• The Journal of the Korean bone and joint tumor society
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• v.15 no.2
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• pp.130-137
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• 2009

Purpose: STAT3 is an oncogene that regulates critical cellular processes, and its constitutive activation has been demonstrated to correlate with biological and clinical features in many types of human malignancy. Materials and Methods: In this study, STAT3 activation was assessed in variable benign and malignant chondroid tumors in bone by immunohistochemistry using a monoclonal antibody specific for $tyrosine^{705}$-phosphorylated STAT3 ($pSTAT3^{tyr705}$). Results: Among conventional chondrosarcomas (n=17), three cases(50%) of grade III chondrosarcomas were pSTAT3-positive. All grade I and II chondrosarcomas were pSTAT3-negative. This pSTAT3 positivity according to the histologic grade was statistically significant (p=0.0432). Two cases(50%) of clear cell chondrosarcomas were pSTAT3-positive. Six cases (50%) among 12 benign chondroid tumors(6 enchondromas, 3 chondroblastomas, and 3 chondromyxoid fibromas) were also $pSTAT3^{tyr705}$-positive. Conclusion: In conclusion, STAT3 activation is associated with higher tumor grade in conventional chondrosarcomas. Our results suggest that STAT3 is activated in a subset of benign and malignant chondroid tumors, and may support the extension of the cancer stem cell hypothesis to include tumors of cartilaginous lineage.

• Journal of Chest Surgery
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• v.31 no.6
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• pp.553-559
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• 1998

Introduction: The most dramatic application of hypothermia in cardiac surgery is in deep hypothermic circulatory arrest(DHCA). Because man in natural circumstances is never exposed to this extreme hypothermic condition, one of the controversial aspects of clinical hypothermia is appropriate acid-base management($\alpha$-stat versus pH-stat). This study aims to compare $\alpha$-stat with pH-stat for: (1) brain cooling and re-warming speed during hypothermia induction and re-warming by cardiopulmonary bypass (CPB); (2) cerebral perfusion, metabolism, and their coupling; and (3) the extent of development of cerebral edema after circulatory arrest, in young pigs. Materials & Methods: Fourteen young pigs were assigned to one of two strategies of gas manipulation. Cerebral blood flow was measured with a cerebral venous outflow technique. After a median sternotomy, CPB was established. Core cooling was initiated and continued until nasopHaryngeal temperature fell below $20^{\circ}C$. The flow rate was set at 2,500 ml/min. Once their temperatures were below $20^{\circ}C$, the animals were subjected to DHCA for 40 mins. During cooling, acid-base balance was maintained according to either $\alpha$-STAT or pH-STAT strategies. After DHCA, the body was re-warmed to normal body temperature. The animals were then sacrificed, and their brains measured for edema. Cerebral perfusion and metabolism were measured before the onset of CPB, before cooling, before DHCA, 15 mins after re-warming, and upon completion of re-warming. Results & Conclusion: Cooling time was significantly shorter with $\alpha$-stat than with pH-stat strategy, while there were no significant differences in rewarming time between the two groups. Nosignificant differences were found in cerebral blood flow, metabolic rate, or flow/ metabolic rate ratio between two groups. Temperature-related differences were significant in cerebral blood flow, metabolic rate, and flow/metabolic rate ratio within each group. Brain water content showed no significant differences between two groups.

• Korean Journal of Veterinary Research
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• v.44 no.2
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• pp.163-169
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• 2004

To elucidate the molecular mechanisms of autoimmune inflammation in the central nervous system, we examined the expression and localization of STAT1, STAT3, STAT4 and STAT6 molecules during experimental autoimmune encephalomyelitis (EAE) by competitive PCR. In the present study, we quantitated IL-4 and IL-12 p40 mRNA by competitive PCR in the CNS during EAE. IL-4 mRNA was found at early and peak stages. On the other hand, the IL-12 p40 mRNA level reached maximal levels at the peak stage and still found at the recovery stage of the disease. We examined the kinetics of STAT mRNA in the CNS during EAE and demonstrated that STAT1 and STAT4 mRNA reached a maximal level at the peak stage of EAE, whereas STAT3 mRNA level increased gradually to the recovery stage. STAT6 mRNA increased rapidly at the early stage followed by gradual decrease till the recovery stage. Taken together, these findings suggest that STAT4 which was probably activated by IL-12 plays a pro-inflammatory role and that STAT3 which was activated throughout the disease course seems to serve as a transducer of anti-inflammatory signals.

• Journal of Life Science
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• v.9 no.1
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• pp.50-57
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• 1999

STATs activated by various cytokine and growth factors trigger a quick response in the nucleus and induce changes in gene expression. We have found the sequences homologous to STAT binding site in the 5'-flanking region of the D-raf gene. In this study, we examined role of the STAT binding site in D-raf gene promoter activity in vivo by using transgenic flies. The reporter plasmid pDraf-STATmut-lacZ was constructed by fusing D-raf promoter fragment having the base-substituted STAT binding site with the lacZ gene in a P-element vector. Transgenic flies bearing the Draf-STATmut-lacZ fusion genes were established by P-element mediated transformation. The expression of lacZ in transgenic flies bearing Draf-STATmut-lacZ fusion genes carrying base substitution in STAT site throughout various developmental stages was extensively reduced in comparison with that in transgenic flies bearing wild type Draf-lacZ fusion gene. These results show that the STAT binding site plays an important role in regulation of the D-raf gene.

• Journal of Ginseng Research
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• v.48 no.4
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• pp.405-416
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• 2024

Background: Hypoxic pulmonary hypertension (HPH) is the main pathological change in vascular remodeling, a complex cardiopulmonary disease caused by hypoxia. Some research results have shown that ginsenoside Rg1 (Rg1) can improve vascular remodeling, but the effect and mechanism of Rg1 on hypoxia-induced pulmonary hypertension are not clear. The purpose of this study was to discuss the potential mechanism of action of Rg1 on HPH. Methods: C57BL/6 mice, calpain-1 knockout mice and Pulmonary artery smooth muscle cells (PASMCs) were exposed to a low oxygen environment with or without different treatments. The effect of Rg1 and calpain-1 silencing on inflammation, fibrosis, proliferation and the protein expression levels of calpain-1, STAT3 and p-STAT3 were determined at the animal and cellular levels. Results: At the mouse and cellular levels, hypoxia promotes inflammation, fibrosis, and cell proliferation, and the expression of calpain-1 and p-STAT3 is also increased. Ginsenoside Rg1 administration and calpain-1 knockdown, MDL-28170, and HY-13818 treatment showed protective effects on hypoxia-induced inflammation, fibrosis, and cell proliferation, which may be associated with the downregulation of calpain-1 and p-STAT3 expression in mice and cells. In addition, overexpression of calpain 1 increased p-STAT3 expression, accelerating the onset of inflammation, fibrosis and cell proliferation in hypoxic PASMCs. Conclusion: Ginsenoside Rg1 may ameliorate hypoxia-induced pulmonary vascular remodeling by suppressing the calpain-1/STAT3 signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3117-3120
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• 2015

Objective: Interferon-${\gamma}$ (IFN-${\gamma}$) and signal transducers and activators of transcription (STATs) each play an important role in carcinogenesis associated with viral infection. Cervical cancer is almost invariably associated with infection by human papillomavirus (HPV), and previous studies suggested that dysregulation of the signal pathway involved in IFN-${\gamma}$ and STATs is associated. Our objective was to evaluate the association of SNPs in STAT2, STAT3, and IFN-${\gamma}$ with cervical cancer susceptibility in Chinese Han women in Hunan province. Materials and Methods: Genomic DNA was extracted from peripheral blood samples of 234 cervical cancer patients and 216 healthy female controls. STAT2 and STAT3 genotyping was performed using polymerase chain reaction-restriction enzyme (PCR-RE) analysis. IFN-${\gamma}$ genotyping was detected by PCR-amplification of specific allele (PASA). Results: For STAT2 rs2066807 polymorphisms, there was no significant difference of genotype distribution (P=0.827) and allele frequencies (P=0.830, OR=1.09, 95% CI: 0.51-2.31) between cases and controls. For STAT3 rs957970 polymorphisms, there was no significant difference of genotype distribution (P=0.455) and allele frequencies (P=0.560, OR=0.92, 95% CI: 0.71-1.20) between cases and controls. For IFN-${\gamma}$ +874A/T polymorphisms, there was no significant difference of genotype distribution (P=0.652) and allele frequencies (P=0.527, OR=1.12, 95% CI: 0.79-1.59) between cases and controls. Conclusion: These results suggest that polymorphisms in STAT2, STAT3 and IFN-${\gamma}$ genes are not likely to be strong predictors of cervical cancer in Han women in southern China.

• BMB Reports
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• v.57 no.5
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• pp.238-243
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• 2024

Bone marrow-derived mesenchymal stem cells (BM-MSCs) can differentiate into endothelial cells in an inflammatory microenvironment. However, the regulatory mechanisms underlying this process are not entirely understood. Here, we found that TIE2 in BM-MSCs was upregulated at the transcriptional level after stimulation with tumor necrosis factor-alpha (TNFα), a major pro-inflammatory cytokine. Additionally, the STAT-binding sequence within the proximal region of TIE2 was necessary for TNFα-induced TIE2 promoter activation. TIE2 and STAT3 knockdown reduced TNFα-induced endothelial tube formation in BM-MSCs. Among the major TNFα-activated MAP kinases (ERK1/2, JNK1/2, and p38 MAPK) in BM-MSCs, only inhibition of the p38 kinase abrogated TNFα-induced TIE2 upregulation by inhibiting the JAK-STAT signaling pathway. These findings suggest that p38 MAP contributes to the endothelial differentiation of BM-MSCs by activating the JAK-STAT-TIE2 signaling axis in the inflammatory microenvironment.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8405-8410
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• 2016

Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) development. Recent studies demonstrated that single nucleotide polymorphisms (SNPs) rs2293152 in signal transducer and activator of transcription 3 (STAT3) and rs7574865 in signal transducer and activator of transcription 4 (STAT4) are associated with chronic hepatitis B (CHB)-related HCC in the Chinese population. We hypothesized that these polymorphisms might be related to HCC susceptibility in Thai population as well. Study subjects were divided into 3 groups consisting of CHB-related HCC (n=192), CHB without HCC (n=200) and healthy controls (n=190). The studied SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the distribution of different genotypes for both polymorphisms were in Hardy-Weinberg equilibrium (P>0.05). Our data demonstrated positive association of rs7574865 with HCC risk when compared to healthy controls under an additive model (GG versus TT: odds ratio (OR)=2.07, 95% confidence interval (CI)=1.06-4.03, P=0.033). This correlation remained significant under allelic and recessive models (OR=1.46, 95% CI=1.09-1.96, P=0.012 and OR=1.71, 95% CI=1.13-2.59, P=0.011, respectively). However, no significant association between rs2293152 and HCC development was observed. These data suggest that SNP rs7574865 in STAT4 might contribute to progression to HCC in the Thai population.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.4
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• pp.437-440
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• 2012

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that Cryptotanshione(CT), a tanshinone from oriental traditional medicinal herb Danshen (Salvia miltiorrhiza Bunge), had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. CT inhibited the protein expression of hypoxia-inducible factor-1alpha (HIF-$1{\alpha}$) under hypoxic condition. Consistently, CT blocked hypoxia-induced phosphorylation and nuclear accumulation of STAT3. In addition, CT reduced cellular of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Of note, chromatin immunoprecipitation (ChiP) assay revealed that CT inhibited binding of STAT3 to VEGF promoter. Taken together, our results suggest that CT has anti-angiogenic activity by disturbing the binding STAT3 to the VEGF promoter in PC-3 cells.

• Parasites, Hosts and Diseases
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• v.47 no.2
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• pp.117-124
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• 2009

Toxoplasma gondii provokes rapid and sustained nuclear translocation of the signal transducer and activator of transcription 6 (STAT6) in HeLa cells. We observed activation of STAT6 as early as 2hr after infection with T. gondii by the nuclear translocation of fluorescence expressed from exogenously transfected pDsRed2-STAT6 plasmid and by the detection of phosphotyrosine-STAT6 in Western blot. STAT6 activation occurred only by infection with live tachyzoites but not by co-culture with killed tachyzoites or soluble T. gondii extracts. STAT6 phosphorylation was inhibited by small interfering RNA of STAT6 (siSTAT6). In view of the fact that STAT6 is a central mediator of IL-4 induced gene expression, activation of STAT6 by T. gondii infection resembles that infected host cells has been stimulated by IL-4 treatment. STAT1 was affected to increase the transcription and expression by the treatment of siSTAT6. STAT6 activation was not affected by any excess SOCS's whereas that with IL-4 was inhibited by SOCS-1 and SOCS-3. T. gondii infection induced Eotaxin-3 gene expression which was reduced by $IFN-{\gamma}$. These results demonstrate that T. gondii exploits host STAT6 to take away various harmful reactions by $IFN-{\gamma}$. This shows, for the first time, IL-4-like action by T. gondii infection modulates microbicidal action by $IFN-{\gamma}$ in infected cells.