• 대한골관절종양학회지
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• 제15권2호
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• pp.130-137
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• 2009

목적: STAT3는 주요 세포 진행과정을 조절하는 암유전자로, 활성화되면 여러 악성종양의 생물학적, 임상적 특징과 연관된다고 알려져 있고, 한편 배아줄기세포와 연관된 유전자이기도 하다. 본 연구에서는 연골종양의 발생에 STAT3 활성화가 관여하는지 살펴보았다. 대상 및 방법: 총 33예의 각종 양성 및 악성 연골종양에서 STAT3 활성화를 살펴보기 위해 활성화된 $pSTAT3^{tyr705}$에 특이한 단클론성 항체를 이용한 면역조직화학법을 시행하였다. 결과: 통상적인 연골육종 17예 중, 조직학적 등급 3의 연골육종은 3예(50%)에서 pSTAT3에 양성이었고, 등급 1 및 2 연골육종은 모두 음성이었다. 즉 pSTAT3 양성도는 조직학적 등급과 통계학적으로 유의한 상관관계(p=0.0432)를 나타내었다. 또한 투명세포 연골육종 2예(50%)도 pSTAT3에 양성이었다. 내연골종, 연골모세포종, 연골점액양섬유종 등 12예의 양성 연골종양 중 6예(50%)에서 pSTAT3가 관찰되었다. 결론: STAT3 활성화는 통상적인 연골육종 중 고도의 조직학적 분화도가 나쁜 등급에서 주로 발견된다. 배아줄기세포 표지자인 STAT3가 양성 및 악성 연골종양 일부에서 활성화되는 것으로 미루어보아 연골 기원 종양에서도 악성종양의 줄기세포 가설을 제안할 수 있다.

• Asian Pacific Journal of Cancer Prevention
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• 제13권6호
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• pp.2873-2877
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• 2012

Objective: To determine STAT3, P-STAT3, and VEGF-C expression levels in small cell lung cancers (SCLCs), and discuss their role and clinical significance in SCLC development. Method: Immunohistochemical methods were applied to 128 cases of SCLC and 40 cases of adjacent normal tissue. Results: The expression levels of STAT3, P-STAT3, and VEGF-C were higher in SCLC than in normal tissue (P<0.05). Pairwise comparisons showed positive correlations with lymph node metastasis, clinical stage, and tumor size (P<0.05). The expression levels were also related with the overall survival rates. Conclusion: STAT3 and VEGF-C play important roles in the development of SCLC, and might be expected to become new targets for SCLC treatment.

• 생명과학회지
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• 제30권10호
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• pp.867-876
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• 2020

본 연구는 magnolol에 의한 UVB 유도 세포 손상의 복구를 조사하였다. 우리는 약물재배치를 위해 STAT3 기작을 분석하였고, magnolol HDF 세포에서 세포 생존력을 향상시키며, STAT3의 억제제인 것을 확인하였다. IL-6, UVB 및 IFNγ로 처리 된 HDF 세포는 Jak2 및 인산화 된 STAT3 (p-STAT3)의 높은 발현을 나타냈다. Magnolol 의 처리는 UVB 유도 세포에서 Jak2 및 p-STAT3의 발현을 감소시킬 수 있었다. 또한, UVB- 손상된 세포 성장은 용량 의존적 방식으로 재 활성화 및 magnolol 과의 상관 관계가 상당히 증가되었다. UVB 처리 된 HDF 세포에 대한 AG490 (Jak2 억제제) 처리와 비교하여, 세포 증식이 유의하게 증가 하였다. 우리는 AG490 및 magnolol 이 TNF-α 농도를 감소시키는 것을 확인했다. Western blot (단백질 수준)은 오직 magnolol 처리 된 세포에서만 Jak2 및 p-STAT3 발현의 감소를 나타냈고, Jak2, p-STAT3 및 SOCS3의 발현은 또한 magnolol 처리한 세포에서만 증가하였다. 세포를 magnolol 및 ML385 (NRF2 억제제)로 동시 처리시 세포 증식 및 NRF2 발현을 감소시켰다. MMP9의 양은 magnolol 및 ML385 로의 처리에 의해 증가되었다. 종합적으로, 이들 결과는 NRF2, SOCS3, Jak2 및 STAT3의 발현을 조절함으로써 UVB 손상 후 세포를 회복시키는데 있어 magnolol의 가능성을 입증한다.

• The Korean Journal of Physiology and Pharmacology
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• 제24권3호
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• pp.203-212
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• 2020

Promyelocytic leukemia (PML) gene, through alternative splicing of its C-terminal region, generates several PML isoforms that interact with specific partners and perform distinct functions. The PML protein is a tumor suppressor that plays an important role by interacting with various proteins. Herein, we investigated the effect of the PML isoforms on oncostatin M (OSM)-induced signal transducer and activator of transcription-3 (STAT-3) transcriptional activity. PML influenced OSM-induced STAT-3 activity in a cell type-specific manner, which was dependent on the p53 status of the cells but regardless of PML isoform. Interestingly, overexpression of PML exerted opposite effects on OSM-induced STAT-3 activity in p53 wild-type and mutant cells. Specifically, overexpression of PML in the cell lines bearing wild-type p53 (NIH3T3 and U87-MG cells) decreased OSM-induced STAT-3 transcriptional activity, whereas overexpression of PML increased OSM-induced STAT-3 transcriptional activity in mutant p53-bearing cell lines (HEK293T and U251-MG cells). When wild-type p53 cells were co-transfected with PML-IV and R273H-p53 mutant, OSM-mediated STAT-3 transcriptional activity was significantly enhanced, compared to that of cells which were transfected with PML-IV alone; however, when cells bearing mutant p53 were co-transfected with PML-IV and wild-type p53, OSM-induced STAT-3 transcriptional activity was significantly decreased, compared to that of transfected cells with PML-IV alone. In conclusion, PML acts together with wild-type or mutant p53 and influences OSM-mediated STAT-3 activity in a negative or positive manner, resulting in the aberrant activation of STAT-3 in cancer cells bearing mutant p53 probably might occur through the interaction of mutant p53 with PML.

• 대한수의학회지
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• 제44권2호
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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 Chest Surgery
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• 제31권6호
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• pp.553-559
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• 1998

서론: 초저체온 순환정지법은 일부 심장수술에서 매우 유용하게 사용되고 있다. 그러나 사람은 정상 생리상태에서 이 정도 저체온에 노출되는 적이 없기 때문에 초저체온 상태에서 $\alpha$-STAT와 pH-STAT 산-염기 조절법 중 어느 쪽을 택하는 것이 좋으냐에는 여전히 이론이 많다. 본실험에서는 어린 돼지에서 초저체온 순환정지 실험모델을 확립한뒤 pH-STAT와 $\alpha$-STAT 간에 (1) 심폐바이패스 냉각 및 재가온시 뇌냉각 및 재가온 속도 비교, (2) 뇌혈류, 뇌대사 및 뇌혈류/뇌대사 비의 변화 양상 분석, 그리고 (3) 초저체온 순환정지후 뇌부종 정도를 비교 분석하였다. 대상 및 방법: 25~30 KG의 어린 돼지를 실험군마다 7마리씩 사용하였다. 마취후 두개골을 절제하고 상시상동 삽관을 통해 뇌혈류를 측정하였다. 그리고 정중흉골절개술 및 캐뉼라 삽관후 심폐바이패스를 시행하였다. 막형 산화기와 롤러펌프를 사용하였고, 관류속도는 2500 ml/min로 유지시켰다. 심폐바이패스 시작후 첫 10~15분 동안 정상체온 관류를 시행한 뒤 이어 $20^{\circ}C$(비인두체온) 까지 관류냉각을 시행하였다. $20^{\circ}C$에서 40분 동안 완전순환정지를 시행하였다. 냉각기간 동안 실험군에 따라 $\alpha$-STAT 또는 pH-STAT에 따른 산-염기 조절을 시행하였다. 순환정지후에는 정상 체온까지 재가온하였다. 재가온 종료후 실험동물을 희생시키고 뇌를 추출하였다. 뇌혈류 및 뇌대사 측정은 바이패스전, 냉각전, 순환정지전, 재가온후 15분, 재가온 종료시, 재가온 종료후 1시간에 각각 시행하였다. 결과: 양군간 냉각시간은 $\alpha$-STAT군이 16.57$\pm$5.13분으로 pH-STAT 군의 22.83$\pm$2.14분 보다 유의하게 짧았으나(P<0.05), 재가온시간에서는 $\alpha$-STAT군(40.0$\pm$5.07분)과 pH-STAT군(46.5$\pm$6.32) 사이에 유의한 차이는 없었다. 뇌혈류 및 뇌대사에서는 pH-STAT군이 $\alpha$-STAT군에 비하여 높은 경향을 보였지만 통계학적으로 유의한 차이는 없었다. 뇌혈류량/뇌대사율의 비에서도 두군간에 차이가 없었다. 그러나 두 실험군내에서 체온변화에 따른 뇌혈류량 및 뇌대사의 차이는 유의하였다. 특히 비인두체온 20도에서는 뇌대사율의 감소가 뇌혈류의 감소 보다 더욱 커서 결과적으로 뇌혈류량/뇌대사율의 비는 1 보다 높은 수치로 기록되었다. 뇌수분양은 두 실험군간에 유의한 차이는 없었다. 결론: 본 실험에서 $\alpha$-stat와 pH-STAT 산염기 조절법간에 냉각시간 이외에는 유의한 차이가 없음을 알 수 있었다.

• BMB Reports
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• 제53권6호
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• pp.335-340
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• 2020

Since cancer is the leading cause of death worldwide, there is an urgent need to understand the mechanisms underlying cancer progression and the development of cancer inhibitors. Signal transducer and activator of transcription 3 (STAT3) is a major transcription factor that regulates the proliferation and survival of various cancer cells. Here, dual-specificity phosphatase 3 (DUSP3) was identified as a regulator of STAT3 based on an interaction screening performed using the protein tyrosine phosphatase library. DUSP3 interacted with the C-terminal domain of STAT3 and dephosphorylated p-Y705 of STAT3. In vitro dephosphorylation assay revealed that DUSP3 directly dephosphorylated p-STAT3. The suppressive effects of DUSP3 on STAT3 were evaluated by a decreased STAT3-specific promoter activity, which in turn reduced the expression of the downstream target genes of STAT3. In summary, DUSP3 downregulated the transcriptional activity of STAT3 via dephosphorylation at Y705 and also suppressed the migratory activity of cancer cells. This study demonstrated that DUSP3 inhibits interleukin 6 (IL-6)/STAT3 signaling and is expected to regulate cancer development. Novel functions of DUSP3 discovered in IL-6/STAT3 signaling regulation would help expand the understanding of cancer development mechanisms.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7439-7444
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• 2013

Aim: ATF3, a member of the ATF/CREB family of transcription factors, has been found to be selectively induced by calcineurin/NFAT inhibition and to enhance keratinocyte tumor formation, although the precise role of ATF3 in human skin cancer and possible mechanisms remain unknown. Methods: In this study, clinical analysis of 30 skin cancer patients and 30 normal donors revealed that ATF3 was accumulated in skin cancer tissues. Functional assays demonstrated that ATF3 significantly promoted skin cancer cell proliferation. Results: Mechanically, ATF3 activated Stat3 phosphorylation in skin cancer cell through regulation of p53 expression. Moreover, the promotion effect of ATF3 on skin cancer cell proliferation was dependent on the p53-Stat3 signaling cascade. Conclusion: Together, the results indicate that ATF3 might promote skin cancer cell proliferation and enhance skin keratinocyte tumor development through inhibiting p53 expression and then activating Stat3 phosphorylation.

• Asian Pacific Journal of Cancer Prevention
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• 제16권8호
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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.

• Molecules and Cells
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• 제23권1호
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• pp.94-99
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• 2007

Suppressors of cytokine signaling (SOCS) family members are negative feedback regulators of the Jak/Stat pathway, which is an essential inflammatory signaling pathway. We investigated expression of eight members of the SOCS family in rat astrocytes, using two inflammatory stimulants, PMA and IFN-${\gamma}$. Only a few SOCS genes were induced by both stimulants, and we detected an increase in SOCS5 protein with PMA. PMA activated the Jnk, Erk, p38, and Jak/Stat signal pathways. In addition, it increased the level of activated-Stat3 resulting from tyrosine phosphorylation. A gel-shift assay showed that a protein in nuclear extracts from PMA-treated cells was able to bind to Stat binding elements. These results suggest that activated Stat3 binds to SOCS promoters and leads to their transcriptional induction.