siRNA干扰SOCS3表达对TNF-α诱导前体脂肪细胞凋亡的影响
|
摘要
脂肪细胞不仅是机体能量的主要贮存和释放场所,它还分泌多种细胞因子对其自身和其他细胞发挥重要的调节作用。TNF-α作为其中最早发现的分泌产物之一,它对脂肪细胞可产生多种效应,如抑制脂肪细胞生长,诱导前体脂肪细胞和脂肪细胞凋亡。但由于脂肪细胞自身的特点,TNF-α诱导脂肪细胞凋亡鲜有研究和报道。SOCS家族是JAK/STAT信号通路的负调控因子。JAK2/STAT3通路是多种细胞生长、存活、分化及凋亡功能发挥过程中重要的细胞内信号传导途径。
本试验以3T3-L1前体脂肪细胞和小鼠前体脂肪细胞为研究对象,应用siRNA沉默SOCS3基因,研究其对TNF-α诱导的前体脂肪细胞凋亡的影响,主要研究结果如下:
1.以20、40、60、80、100、150、200 ng/mL TNF-α处理3T3-L1前体脂肪细胞24 h,光学显微镜观察细胞的形态学变化。结果表明,TNF-α诱导3T3-L1前体脂肪细胞凋亡呈剂量依赖性。100 ng/mL TNF-α处理后,3T3-L1前体脂肪细胞出现明显的细胞凋亡,并伴随出现细胞体积缩小,染色质凝集,核质固缩等特征。
2.采用siRNA干扰技术,成功干扰SOCS3基因的表达,其中SOCS3 siRNA1基因沉默效果最明显,在3T3-L1前体脂肪细胞和小鼠前体脂肪细胞中SOCS3 mRNA表达分别下降了57%和50%,为后续以SOCS3基因为靶点的研究工作奠定基础。
3. siRNA沉默3T3-L1前体脂肪细胞中SOCS3基因后,100 ng/mL TNF-α处理24 h,采用Hoechst 33258和PI染色剂染色,荧光显微镜观察细胞的形态学变化。RT-PCR和Western Blotting方法检测凋亡相关基因c-myc、survivin、mcl-1、bcl-2、bax、NF-κB和JAK2/STAT3通路关键基因SOCS1、SOCS2、JAK2、STAT3的mRNA和蛋白的表达变化。结果表明,与对照组相比,沉默SOCS3表达后细胞凋亡数量明显减少;survivin和NF-κB mRNA表达显著上升(P<0.05),c-myc和bcl-2 mRNA表达极显著上升(P<0.01),bax和SOCS1 mRNA表达显著下降(P<0.05),而mcl-1 mRNA表达无显著变化(P>0.05);Western blotting检测发现,p-STAT3蛋白表达显著上升(P<0.05),Bcl-2和NF-κB蛋白表达极显著上升(P<0.01),Bax蛋白表达显著下降(P<0.05)。而脂质体组和阴性对照组中各基因、蛋白的表达与空白对照组之间均无显著变化。结果表明,沉默SOCS3通过调控JAK2/STAT3通路关键基因和凋亡相关基因的表达,显著抑制了TNF-α诱导的3T3-L1前体脂肪细胞凋亡。
4. siRNA沉默小鼠前体脂肪细胞中SOCS3基因后,100 ng/mL TNF-α处理24 h,Hoechst 33258和PI染色发现,沉默SOCS3表达后细胞凋亡数量明显减少;RT-PCR检测证明,NF-κB mRNA表达显著上升(P<0.05),mcl-1和bcl-2 mRNA表达极显著上升(P<0.01),SOCS1 mRNA表达极显著下降(P<0.01),而bax、c-myc和survivin mRNA表达无显著变化(P>0.05);Western blotting检测发现,Bcl-2、NF-κB和p-STAT3蛋白表达极显著上升(P<0.01),Bax蛋白表达显著下降(P<0.05)。结果表明,沉默SOCS3通过JAK2/STAT3通路调控了凋亡相关基因的表达,从而显著抑制了TNF-α诱导的小鼠前体脂肪细胞凋亡。
Adipocyte can not only reserve or release energy, but also secrete many cytokines to play an important role in regulating itself and other cells. TNF-αis one of the cytokines, it can produce a variety of effects to adipocyte, such as inhibit the growth of adipocyte, inducing the apoptosis of preadipocytes and adipocytes. However, owing to the evidently ability of adipocyte to resist apoptosis, TNF-αinduced adipocyte apoptosis was not well studied and poorly understood. SOCS is a negative feedback regulator of the JAK/STAT signaling pathway. JAK2/STAT3 signaling pathway participate in many signal transduction systems, influencing cell growth, survival, differentiation and apoptosis functions.
In this study, we used siRNA interfere technique to silence SOCS3 gene in 3T3-L1 preadipocytes and mouse preadipocytes. Study the effect of SOCS3 siRNA on TNF-αinduced apoptosis in both cells. The main results were summarized as following:
1. 3T3-L1 preadipocytes were cultured in vitro and treated with TNF-αat the concentrations of 20、40、60、80、100、150、200 ng/mL for 24 h, respectively. Optical microscope to observe morphological changes during apoptosis. TNF-αinduced 3T3-L1 preadipocytes apoptosis showed a dose dependent manner. After treated with 100 ng/mL TNF-αfor 24h, primary preadipocyte apoptosis was apparent, accompanied by reduced cell volume, chromatin condensation, and nuclear shrinkage.
2. Using siRNA interfere technique, this study successfully interfere the expression of SOCS3 gene. The gene silencing effect of SOCS3 siRNA1 is the most obvious. SOCS3 mRNA expression were suppressed by 57% and 50% by SOCS3 siRNA1 in 3T3-L1 preadipocytes and mouse preadipocytes, it may lay solid foundation for the further research on the function of SOCS3.
3. After SOCS3 expression was inhibited by SOCS3 siRNA infection, 3T3-L1 preadipocytes were treated with TNF-αat 100 ng/mL for 24 h. Morphological changes during apoptosis were observed by fluorescence microscope after staining by Hoechst 33258 and PI fluorescent dyes respectively. RT-PCR and Western blotting to measure the expression of apoptosis-associated gene c-myc、survivin、mcl-1、bcl-2、bax、NF-κB, and JAK2/STAT3 pathway key gene SOCS1, SOCS2, JAK2, STAT3. Compared with control group, in SOCS3 siRNA group the number of cells apoptosis was decreased remarkably; the expression level of survivin and NF-κB mRNA increased significantly (P<0.05), the expression level of c-myc and bcl-2 mRNA increased extremely significantly (P<0.01), the expression level of bax and SOCS1 mRNA decreased significantly (P<0.05), no changes were found for the expression of mcl-1 (P>0.05); Western blotting analysis showed that inhibition of SOCS3 also upregulated the expression of Bcl-2、NF-κB and p-STAT3 (P<0.05), but downgulated bax expression (P<0.05). Here, no distinct change was detected in LipofectineTM2000 group or negative control group. Taken together, our data established that knocking down SOCS3 can regulate the expression of apoptosis-associated gene by JAK2/STAT3 pathway, then effectively inhibit TNF-αinduced apoptosis in 3T3-L1 preadipocytes.
4. After SOCS3 expression was inhibited by SOCS3 siRNA infection, mouse preadipocytes were treated with TNF-αat 100 ng/mL for 24 h. Hoechst 33258 and PI staining showed that the number of cells apoptosis was decreased remarkably; RT-PCR analysis showed that, the expression level of NF-κB mRNA increased significantly (P<0.05), the expression level of mcl-1 and bcl-2 mRNA increased extremely significantly (P<0.01), the expression level of bax and SOCS1 mRNA decreased extremely significantly (P<0.01), no changes were found for the expression of bax、c-myc and survivin (P>0.05); Western blotting analysis showed that inhibition of SOCS3 also upregulated the expression of p-STAT3、Bcl-2 and NF-κB (P<0.01), but downgulated bax expression (P<0.05). Our data established that knocking down SOCS3 can regulate the expression of apoptosis-associated gene by JAK2/STAT3 pathway, then effectively inhibit TNF-αinduced apoptosis in mouse preadipocytes.
本试验以3T3-L1前体脂肪细胞和小鼠前体脂肪细胞为研究对象,应用siRNA沉默SOCS3基因,研究其对TNF-α诱导的前体脂肪细胞凋亡的影响,主要研究结果如下:
1.以20、40、60、80、100、150、200 ng/mL TNF-α处理3T3-L1前体脂肪细胞24 h,光学显微镜观察细胞的形态学变化。结果表明,TNF-α诱导3T3-L1前体脂肪细胞凋亡呈剂量依赖性。100 ng/mL TNF-α处理后,3T3-L1前体脂肪细胞出现明显的细胞凋亡,并伴随出现细胞体积缩小,染色质凝集,核质固缩等特征。
2.采用siRNA干扰技术,成功干扰SOCS3基因的表达,其中SOCS3 siRNA1基因沉默效果最明显,在3T3-L1前体脂肪细胞和小鼠前体脂肪细胞中SOCS3 mRNA表达分别下降了57%和50%,为后续以SOCS3基因为靶点的研究工作奠定基础。
3. siRNA沉默3T3-L1前体脂肪细胞中SOCS3基因后,100 ng/mL TNF-α处理24 h,采用Hoechst 33258和PI染色剂染色,荧光显微镜观察细胞的形态学变化。RT-PCR和Western Blotting方法检测凋亡相关基因c-myc、survivin、mcl-1、bcl-2、bax、NF-κB和JAK2/STAT3通路关键基因SOCS1、SOCS2、JAK2、STAT3的mRNA和蛋白的表达变化。结果表明,与对照组相比,沉默SOCS3表达后细胞凋亡数量明显减少;survivin和NF-κB mRNA表达显著上升(P<0.05),c-myc和bcl-2 mRNA表达极显著上升(P<0.01),bax和SOCS1 mRNA表达显著下降(P<0.05),而mcl-1 mRNA表达无显著变化(P>0.05);Western blotting检测发现,p-STAT3蛋白表达显著上升(P<0.05),Bcl-2和NF-κB蛋白表达极显著上升(P<0.01),Bax蛋白表达显著下降(P<0.05)。而脂质体组和阴性对照组中各基因、蛋白的表达与空白对照组之间均无显著变化。结果表明,沉默SOCS3通过调控JAK2/STAT3通路关键基因和凋亡相关基因的表达,显著抑制了TNF-α诱导的3T3-L1前体脂肪细胞凋亡。
4. siRNA沉默小鼠前体脂肪细胞中SOCS3基因后,100 ng/mL TNF-α处理24 h,Hoechst 33258和PI染色发现,沉默SOCS3表达后细胞凋亡数量明显减少;RT-PCR检测证明,NF-κB mRNA表达显著上升(P<0.05),mcl-1和bcl-2 mRNA表达极显著上升(P<0.01),SOCS1 mRNA表达极显著下降(P<0.01),而bax、c-myc和survivin mRNA表达无显著变化(P>0.05);Western blotting检测发现,Bcl-2、NF-κB和p-STAT3蛋白表达极显著上升(P<0.01),Bax蛋白表达显著下降(P<0.05)。结果表明,沉默SOCS3通过JAK2/STAT3通路调控了凋亡相关基因的表达,从而显著抑制了TNF-α诱导的小鼠前体脂肪细胞凋亡。
Adipocyte can not only reserve or release energy, but also secrete many cytokines to play an important role in regulating itself and other cells. TNF-αis one of the cytokines, it can produce a variety of effects to adipocyte, such as inhibit the growth of adipocyte, inducing the apoptosis of preadipocytes and adipocytes. However, owing to the evidently ability of adipocyte to resist apoptosis, TNF-αinduced adipocyte apoptosis was not well studied and poorly understood. SOCS is a negative feedback regulator of the JAK/STAT signaling pathway. JAK2/STAT3 signaling pathway participate in many signal transduction systems, influencing cell growth, survival, differentiation and apoptosis functions.
In this study, we used siRNA interfere technique to silence SOCS3 gene in 3T3-L1 preadipocytes and mouse preadipocytes. Study the effect of SOCS3 siRNA on TNF-αinduced apoptosis in both cells. The main results were summarized as following:
1. 3T3-L1 preadipocytes were cultured in vitro and treated with TNF-αat the concentrations of 20、40、60、80、100、150、200 ng/mL for 24 h, respectively. Optical microscope to observe morphological changes during apoptosis. TNF-αinduced 3T3-L1 preadipocytes apoptosis showed a dose dependent manner. After treated with 100 ng/mL TNF-αfor 24h, primary preadipocyte apoptosis was apparent, accompanied by reduced cell volume, chromatin condensation, and nuclear shrinkage.
2. Using siRNA interfere technique, this study successfully interfere the expression of SOCS3 gene. The gene silencing effect of SOCS3 siRNA1 is the most obvious. SOCS3 mRNA expression were suppressed by 57% and 50% by SOCS3 siRNA1 in 3T3-L1 preadipocytes and mouse preadipocytes, it may lay solid foundation for the further research on the function of SOCS3.
3. After SOCS3 expression was inhibited by SOCS3 siRNA infection, 3T3-L1 preadipocytes were treated with TNF-αat 100 ng/mL for 24 h. Morphological changes during apoptosis were observed by fluorescence microscope after staining by Hoechst 33258 and PI fluorescent dyes respectively. RT-PCR and Western blotting to measure the expression of apoptosis-associated gene c-myc、survivin、mcl-1、bcl-2、bax、NF-κB, and JAK2/STAT3 pathway key gene SOCS1, SOCS2, JAK2, STAT3. Compared with control group, in SOCS3 siRNA group the number of cells apoptosis was decreased remarkably; the expression level of survivin and NF-κB mRNA increased significantly (P<0.05), the expression level of c-myc and bcl-2 mRNA increased extremely significantly (P<0.01), the expression level of bax and SOCS1 mRNA decreased significantly (P<0.05), no changes were found for the expression of mcl-1 (P>0.05); Western blotting analysis showed that inhibition of SOCS3 also upregulated the expression of Bcl-2、NF-κB and p-STAT3 (P<0.05), but downgulated bax expression (P<0.05). Here, no distinct change was detected in LipofectineTM2000 group or negative control group. Taken together, our data established that knocking down SOCS3 can regulate the expression of apoptosis-associated gene by JAK2/STAT3 pathway, then effectively inhibit TNF-αinduced apoptosis in 3T3-L1 preadipocytes.
4. After SOCS3 expression was inhibited by SOCS3 siRNA infection, mouse preadipocytes were treated with TNF-αat 100 ng/mL for 24 h. Hoechst 33258 and PI staining showed that the number of cells apoptosis was decreased remarkably; RT-PCR analysis showed that, the expression level of NF-κB mRNA increased significantly (P<0.05), the expression level of mcl-1 and bcl-2 mRNA increased extremely significantly (P<0.01), the expression level of bax and SOCS1 mRNA decreased extremely significantly (P<0.01), no changes were found for the expression of bax、c-myc and survivin (P>0.05); Western blotting analysis showed that inhibition of SOCS3 also upregulated the expression of p-STAT3、Bcl-2 and NF-κB (P<0.01), but downgulated bax expression (P<0.05). Our data established that knocking down SOCS3 can regulate the expression of apoptosis-associated gene by JAK2/STAT3 pathway, then effectively inhibit TNF-αinduced apoptosis in mouse preadipocytes.
引文
林亚秋,陈国柱,卢建雄,杨公社. 2005. TNF-α对培养大鼠脂肪细胞凋亡的影响.畜牧兽医学报, 36(8): 823-827
Alas S, Bonavida B. 2003. Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res, 9: 316-326
Alkhouri N, Gornicka A, Berk M P, Thapaliya S, Dixon L J, Kashyap S, Schauer P R, Feldstein A E. 2010. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem, 285(5): 3428-3438
Almind K, Manieri M, Sivitz W I, Cinti S, Kahn C R. 2007. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc Natl Acad Sci USA, 104: 2366-2371
Almudena P, Alberto M, Ampara V, Manuel B. 1997. TNF-αinduces apoptosis in rat fetal brown adipocyte in primary culture. FEBS, 416(3): 324-328
Azambuja E, Durbecq V, Rosa D D, Colozza M, Larsimont D, Piccart G M, Cardoso F. 2008. HER-2 overexpression/amplification and its interaction with taxane-based therapy in breast cancer. Ann Oncol, 19(2): 223-232
Berishaj M, Gao S P, Ahmed S, Leslie K, Al H A, Gerald W L, Bornmann W, Bromberg J F. 2007. Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res, 9: R32
Bruun C, Heding P E, R?nn S G, Frobqse H, Rhodes C J, Mandrup P T, Billestrup N. 2009. Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells. Molecular and Cellular Endocrinology, 311: 32-38
Calvisi D F, Ladu S, Gorden A, Farina M, Conner E A, Lee J S, Factor V M, Thorgeirsson S S. 2006.
Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology, 130: 1117-1128
Chae G N, Kwak S J. 2003. NF-κB is involved in the TNF-alpha induced inhibition of the differentiation of 3T3-L1 cells by reducing PPAR gamma expression. Exp Mol Med, 35: 431-437
Chen C Y, Tsay W, Tang J L, Shen H L, Lin S W, Huang S Y, Yao M, Chen Y C, Shen M C, Wang C H, Tien H F. 2003. SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer, 37(3): 300-305
Chen C L, Hsieh F C, Lieblein J C, Brown J, Chan C, Wallace J A , Cheng G, Hall B M , Lin J. 2007. Stat3 activation in human endometrial and cervical cancers. Br J Cancer, 96: 591-599
Cinti S. 2006. The role of brown adipose tissue in human obesity. Nutr Metab Cardiovasc Dis, 16: 569-574
Coppo P, Flamant S, De M V, Jarrier P, Guillier M, Bonnet M L, Lacout C, Guilhot F, Vainchenker W, Turhan A G. 2006. BCR-ABL activates STAT3 via JAK and MEK pathways in human cells. Br J Haematol, 134(2): 171-179
Darnell J E J. 1997. STATs and gene regulation. Science, 277: 1630-1635
Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, Eweis I, Wloch M, Livingston S, Seijo E, Cantor A, Lee J H, Beam C A, Sullivan D, Jove R, Muro C C A. 2006. Activation of stat3 in primarytumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res, 12(1): 20-28
Duan Z, Foster R, Bell D A, Mahoney J, Wolak K, Vaidya A, Hampel C, Lee H, Seiden M V. 2006. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res, 12(17): 5055-5063
Farmer S R. 2006. Transcriptional control of adipocyte formation. Cell Metab, 4: 263-273
Fukushima N, Sato N, Sahin F, Su G H, Hruban R H, Goggins M. 2003. Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms. Br J Cancer, 89: 338-343
Galm O, Yoshikawa H, Esteller M, Osieka R, Herman J G. 2003. SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood, 101: 2784-2788
Gao Z, He Q, Peng B, Chiao P J, Ye J. 2006. Regulation of nuclear translocation of HDAC3 by IκBαis required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptorγfunction. J Biol Chem, 281: 4540-4547
Garcia R, Yu C L, Hudnall A, Catlett R, Nelson K L, Smithgall T, Fujita D J, Ethier S P, Jove R. 1997.
Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Diff, 8: 1267-1276
Cawthorn W P, Heyd F, Hegyi K, Sethi J K. 2007. Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Di er, 14: 1361-1373
Good M, Newell F M, Haupt L M, Whitehead J P, Hutley L J, Prins J B. 2006. TNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue–in?uence of BMI and adipose distribution. Diab Vasc Dis Res, 3: 26-33
Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee J H, Beam C A, Cheng J, Minton S, Muro C C A, Jove R. 2006.
Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res, 12(1): 11-19
Grivennikov S I, Karin M I. 2010. Dangerous liaisons: STAT3 and NF-kB collaboration and crosstalk in cancer. Cytokine & Growth Factor Reviews, 21(1): 11-19
Hadri K E, Courtalon A, Gauthereau X, Chambaut G A M, Pairault J, Feve B. 1997. Differential regulation by tumor necrosis factor-alpha of beta1-, beta2-, and beta3-adrenoreceptor gene expression in 3T3-F442A adipocytes. J Biol Chem, 272: 24514-24521
He B, You L, Uematsu K, Zang K, Xu Z, Lee A Y, Costello J B, Mc C F, Jablons D M. 2003. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA, 100: 14133-14138
Hector J, Schwarzloh B, Goehring J, Strate T G, Hess U F, Deuretzbacher G, Hansen A N, Beil F U, Algenstaedt P. 2007. TNF-alpha alters visfatin and adiponectin levels in human fat. Horm Metab Res, 39: 250-255
Hotamisligil G S, Arner P, Atkinson R L, Spiegelman B M. 1997. Di erential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes, 46: 451-455
Isomoto H, Mott J L, Kobayashi S, Werneburg N W, Bronk S F, Haan S, Gores G J. 2007. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing.Gastroenterology, 132(1): 384-396
Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y. 2007. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene, 26(17): 2435-2444
Jimenez M, Barbatelli G, Allevi R, Cinti S, Seydoux J, Giacobino J P, Muzzin P, Preitner F. 2003. Beta 3-adrenoceptor knockout in C57BL/6J mice depresses the occurrence of brown adipocytes in white fat. Eur J Biochem, 270: 699-705
Kaser S, Kaser A, Sandhofer A, Ebenbichler C F, Tilg H, Patsch J R. 2003. Resistin messenger-RNA expression is increased by proin?ammatory cytokines in vitro. Biochem Biophys Res Commun. 309: 286-290
Kawamata Y, Imamura T, Babendure J L, Lu J C, Yoshizaki T, Olefsky J M. 2007. Tumor necrosis factor receptor-1 can function through a G alpha q/11-beta-arrestin-1 signaling complex. J Biol Chem, 282: 28549-28556
Kern P A, Di G, Gregorio B, Lu T, Rassouli N, Ranganathan G. 2003. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-αexpression. Diabetes, 52: 1779-1785
Kirchgessner T G, Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S. 1997. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest, 100: 2777-2782
Kotha A, Sekharam M, Cilenti L, Siddiquee K, Khaled A, Zervos A S, Carter B, Turkson J, Jove R. 2006.
Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol Cancer Ther, 5(3): 621-629
Konnikova L, Kotecki M, Kruger M M, Cochran B H. 2003. Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer, 3: 23
Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T, Sekine I. 2006.
Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep, 15(6): 1445-1451
Lee H, Herrmann A, Deng J H, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll D M, Yu H. 2009.
Persistently activated Stat3 maintains constitutive NF-kB activity in tumors. Cancer Cell, 15(4): 283-293
Lee Y K, Isham C R, Kaufman S H, Bible K C. 2006. Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy. Mol Cancer Ther, 5: 138-148
Leu C M, Wong F H, Chang C, Huang S F, Hu C P. 2003. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene, 22: 7809-7818
Lopez S J, Llovera M, Carbo N, Garcia M C,Lopez S F J, Argiles J M. 1997. Lipid metabolism in tumour-bearing mice: studies with knockout mice for tumour necrosis factor receptor 1 protein. Mol Cell Endocrinol, 132: 93-99
Lowell B B, Flier J S. 1997. Brown adipose tissue, beta 3-adrenergic receptors, and obesity. Annu Rev Med, 48: 307-316
Miles P D, Romeo O M, Higo K, Cohen A, Rafaat K, Olefsky J M. 1997. TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes, 46: 1678-1683
Mishra1 K K, Gupta1 S, Ghosal K. 2010. Novel role of SOCS3 molecules in neural cells survival and differentiation. Clinical Neurophysiology, 121(1): S238
Nagai H, Naka T, Terada Y, Komazaki T, Yabe A, Jin E, Kawanami O, Kishimoto T, Konishi N, Nakamura M, Kobayashi Y, Emi M. 2003. Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet, 48: 65-69
Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akir S, Kishimoto T. 1997. Structure and function of a new STAT-induced STAT inhibitor. Nature, 387(6636): 924-929
Nasr M R, Laver J H, Chang M, Hutchison R E. 2007. Expression of anaplastic lymphoma kinase, tyrosine-phosphorylated STAT3, and associated factors in pediatric anaplastic large cell lymphoma: A report from the children's oncology group. Am J Clin Pathol, 127: 770-778
Nikitakis N G, Scheper M A, Papanikolaou V S, Sauk J J. 2009. The oncogenic effects of constitutive Stat3 signaling in salivary gland cancer cells are mediated by survivin and modulated by the NSAID sulindac. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 107(6): 826-836
Nisoli E, Briscini L, Tonello C, De G M C, Carruba M O. 1997. Tumor necrosis factor-alpha induces apoptosis in rat brown adipocytes. Cell Death Di er, 4: 771-778
Oba T, Yasukawa H, Sasaki K I, Futamata N, Mawatari K, Nagata T, Kyougoku S, Yajima T, Hoshijima M, Knowlton K U, Imaizumi T. 2009. Cardiac-Specific Deletion of SOCS3 Prevented Myocardial Apoptosis After Acute Myocardial Infarction Through Inhibiting Mitochondrial Damage. Journal of Cardiac Failure, 15(7): S151
Okochi O, Hibi K, Sakai M, Inoue S, Takeda S, Kaneko T, Nakao A. 2003. Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis. Clin Cancer Res, 9: 5295-5298 Onishi A, Chen Q, Humtsoe J O, Kramer R H. 2008. STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells. Exp Cell Res, 314: 377-386
Pandey M, Tuncman G, Hotamisligil G S, Samad F. 2003. Divergent roles for p55 and p75 TNF-alpha receptors in the induction of plasminogen activator inhibitor-1. Am J Pathol, 162: 933-941
Peraldi P, Xu M, Spiegelman B M. 1997. Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest, 100: 1863-1869
Pfeiffer A, Janott J, Mohlig M, Ristow M, Rochlitz H, Busch K, Schatz H, Schifferdecker E. 1997.
Circulating tumor necrosis factor alpha is elevated in male but not in female patients with type II diabetes mellitus. Horm Metab Res, 29: 111-114
Porras A, A lvarez A M, Valladares A, Benito M. 1997. TNF-alpha induces apoptosis in rat fetal brown adipocyte in primary culture. FEBS lett, 416(3): 324-328
Prins J B, Niesler C U, Winterford C M, Bright N A, Siddle K, O’Rahilly S, Walker N I, Cameron D P. 1997. Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes, 46: 1939-1944
Qian H, Hausman D B, Compton M M, Martin R J, Della F M A, Hartzell D L, Baile C A. 2001. TNF alpha induces and insulin inhibits caspase-3 dependent adipocyte apoptosis. Academic press, 284(5): 1176-1183
Rahaman S O, Harbor P C, Chernova O, Barnett G H, Vogelbaum M A, Haque S J. 2002. Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene, 21: 8404-8413
Real P J, Sierra A, De J A, Segovia J C, Lopez V J M, Fernandez L J L. 2002. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene, 21: 7611-7618
Ren W, Duan Y, Yang Y, Ji Y, Chen F. 2008. Down-regulation of Stat3 induces apoptosis of human glioma cell: a potential method to treat brain cancer. Neurol Res, 30(3): 297-301
Rosen E D, Mac D O A. 2006. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol, 7: 885-896
Ruan H, Miles P D G, Ladd C M, Ross K, Golub T R,Olefsky J M, Lodish H F, 2002a. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α: implications for insulin resistance. Diabetes, 51: 3176-3188
Ruan H, Hacohen N, Golub T R, Parijs V L, Lodish H F. 2002b. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes, 51: 1319-1336
Ryden M, Dicker A, Harmelen V V, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F, Arner P. 2002.
Mapping of early signaling events in tumor necrosis factor-alpha mediated lipolysis in human fat cells. J Biol Chem, 277: 1085-1091
Sakai I, Takeuchi K, Yamauchi H, Narumi H, Fujita S. 2002. Constitutive expression of SOCS3 confers resistance to IFN-alpha in chronic myelogenous leukemia cells. Blood, 100: 2926-2931
Schaefer L K, Ren Z, Fuller G N, Schaefer T S. 2002. Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene, 21: 2058-2065
Sethi J K, Vidal P A J. 2007. Thematic review series:adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res, 48: 1253-1262
Shi H, Cave B, Inouye K, Bjorbaek C, Flier J S. 2006. Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes, 55: 699-707
Siddiquee K A, Gunning P T, Glenn M, Katt W P, Zhang S, Schrock C, Sebti S M, Jove R, Hamilton A D, Turkson J. 2007a. An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem Biol, 2(12): 787-798
Siddiquee K A, Zhang S, Guida W C, Blaskovich M A, Greedy B, Lawrence H R, Yip M L, Jove R, McLaughlin M M, Lawrence N J, Sebti S M, Turkson J. 2007b. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A, 104: 7391-7396
Starr R, Willson, Viney E M, Murray L J L, Rayner J R, Jenkins B J, Gonda T J, Alexander W S, Metcalf D, Nicola N A, Hilton D J. 1997. A family of cytokine-induciable inhibitors of signaling. Nature, 387(6636): 917-921
Stephens J M, Lee J L, Pilch P F, 1997. Tumor necrosis factor alpha induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression with a loss of insulin receptor-mediated signal transduction. J Biol Chem, 272: 971-976
Sumita N, Bito T, Nakajima K, Nishigori C. 2006. Stat3 activation is required for cell proliferation and tumorigenesis but not for cell viability in cutaneous squamous cell carcinoma cell lines. Exp Dermatol, 15: 291-299
Sun X, Zhang J, Wang L, Tian Z. 2008. Growth inhibition of human hepatocellular carcinoma cells by blocking STAT3 activation with decoy-ODN. Cancer Letters, 262(2): 201-213
Tam L, McGlynn L M, Traynor P, Mukherjee R, Bartlett J M, Edwards J. 2007. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer, 97: 378-383
Tamori Y, Masugi J, Nishino N, Kasuga M. 2002. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes, 51: 2045-2055
Tang X Q, Guilherme A, Chakladar A, Powelka A M, Konda S, Virbasius J V, Nicoloro S M C, Straubhaar J, Czech M P. 2006. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci USA, 103: 2087-2092
Tesz G J, Guilherme A, Guntur K V, Hubbard A C, Tang X, Chawla A, Czech M P. 2007. Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNF-alpha receptor 1 signaling to c-Jun and activating transcription factor 2. J Biol Chem, 282: 19302-19312
Tischoff I, Hengge UR, Vieth M, Ell C, Stolte M, Weber A, Schmidt W E, Tannapfel A. 2007. Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma. Gut, 56: 1047-1053
Trevino J G, Gray M J, Nawrocki S T, Summy J M, Lesslie D P, Evans D B, Sawyer T K, Shakespeare W C, Watowich S S, Chiao P J, McConkey D J, Gallick G E. 2006. Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis, 9: 101-110
Xiao Y, Yuan T, Yao W, Liao K. 2009. 3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-gammol/L a-dependent and mediated by the caspase-3-dependent apoptotic pathway. FEBS J, 277: 687-696
Xie T X, Huang F J, Aldape K D, Kang S H, Liu M, Gershenwald J E, Xie K, Sawaya R, Huang S. 2006.
Activation of Stat3 in Human Melanoma Promotes Brain Metastasis. Cancer Res, 66(6): 3188-3196
Yakata Y, Nakayama T, Yoshizaki A, Kusaba T, Inoue K, Sekine I. 2007. Expression of p-STAT3 in human gastric carcinoma: significant correlation in tumour invasion and prognosis. Int J Oncol, 30: 437-442
Yu ZB, Bai L, Qian P. 2009. Restoration of SOCS3 suppresses human lung adenocarcinoma cell growth by downregulating activation of Erk1/2, Akt apart from STAT3. Cell Biology International, 33(9): 995-1001
Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy D E, Inghirami G. 2002. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene, 21: 1038-1047
Zhang H H, Halbleib M, Ahmad F, Manganiello V C, Greenberg A S. 2002. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes, 51: 2929-2935
Zhuang L, Lee C S, Scolyer R A, McCarthy S W, Zhang X D, Thompson J F, Hersey P. 2007. Mcl-1,Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol, 20(4): 416-426
Zu L, Jiang H, He J, Xu C, Pu S, Liu M, Xu G. 2008. Salicylate Blocks Lipolytic Actions of Tumor Necrosis Factor-TNF-αin Primary Rat Adipocytes. Mol Pharmacol, 73(1): 215-223
Alas S, Bonavida B. 2003. Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res, 9: 316-326
Alkhouri N, Gornicka A, Berk M P, Thapaliya S, Dixon L J, Kashyap S, Schauer P R, Feldstein A E. 2010. Adipocyte apoptosis, a link between obesity, insulin resistance, and hepatic steatosis. J Biol Chem, 285(5): 3428-3438
Almind K, Manieri M, Sivitz W I, Cinti S, Kahn C R. 2007. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice. Proc Natl Acad Sci USA, 104: 2366-2371
Almudena P, Alberto M, Ampara V, Manuel B. 1997. TNF-αinduces apoptosis in rat fetal brown adipocyte in primary culture. FEBS, 416(3): 324-328
Azambuja E, Durbecq V, Rosa D D, Colozza M, Larsimont D, Piccart G M, Cardoso F. 2008. HER-2 overexpression/amplification and its interaction with taxane-based therapy in breast cancer. Ann Oncol, 19(2): 223-232
Berishaj M, Gao S P, Ahmed S, Leslie K, Al H A, Gerald W L, Bornmann W, Bromberg J F. 2007. Stat3 is tyrosine-phosphorylated through the interleukin-6/glycoprotein 130/Janus kinase pathway in breast cancer. Breast Cancer Res, 9: R32
Bruun C, Heding P E, R?nn S G, Frobqse H, Rhodes C J, Mandrup P T, Billestrup N. 2009. Suppressor of cytokine signalling-3 inhibits tumor necrosis factor-alpha induced apoptosis and signalling in beta cells. Molecular and Cellular Endocrinology, 311: 32-38
Calvisi D F, Ladu S, Gorden A, Farina M, Conner E A, Lee J S, Factor V M, Thorgeirsson S S. 2006.
Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology, 130: 1117-1128
Chae G N, Kwak S J. 2003. NF-κB is involved in the TNF-alpha induced inhibition of the differentiation of 3T3-L1 cells by reducing PPAR gamma expression. Exp Mol Med, 35: 431-437
Chen C Y, Tsay W, Tang J L, Shen H L, Lin S W, Huang S Y, Yao M, Chen Y C, Shen M C, Wang C H, Tien H F. 2003. SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer, 37(3): 300-305
Chen C L, Hsieh F C, Lieblein J C, Brown J, Chan C, Wallace J A , Cheng G, Hall B M , Lin J. 2007. Stat3 activation in human endometrial and cervical cancers. Br J Cancer, 96: 591-599
Cinti S. 2006. The role of brown adipose tissue in human obesity. Nutr Metab Cardiovasc Dis, 16: 569-574
Coppo P, Flamant S, De M V, Jarrier P, Guillier M, Bonnet M L, Lacout C, Guilhot F, Vainchenker W, Turhan A G. 2006. BCR-ABL activates STAT3 via JAK and MEK pathways in human cells. Br J Haematol, 134(2): 171-179
Darnell J E J. 1997. STATs and gene regulation. Science, 277: 1630-1635
Diaz N, Minton S, Cox C, Bowman T, Gritsko T, Garcia R, Eweis I, Wloch M, Livingston S, Seijo E, Cantor A, Lee J H, Beam C A, Sullivan D, Jove R, Muro C C A. 2006. Activation of stat3 in primarytumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression. Clin Cancer Res, 12(1): 20-28
Duan Z, Foster R, Bell D A, Mahoney J, Wolak K, Vaidya A, Hampel C, Lee H, Seiden M V. 2006. Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer. Clin Cancer Res, 12(17): 5055-5063
Farmer S R. 2006. Transcriptional control of adipocyte formation. Cell Metab, 4: 263-273
Fukushima N, Sato N, Sahin F, Su G H, Hruban R H, Goggins M. 2003. Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms. Br J Cancer, 89: 338-343
Galm O, Yoshikawa H, Esteller M, Osieka R, Herman J G. 2003. SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood, 101: 2784-2788
Gao Z, He Q, Peng B, Chiao P J, Ye J. 2006. Regulation of nuclear translocation of HDAC3 by IκBαis required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptorγfunction. J Biol Chem, 281: 4540-4547
Garcia R, Yu C L, Hudnall A, Catlett R, Nelson K L, Smithgall T, Fujita D J, Ethier S P, Jove R. 1997.
Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Diff, 8: 1267-1276
Cawthorn W P, Heyd F, Hegyi K, Sethi J K. 2007. Tumour necrosis factor-alpha inhibits adipogenesis via a beta-catenin/TCF4(TCF7L2)-dependent pathway. Cell Death Di er, 14: 1361-1373
Good M, Newell F M, Haupt L M, Whitehead J P, Hutley L J, Prins J B. 2006. TNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue–in?uence of BMI and adipose distribution. Diab Vasc Dis Res, 3: 26-33
Gritsko T, Williams A, Turkson J, Kaneko S, Bowman T, Huang M, Nam S, Eweis I, Diaz N, Sullivan D, Yoder S, Enkemann S, Eschrich S, Lee J H, Beam C A, Cheng J, Minton S, Muro C C A, Jove R. 2006.
Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res, 12(1): 11-19
Grivennikov S I, Karin M I. 2010. Dangerous liaisons: STAT3 and NF-kB collaboration and crosstalk in cancer. Cytokine & Growth Factor Reviews, 21(1): 11-19
Hadri K E, Courtalon A, Gauthereau X, Chambaut G A M, Pairault J, Feve B. 1997. Differential regulation by tumor necrosis factor-alpha of beta1-, beta2-, and beta3-adrenoreceptor gene expression in 3T3-F442A adipocytes. J Biol Chem, 272: 24514-24521
He B, You L, Uematsu K, Zang K, Xu Z, Lee A Y, Costello J B, Mc C F, Jablons D M. 2003. SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA, 100: 14133-14138
Hector J, Schwarzloh B, Goehring J, Strate T G, Hess U F, Deuretzbacher G, Hansen A N, Beil F U, Algenstaedt P. 2007. TNF-alpha alters visfatin and adiponectin levels in human fat. Horm Metab Res, 39: 250-255
Hotamisligil G S, Arner P, Atkinson R L, Spiegelman B M. 1997. Di erential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes, 46: 451-455
Isomoto H, Mott J L, Kobayashi S, Werneburg N W, Bronk S F, Haan S, Gores G J. 2007. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing.Gastroenterology, 132(1): 384-396
Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y. 2007. A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene, 26(17): 2435-2444
Jimenez M, Barbatelli G, Allevi R, Cinti S, Seydoux J, Giacobino J P, Muzzin P, Preitner F. 2003. Beta 3-adrenoceptor knockout in C57BL/6J mice depresses the occurrence of brown adipocytes in white fat. Eur J Biochem, 270: 699-705
Kaser S, Kaser A, Sandhofer A, Ebenbichler C F, Tilg H, Patsch J R. 2003. Resistin messenger-RNA expression is increased by proin?ammatory cytokines in vitro. Biochem Biophys Res Commun. 309: 286-290
Kawamata Y, Imamura T, Babendure J L, Lu J C, Yoshizaki T, Olefsky J M. 2007. Tumor necrosis factor receptor-1 can function through a G alpha q/11-beta-arrestin-1 signaling complex. J Biol Chem, 282: 28549-28556
Kern P A, Di G, Gregorio B, Lu T, Rassouli N, Ranganathan G. 2003. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-αexpression. Diabetes, 52: 1779-1785
Kirchgessner T G, Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S. 1997. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest, 100: 2777-2782
Kotha A, Sekharam M, Cilenti L, Siddiquee K, Khaled A, Zervos A S, Carter B, Turkson J, Jove R. 2006.
Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein. Mol Cancer Ther, 5(3): 621-629
Konnikova L, Kotecki M, Kruger M M, Cochran B H. 2003. Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer, 3: 23
Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T, Sekine I. 2006.
Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep, 15(6): 1445-1451
Lee H, Herrmann A, Deng J H, Kujawski M, Niu G, Li Z, Forman S, Jove R, Pardoll D M, Yu H. 2009.
Persistently activated Stat3 maintains constitutive NF-kB activity in tumors. Cancer Cell, 15(4): 283-293
Lee Y K, Isham C R, Kaufman S H, Bible K C. 2006. Flavopiridol disrupts STAT3/DNA interactions, attenuates STAT3-directed transcription, and combines with the Jak kinase inhibitor AG490 to achieve cytotoxic synergy. Mol Cancer Ther, 5: 138-148
Leu C M, Wong F H, Chang C, Huang S F, Hu C P. 2003. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene, 22: 7809-7818
Lopez S J, Llovera M, Carbo N, Garcia M C,Lopez S F J, Argiles J M. 1997. Lipid metabolism in tumour-bearing mice: studies with knockout mice for tumour necrosis factor receptor 1 protein. Mol Cell Endocrinol, 132: 93-99
Lowell B B, Flier J S. 1997. Brown adipose tissue, beta 3-adrenergic receptors, and obesity. Annu Rev Med, 48: 307-316
Miles P D, Romeo O M, Higo K, Cohen A, Rafaat K, Olefsky J M. 1997. TNF-alpha-induced insulin resistance in vivo and its prevention by troglitazone. Diabetes, 46: 1678-1683
Mishra1 K K, Gupta1 S, Ghosal K. 2010. Novel role of SOCS3 molecules in neural cells survival and differentiation. Clinical Neurophysiology, 121(1): S238
Nagai H, Naka T, Terada Y, Komazaki T, Yabe A, Jin E, Kawanami O, Kishimoto T, Konishi N, Nakamura M, Kobayashi Y, Emi M. 2003. Hypermethylation associated with inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human hepatoblastomas. J Hum Genet, 48: 65-69
Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, Aono A, Nishimoto N, Kajita T, Taga T, Yoshizaki K, Akir S, Kishimoto T. 1997. Structure and function of a new STAT-induced STAT inhibitor. Nature, 387(6636): 924-929
Nasr M R, Laver J H, Chang M, Hutchison R E. 2007. Expression of anaplastic lymphoma kinase, tyrosine-phosphorylated STAT3, and associated factors in pediatric anaplastic large cell lymphoma: A report from the children's oncology group. Am J Clin Pathol, 127: 770-778
Nikitakis N G, Scheper M A, Papanikolaou V S, Sauk J J. 2009. The oncogenic effects of constitutive Stat3 signaling in salivary gland cancer cells are mediated by survivin and modulated by the NSAID sulindac. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 107(6): 826-836
Nisoli E, Briscini L, Tonello C, De G M C, Carruba M O. 1997. Tumor necrosis factor-alpha induces apoptosis in rat brown adipocytes. Cell Death Di er, 4: 771-778
Oba T, Yasukawa H, Sasaki K I, Futamata N, Mawatari K, Nagata T, Kyougoku S, Yajima T, Hoshijima M, Knowlton K U, Imaizumi T. 2009. Cardiac-Specific Deletion of SOCS3 Prevented Myocardial Apoptosis After Acute Myocardial Infarction Through Inhibiting Mitochondrial Damage. Journal of Cardiac Failure, 15(7): S151
Okochi O, Hibi K, Sakai M, Inoue S, Takeda S, Kaneko T, Nakao A. 2003. Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis. Clin Cancer Res, 9: 5295-5298 Onishi A, Chen Q, Humtsoe J O, Kramer R H. 2008. STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells. Exp Cell Res, 314: 377-386
Pandey M, Tuncman G, Hotamisligil G S, Samad F. 2003. Divergent roles for p55 and p75 TNF-alpha receptors in the induction of plasminogen activator inhibitor-1. Am J Pathol, 162: 933-941
Peraldi P, Xu M, Spiegelman B M. 1997. Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest, 100: 1863-1869
Pfeiffer A, Janott J, Mohlig M, Ristow M, Rochlitz H, Busch K, Schatz H, Schifferdecker E. 1997.
Circulating tumor necrosis factor alpha is elevated in male but not in female patients with type II diabetes mellitus. Horm Metab Res, 29: 111-114
Porras A, A lvarez A M, Valladares A, Benito M. 1997. TNF-alpha induces apoptosis in rat fetal brown adipocyte in primary culture. FEBS lett, 416(3): 324-328
Prins J B, Niesler C U, Winterford C M, Bright N A, Siddle K, O’Rahilly S, Walker N I, Cameron D P. 1997. Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes, 46: 1939-1944
Qian H, Hausman D B, Compton M M, Martin R J, Della F M A, Hartzell D L, Baile C A. 2001. TNF alpha induces and insulin inhibits caspase-3 dependent adipocyte apoptosis. Academic press, 284(5): 1176-1183
Rahaman S O, Harbor P C, Chernova O, Barnett G H, Vogelbaum M A, Haque S J. 2002. Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene, 21: 8404-8413
Real P J, Sierra A, De J A, Segovia J C, Lopez V J M, Fernandez L J L. 2002. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene, 21: 7611-7618
Ren W, Duan Y, Yang Y, Ji Y, Chen F. 2008. Down-regulation of Stat3 induces apoptosis of human glioma cell: a potential method to treat brain cancer. Neurol Res, 30(3): 297-301
Rosen E D, Mac D O A. 2006. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol, 7: 885-896
Ruan H, Miles P D G, Ladd C M, Ross K, Golub T R,Olefsky J M, Lodish H F, 2002a. Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α: implications for insulin resistance. Diabetes, 51: 3176-3188
Ruan H, Hacohen N, Golub T R, Parijs V L, Lodish H F. 2002b. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes, 51: 1319-1336
Ryden M, Dicker A, Harmelen V V, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F, Arner P. 2002.
Mapping of early signaling events in tumor necrosis factor-alpha mediated lipolysis in human fat cells. J Biol Chem, 277: 1085-1091
Sakai I, Takeuchi K, Yamauchi H, Narumi H, Fujita S. 2002. Constitutive expression of SOCS3 confers resistance to IFN-alpha in chronic myelogenous leukemia cells. Blood, 100: 2926-2931
Schaefer L K, Ren Z, Fuller G N, Schaefer T S. 2002. Constitutive activation of Stat3alpha in brain tumors: localization to tumor endothelial cells and activation by the endothelial tyrosine kinase receptor (VEGFR-2). Oncogene, 21: 2058-2065
Sethi J K, Vidal P A J. 2007. Thematic review series:adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res, 48: 1253-1262
Shi H, Cave B, Inouye K, Bjorbaek C, Flier J S. 2006. Overexpression of suppressor of cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes, 55: 699-707
Siddiquee K A, Gunning P T, Glenn M, Katt W P, Zhang S, Schrock C, Sebti S M, Jove R, Hamilton A D, Turkson J. 2007a. An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects. ACS Chem Biol, 2(12): 787-798
Siddiquee K A, Zhang S, Guida W C, Blaskovich M A, Greedy B, Lawrence H R, Yip M L, Jove R, McLaughlin M M, Lawrence N J, Sebti S M, Turkson J. 2007b. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A, 104: 7391-7396
Starr R, Willson, Viney E M, Murray L J L, Rayner J R, Jenkins B J, Gonda T J, Alexander W S, Metcalf D, Nicola N A, Hilton D J. 1997. A family of cytokine-induciable inhibitors of signaling. Nature, 387(6636): 917-921
Stephens J M, Lee J L, Pilch P F, 1997. Tumor necrosis factor alpha induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression with a loss of insulin receptor-mediated signal transduction. J Biol Chem, 272: 971-976
Sumita N, Bito T, Nakajima K, Nishigori C. 2006. Stat3 activation is required for cell proliferation and tumorigenesis but not for cell viability in cutaneous squamous cell carcinoma cell lines. Exp Dermatol, 15: 291-299
Sun X, Zhang J, Wang L, Tian Z. 2008. Growth inhibition of human hepatocellular carcinoma cells by blocking STAT3 activation with decoy-ODN. Cancer Letters, 262(2): 201-213
Tam L, McGlynn L M, Traynor P, Mukherjee R, Bartlett J M, Edwards J. 2007. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br J Cancer, 97: 378-383
Tamori Y, Masugi J, Nishino N, Kasuga M. 2002. Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes, 51: 2045-2055
Tang X Q, Guilherme A, Chakladar A, Powelka A M, Konda S, Virbasius J V, Nicoloro S M C, Straubhaar J, Czech M P. 2006. An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. Proc Natl Acad Sci USA, 103: 2087-2092
Tesz G J, Guilherme A, Guntur K V, Hubbard A C, Tang X, Chawla A, Czech M P. 2007. Tumor necrosis factor alpha (TNFalpha) stimulates Map4k4 expression through TNF-alpha receptor 1 signaling to c-Jun and activating transcription factor 2. J Biol Chem, 282: 19302-19312
Tischoff I, Hengge UR, Vieth M, Ell C, Stolte M, Weber A, Schmidt W E, Tannapfel A. 2007. Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma. Gut, 56: 1047-1053
Trevino J G, Gray M J, Nawrocki S T, Summy J M, Lesslie D P, Evans D B, Sawyer T K, Shakespeare W C, Watowich S S, Chiao P J, McConkey D J, Gallick G E. 2006. Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis, 9: 101-110
Xiao Y, Yuan T, Yao W, Liao K. 2009. 3T3-L1 adipocyte apoptosis induced by thiazolidinediones is peroxisome proliferator-activated receptor-gammol/L a-dependent and mediated by the caspase-3-dependent apoptotic pathway. FEBS J, 277: 687-696
Xie T X, Huang F J, Aldape K D, Kang S H, Liu M, Gershenwald J E, Xie K, Sawaya R, Huang S. 2006.
Activation of Stat3 in Human Melanoma Promotes Brain Metastasis. Cancer Res, 66(6): 3188-3196
Yakata Y, Nakayama T, Yoshizaki A, Kusaba T, Inoue K, Sekine I. 2007. Expression of p-STAT3 in human gastric carcinoma: significant correlation in tumour invasion and prognosis. Int J Oncol, 30: 437-442
Yu ZB, Bai L, Qian P. 2009. Restoration of SOCS3 suppresses human lung adenocarcinoma cell growth by downregulating activation of Erk1/2, Akt apart from STAT3. Cell Biology International, 33(9): 995-1001
Zamo A, Chiarle R, Piva R, Howes J, Fan Y, Chilosi M, Levy D E, Inghirami G. 2002. Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. Oncogene, 21: 1038-1047
Zhang H H, Halbleib M, Ahmad F, Manganiello V C, Greenberg A S. 2002. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes, 51: 2929-2935
Zhuang L, Lee C S, Scolyer R A, McCarthy S W, Zhang X D, Thompson J F, Hersey P. 2007. Mcl-1,Bcl-XL and Stat3 expression are associated with progression of melanoma whereas Bcl-2, AP-2 and MITF levels decrease during progression of melanoma. Mod Pathol, 20(4): 416-426
Zu L, Jiang H, He J, Xu C, Pu S, Liu M, Xu G. 2008. Salicylate Blocks Lipolytic Actions of Tumor Necrosis Factor-TNF-αin Primary Rat Adipocytes. Mol Pharmacol, 73(1): 215-223