SA, Schachtschneider P, Moser C, et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther, 2008, 7(11): 3509-3518.
40. Choi JH, Ahn MJ, Park CK, et al. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS, 2006, 114(9): 619-625.
41. Xie TX, Huang FJ, Aldape KD, et al. Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
42. Tsareva SA, Moriggl R, Corvinus FM, et al. Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia, 2007, 9(4): 279-291.
43. Kusaba T, Nakayama T, Yamazuni K. et a1. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rcp. 2006, 15(6): 1445-1451.
44. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorec- tal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol, 2005, 58(8): 833-838.
45. Ma XT, Wang S, Ye YJ, et al. Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. World J Gastroenterol, 2004, 10(11): 1569-1573.
46. Mello CC, Conte D Jr. Revealing the world of RNA interference. Nature, 2004, 431(7006): 338-342.
47. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 2l-and 22- nucleotide RNAs. Genes Dev, 200l, l5(2): l88-200.
48. Hannon GJ. RNA interference. Nature, 2002, 418(6894): 244-251.
49. Scherr M, Morgan MA, Eder M. Gene siliencing mediated by small interfering RNAs in Mammalian cells . Curr Med Chem, 2003, 10(3): 245-256.
50. Lee SS, Lee RY, Fraser AG, et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans lonevity . Nat Genet, 2003, 33(1): 40-48.
51. Brummelkamp TR, Bernards R, Agami R. A system for stable expressing of short interfering RNAs in mammalian cells . Science, 2002, 296(5567): 550-553.
1. Lu J, Zhang K, Nam S, et al. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis, 2010, 31(3): 481- 488.
2. Kim JY, Bae YH, Bae MK,et al. Visfatin through STAT3 activation enhances IL-6 expression that promotes endothelial angiogenesis. Biochim Biophys Acta, 2009, 1793 (11): 1759-67.
3. Shinriki S, Jono H, Ota K,et al. Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res, 2009, 15(17): 5426-5434.
4. van Cruijsen H, Ruiz MG, van der Valk P, et al. Tissue microarray analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer. BMC Cancer, 2009, 9: 180.
5. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5 (1): 13-17.
6. Zhu BH, Zhan WH, Li ZR, et al. (-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis. World J Gastroenterol, 2007, 13(8): 1162-1169.
7. Tran PT, Felsher DW. The current STATe of biomarkers to predict the response to anti-angiogenic therapies.Cancer Biol Ther, 2008, 7(12): 2004-2006.
8. Chen SH, Murphy DA, Lassoued W, et al. Activated STAT3 is a mediator and biomark- er of VEGF endothelial activation. Cancer Biol Ther, 2008, 7(12): 1994-2003.
9. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth factor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and PI3-kinase/Akt pathways. J Inves Dermatol, 2004, 123(6): 1169-1175.
10. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of STAT3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
11. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
12. Saito H, Tsujitani S, Oka S, et al. The expressing of thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using floyouracil derivatives in advanced gastric carcinoma. Br J Cancer, 1998, 81(3):484-489.
13. Giordano FJ, Johnson RS. Angiogenesis:the role of the microenvronment in flipping the switch.Curr Opin Genet Dev, 2001, 11(1): 35-40.
14. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer, 2003, 3(6): 401-410.
15. Blagosklonny MV. Antiangiogenic therapy and tumor progression. Cancer Cell, 2004, 5(1): 13-17.
16. Weidner N, Cady B, Goodson WH 3rd, et al. Pathologic prognostic factors for patients with breast carcinoma. Which factors are important. Surg-Oncol-Clin-N-Am, 1997, 6(3): 415-462.
17. Chung YS, Maeda K, Sowa M. Prognostic value of angiogenesis in gastro-intedtinal tumors. Eur-J-Cancer, 1996, 32(14): 2501-2505.
18. Tanigawa N, Amaya H, Matsumura M, et al. Tumor angiogenesis and mode ofmetastasis in patients with colorectal cancer. Cancer Res, 1997, 57(6): 1043-1046.
19. Wegenka UM, Lutticken C, Buschmann J, et a1. The interleukin-6-activated acute phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription(STAT)family. Mol Cell Biol, 1994, 14(5): 3186-3196.
20. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by yrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155): 95-98.
21. Chung J, Uchidae E, Grammertc TC, et a1. STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation . Mol Cell Biol, 1997, 17(11): 6508-6516.
22. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol, 2002, 3(9): 651-662.
23. Haura EB. SRC and Stat Pathways. J Thorac Oncol, 2006, l(5): 403-405.
24. Murray PJ. The Jak-Stat Signaling Pathway:input and output integration.J Immunol, 2007, 178(5): 2623-2629.
25. Wang LH, Yang XY, Zhang X, et a1. Nuclear receptors as negative modulators of STAT3 in muhiple myeloma. Cell Cycle, 2005; 4(2): 242-245.
26. Han Y, Amin HM, Franko B, et a1. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large cell lymphoma. Blood, 2006, 108(8): 2796-2803.
27. Yang SF, Wang SN, Wu CF, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Cli Pathol, 2007, 60(6): 642-648.
28. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005; 11(4): 1386-13 93.
29. Achcar Rde O, Cagle PT, Jagirdar J.Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and
44 malignant mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-60.
30. Jing N, Tweardy DJ. Targeting STAT3 in cancer therapy. Anticancer Drugs, 2005, 16 (6): 601-607.
31. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
32. Wei D, Le X, Zheng L, et al. STAT3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3): 319-329.
33. Jung JE, Lee HG, Cho IH, et a1. STAT3 is a potential modulator of HIF-l-mediated VEGF expression in human renal carcinoma cells. FASEB J, 2005, 19(10): 1296- 1298.
34. Wang M, Tan J, Coffey A,et al. Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha-induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg, 2009, 138(1): 163-171.
35. Huang W, Yu LF, Zhong J,et al. STAT3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci, 2009, 54(10): 2056-2062.
36. Lang SA, Schachtschneider P, Moser C,et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther, 2008, 7(11): 3509-3518.
37. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, Kim IS. Phospho-STAT3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS, 2006, 114(9): 619-625.
38. Xie TX, Huang FJ, Aldape KD, et al. Activation of STAT3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
39. Ma XT, Wang S, Ye YJ, et al. Constitutive activation of STAT3 signaling pathway in human colorectal carcinoma. World J Gastroenterol, 2004,10(11): 1569-1573.
40. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors.J Clin Pathol, 2005, 58(8): 833-838.
41. Kusaba T, Nakayama T, Yamazuni K. et a1. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rcp, 2006, 15(6): 1445-1451.
1. Kunnumakkara AB, Nair AS, Sung B, et al. Boswellic acid blocks signal transducers and activetors of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res, 2009, 7(1): 118- 128.
2. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16(6): 601-607.
3. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
4. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
5. Gao L, Zhang L, Hu J, et al. Down-regulation of signal transducer and activator of trans- cription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res, 2005, 11(17): 6333-6341.
6. Wang CG, Sun M, Zhao XJ, et al. Effect of Stat3 siRNA- induced inhibition of Stat3 gene expression on the growth and apoptosis of lewis lung cancer cells. Chin J clin oncology, 2006, 3(6): 392-399.
7. Kunigal S, Lakka SS, Sodadasu PK, et al. Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer. Int J Oncol, 2009, 34(5):1209-1220.
8. Chen H, Qin ZJ, Li HM, et al. The inhibitory effects of siRNA expression vector on STAT3 expression of human pancreatic cancer. Chin J Pancreatol, 2006, 6(4): 226-229.
9. Wang HR, Li XM, Lu XY. [Silencing of signal transducer and activator of transcription
3 gene expression using RNAi enhances the efficacy of radiotherapy for laryngeal carcinoma in vivo].Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi, 2009, 44(7): 591-5 96.
10. Li J, Piao YF, Jiang Z, et al. Silencing of signal transducer and activator of transcrip- tion 3 expression by RNA interference suppresses growth of human hepato-cellular carcinoma in tumor-bearing nude mice.World J Gastroenterol, 2009, 15(21): 2602-2608.
11. Li GH, Wei H, Chen ZT, et al. STAT3 silencing with lentivirus inhibits growth andinduces apoptosis and differentiation of U251 cells. J Neurooncol, 2009, 91(2): 165- 174.
12. Qiu Z, Huang C, Sun J, et al. RNA interference-mediated signal transducers and active- teors of transcription 3 gene silencing inhibits invasion and metastasis of human pancr- eatic cancer cells. Cancer Sci, 2007, 98(7): 106-109.
13. Konnikova L, Kotecki M, Kruger M, et al. Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer. 2003, 3: 23.
14. Ma XT, Wang S, Ye YJ, et al. Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. World J Gastroenterol, 2004, 10(11): 1569-1573.
15. Kusaba T, Nakayama T, Yamazumi K, et al. Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol, 2005, 58(8): 833-838.
16. Kusaba T, Nakayama T, Yamazuni K. et a1. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rcp, 2006, 15(6): 1445-1451.
17. Tsareva SA, Moriggl R,Corvinus FM, et al. Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia, 2007, 9(4): 279-291.
18. Meister G, Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature, 2004, 431(7006): 343-349.
19. Mello CC, Conte D Jr. Revealing the world of RNA interference. Nature, 2004; 431(7006): 338-342.
20. Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 2l-and 22- nucleotide RNAs. Genes Dev, 200l, l5(2): l88-200.
21. Hannon GJ. RNA interference. Nature, 2002, 418(6894): 244-251.
22. Scherr M, Morgan MA, Eder M. Gene silencing mediated by small interfering RNAs in Mammalian cells .Curr Med Chem, 2003, 10(3): 245-256.
23. Lee SS, Lee RY, Fraser AG, et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans lonevity . Nat Genet, 2003, 33(1): 40-48.
24. Brummelkamp TR, Bernards R, Agami R, et al. A system for stable expressing of short interfering RNAs in mammalian cells . Science, 2002, 296(5567):550-553.
25. Singer O, Marr R A, Rockenstein E, et a1. Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci, 2005, 8(10):1343-1349.
26. Haura EB, Turkson J, Jove R. Mechanisms of disease:Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol, 2005, 2(6): 3l5-324.
27. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
1. Aggarwal BB, Sethi G, Ahn KS, et al. Targeting signal transducer-and–activator-of- transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann N Y Acad Sci, 2006, 1091: 151-169.
2. Kunnumakkara AB, Nair AS, Sung B, et al. Boswellic acid blocks signal transducers and activetors of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res, 2009, 7(1): 118-128.
3. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16(6): 601-607.
4. Weerasinghe P, Garcia GE, Zhu Q, et al. Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. International Journal of Oncology, 2007, 31(1): 129-136.
5. Srivastava K, Kundumani-Sridharan V, Zhang B, et al. 15(S)-hydroxyleicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. Cancer Res, 2007, 67(9): 4328-4336.
6. Kong HL, Crystal RG. Gene therapy stratetegies for tumor antiagiogenesis. J Natl Cancer 1nst, 1998, 90(4): 270-271.
7. Nesbit M. Abrogation of tumor vasculature using gene therapy. Cancer Mestastasis Rev, 2000, 19(1-2): 45-49.
8. Weidner N, Cady B, Goodson WH 3rd, et al. Pathologic prognostic factors for patients with breast carcinoma. Which factors are important. Surg-Oncol-Clin-N-Am, 1997, 6 (3): 415-462.
9. Chung YS, Maeda K, Sowa M. Prognostic value of angiogenesis in gastro-intedtinal tumors. Eur-J-Cancer, 1996, 32(14): 2501-2503.
10. Tanigawa N, Amaya H, Matsumura M, et al. Tumor angiogenesis and mode of metastasis in patients with colorectal cancer. Cancer Res, 1997, 57(6): 1043-1046.
11. Offersen BV, Borre M, Overgaard J. Quantification of angiogenesis as a prognostic marker in human carcinomas: a critical evalution of histopathological methods for estimation of vascular desity. Eur J Cancer, 2003, 39(7): 881-890.
12. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell, 1999, 98(3): 295-303.
13. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun, 2005, 335(2): 292-299.
14. Yang SF, Wang SN, Wu CF, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Cli Pathol, 2007, 60(6): 642-648.
15. Gong W, Wang L, Yao JC, et al. Expression of activated signal transducer and activator of transcription 3 predicts expression of vascular endothelial growth factor in and angiogenic phenotype of human gastric cancer. Clin Cancer Res, 2005; 11(4): 1386-13 93.
16. Achcar Rde O, Cagle PT, Jagirdar J.Expression of activated and latent signal transducer and activator of transcription 3 in 303 non-small cell lung carcinomas and 44 malignant mesotheliomas: possible role for chemotherapeutic intervention. Arch Pathol Lab Med, 2007, 131(9): 1350-1360.
17. Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs, 2005, 16 (6): 601-607.
18. Gao L, Zhang L, Hu J, et al. Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res, 2005, 11(17): 6333-6341.
19. Zhu BH. Zhan WH. Li ZR. et al. (-)-Epigallocatechin-3-gallate inhibits growth of gastric cancer by reducing VEGF production and angiogenesis. World J Gastroenterol, 2007, 13(8): 1162-1169.
20. Jung JE,Lee HG,Cho IH,et a1.STAT3 is a potential modulator of HIF-l- mediated VEGF expression in human renal carcinoma cells.FASEB J, 2005, 19(10): 1296- 1298.
21. Wang M, Tan J, Coffey A,et al. Signal transducer and activator of transcription 3-stimulated hypoxia inducible factor-1alpha mediates estrogen receptor-alpha- induced mesenchymal stem cell vascular endothelial growth factor production. J Thorac Cardiovasc Surg, 2009, 138(1): 163-171.
22. Huang W, Yu LF, Zhong J,et al. STAT3 is involved in angiotensin II-induced expression of MMP2 in gastric cancer cells. Dig Dis Sci, 2009, 54(10): 2056-2062.
23. Lang SA, Schachtschneider P, Moser C,et al. Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther, 2008, 7(11): 3509-3518.
24. Choi JH, Ahn MJ, Park CK, Han HX, Kwon SJ, Lee YY, Kim IS. Phospho-Stat3 expression and correlation with VEGF, p53, and Bcl-2 in gastric carcinoma using tissue microarray. APMIS, 2006, 114(9): 619-625.
25. Xie TX, Huang FJ, Aldape KD, et al. Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
26. Holash J, Maispnpierre PC, Compton D, et a1. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science, 1999, 284: 1994-1998.
27. Holash J, Wiegand SJ, Yaneopoulos GD. New model of tumor arngiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene, 1999, 18: 5356-5362.
28. Ahmad SA, Liu W, Jung YD, et al. Differential expression of angiopoietin-1 and angiopoietin-2 in colon carcinoma. A possible mechanism for the initiation of angiogenesis. Cancer, 2001, 92: 1138-1143.
29. Lobov IB, Brooks PC, Lang RA. Angiopoielin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA, 2002, 99: 11205-11210.
30. Yonemura Y, Endo Y, Tabata K, et al. Role of VEGF-C VEGF-D in lymphangiogenesis in gastric cancer. Int J Clin Oncol, 2005, 10(5): 318-327.
31. Pellet-Many C, Frankel P, Jia H, et a1. Neuropilins: structure, function and role in dise- ase. Biochem J, 2008, 411(2): 211-226.
1. Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 1994, 264(5164): 1415-1421.
2. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev, 2000, 11(3): l99-207.
3. Bowman T, Garcia R, Turkson J, et a1. STATs in oncogenesis, Oncogene, 2000, 19(21): 2474-2488.
4. Wegenka UM, Lutticken C, Buschmann J, et a1. The interleukin-6-activated acute-phase response factor is antigenically and functionally related to member of the signal transducer and activate of transcription(STAT)family. Mol Cell Bio, 1994, 14(5): 3186- 3196.
5. Zhong Z, Wen Z, Darnell JE Jr. STAT3:a Stat family member activated by yrosine phos- phorrylation in response to epidermal growth factor and interleukin-6. Science, 1994, 264(5155): 95-98.
6. Chung J, Uchida E, Grammer TC, et a1.STAT3 serine phosphorylation by ERK -dependent and -independent pathways negatively modulates its tyrosine phosphor- rylation. Mol Cel1 Biol, 1997, 17(11): 6508-6516.
7. Levy DE, Darnell JE Jr. Stats:transcriptional control and biological impact. Nat RevMol Cell Biol, 2002, 3(9): 651-662.
8. Haura EB. SRC and STAT Pathways. J Thorac Oncol, 2006, l(5): 403-405.
9. Murray PJ. The JAK-STAT signaling Pathway: input and output integration.J Immunol, 2007, 178(5): 2623-2629.
10. Wang LH, Yang XY, Zhang X, et a1. Nuclear receptors as negative modulators of STAT3 in muhiple myeloma. Cell Cycle, 2005, 4(2):242-245.
11. Han Y, Amin HM, Franko B, et a1. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large cell lymphoma. Blood, 2006, 108(8): 2796-2803.
12. Chakraborty A, Dyer KF, Cascio M, et a1. Identification of a nove1 STAT3 recruit- ment and activation motif within the granulocyte colony-stimulating factor receptor. Blood, 1999, 93(1): 15-24.
13. Yu H, Jove R. The STATs of cancer--new molecular targets come of age. Nat Rev Cancer, 2004, 4(2): 97–105.
14. Bromberg J. Stat proteins and oncogenesis. J Clin Invest, 2002, 109(9): 1139-1142.
15. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. Stat3 as an oncogene. Cell, 1999, 99(2):295-303.
16. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity, 1999, 10(1): 105-115.
17. Epling-Burnette PK, Liu JH, Catlett-Falcone R, et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest, 2001, 107(3): 351-362.
18. Ivanov VN, Bhoumik A, Krasilnikov M, et al. Cooperation between STAT3 and c-jun suppresses Fas transcription. Mol Cell, 2001, 7(3): 517-528.
19. Haura EB, Turkson J, Jove R. Mechanisms of disease: insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol, 2005, 2(6): 3l5-324.
20. Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3 regulated genes in human breast cancer . Biochem Biophys Res Commun, 2005, 335(2): 292-299.
21. Nadiminty N, Lou W, Lee SO, et al. STAT3 activation of NF-{kappa}B p100 process- ing involves CBP/p300-mediated acetylation. Proc Natl Acad Sci USA, 2006, 103(19):7264-7269.
22. Niu G, Wright KL, Ma Y, et al. Role of STAT3 in regulating p53 expression and function. Mol Cell Biol, 2005, 25(17): 7432–7440.
23. Kusaba T, Nakayama T, Yamazumi K, et a1. Expression of p-STAT3 in human colore- ctal adenocarcinoma and adenoma;correlation with clinicopathological factors. J Clin Pathol, 2005, 58(8): 833-838.
24. Wei D, Le X, Zheng L, et a1. STAT3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene, 2003, 22(3): 319-329.
25. Jung JE, Lee HG, Cho IH, et a1. STAT3 is a potential modulator of HIF-l-mediated VEGF expression in human renal carcinoma cells. FASEB J, 2005, 19(10): 1296-1298.
26. Gray MJ, Zhang J, Ellis LM, et a1. HIF-l alpha,STAT3,CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia- induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene, 2005, 24(19): 3110-3120.
27. Xu Q, Briggs J, Park S, et al. Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene, 2005, 24(36): 5552-5560.
28. Xie TX, Huang FJ, Aldape KD, et al. Activation of Stat3 in human melanoma promotes brain metastasis. Cancer Res, 2006, 66(6): 3188–3196.
29. Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene, 2004, 23(20): 3550-3560.
30. Itoh M, Murata T, Suzuki T, et al. Requirement of STAT3 activation for maximal collagenase-1(MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene, 2006, 25(8): 1195–1204.
31. Dechow TN, Pedranzini L, Leitch A, et al. Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA, 2004, 101(29): 10602–10607.
32. Cheng F, Wang HW, Cuenca A, et a1. A critical role for Stat3 signaling in immune tolerance. Immunity, 2003, l9(3): 425-436.
33. Nefedova Y, Huang M, Kusmartsev, et al. Hyperactivation of STAT3 is involved inabnormal differentiation ofdendritic cells in cancer. J lmmunol, 2004, 172(1): 464- 474.
34. Wang T, Niu G, Kortylewski M, et a1. Regulation of the innate and adaptive immune responses by STAT3 signaling in tumor cells. Nat Med, 2004, 10(1): 48-54.
35. Kortylewski M, Kujawski M, Wang T.Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med, 2005, 11(12): 1314- 1321.
36. Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene, 2002, 21(13): 2000-2008.
37. Wang FF, Chen HZ, Xie X, et a1. Phosphorylation of Stat3 induced by vascular endot- helial growth factor in ovarian carcinoma cell line in vitro. Zhong hua Fu Chan Ke Za Zhi, 2004, 39(6): 385-389.
38. Deo DD, Axelrad TW, Robert EG, et al. Phosphorylation of STAT-3 in response to basic fibroblast growth factor occurs through a mechanism involving platelet- activating factor, JAK-2, and Src in human umbilical vein endothelial cells. Evidence for a dual kinase mechanism. J Biol Chem, 2002, 277(24): 21237–21245.
39. Bartoli M, Platt D, Lemtalsi T, et al. VEGF differentially activates STAT3 in micro- vascular endothelial cells. FASEB J, 2003, 17(11): 1562-1564.
40. Schaefer LK, Ren Z, Fuller GN, et al. Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene, 2002, 21(13): 2058-2065.