• 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.

• 생명과학회지
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• 제21권1호
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• pp.141-145
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• 2011

본 연구에서는 전사억제제(transcriptional inhibitor)로 알려진 actinomycin D가 전사조절인자(transcription factor)인 STAT의 인산화를 유도한다는 것을 확인하였다. Actinomycin D 처리 시 STAT1의 Tyr701, Ser727 인산화는 유도되지 않았지만 STAT3의 Tyr705 잔기의 인산화를 특이적으로 유도하는 것을 확인하였다. Actinomycin D에 의한 STAT3의 Tyr705 인산화 유도가 어떠한 기전을 통한 것인지 확인하기 위해서 관련 인자의 단백질 및 mRNA 발현을 확인한 결과 SOCS3의 단백질 및 mRNA 발현의 감소를 확인하였다. STAT3의 탈인산화를 유도한다고 알려진 tyrosine phosphatase인 SHP-1와 STAT의 upstream kinase인 JAK2의 인산화는 변화가 없었다. 또한 actinomycin D 뿐 아니라 다른 전사억제제인 DRB를 처리 하였을 경우에도 STAT3의 Tyr705 인산화가 유도되는 것을 확인하였다. 이상의 결과는 전사억제제에 의하여 특이적인 SOCS3 단백질 발현감소는 SOCS3의 하류의 target인 STAT3 인산화를 유도하였다.

• 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.

• BMB Reports
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• 제52권7호
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• pp.415-423
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• 2019

Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that regulates cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immune responses. Aberrant STAT3 activation triggers tumor progression through oncogenic gene expression in numerous human cancers, leading to promote tumor malignancy. On the contrary, STAT3 activation in immune cells cause elevation of immunosuppressive factors. Accumulating evidence suggests that the tumor microenvironment closely interacts with the STAT3 signaling pathway. So, targeting STAT3 may improve tumor progression, and anti-cancer immune response. In this review, we summarized the role of STAT3 in cancer and the tumor microenvironment, and present inhibitors of STAT3 signaling cascades.

• 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.

• BMB Reports
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• 제34권5호
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• pp.484-488
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• 2001

STATs are proteins with a dual function: signal transducers in the cytoplasm and transcriptional activators in the nucleus. Among the six known major STATs (STAT1-6), STAT3 has been implicated in the widest range of signaling pathways that regulate cell growth and differentiation. As a part of our on-going investigation on the pleiotropic functions of STAT proteins, we examined the role of STAT3 as a molecular adaptor that links diverse cell growth signaling pathways. We observed that STAT3 can be specifically activated by multiple cytokines, such as IL-3, in transformed fibroblasts and IL-4 or IFN-$\gamma$ in primary immune cells, respectively. The selective activation of STAT3 in H-ras-transformed NIH3T3 cells is associated with an increased expression of phosphoserioe STAT3 in these cells, compared to the parental cells. Notably phosphoresine-STAT3 interacts with oncogenic ras, shown by immunoprecipitation and Western blots. The results suggest the role of STAT3 in rasinduced cellular transformation as a molecular adaptor linking the Jak/STAT and Ras/MAPK pathways. In primary immune cells, IL-4 and IFN-$\gamma$ each induced (in addition to the characteristic STAT6 and STAT1 homodimers) the formation of STAT3-containing complexes that bind to GAS probes, which correspond to the $Fe{\varepsilon}$ Rll and $Fe{\gamma}$ RI promoter sequences, respectively. Since IL-4 and IFN-$\gamma$ are known to counter-regulate the expression of these genes, the ability of STAT3 to form heterodimeric complexes with STAT6 or STAT1 implies its role in the fine-tuned control of genes that are regulated by IL-4 and IFN-$\gamma$.

• Integrative Medicine Research
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• 제3권2호
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• pp.67-73
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• 2014

Background: The transcription factor signal transducer and activator of transcription 3 (Stat3)is constitutively activated in many human cancers. It promotes tumor cell proliferation,inhibits apoptosis, induces angiogenesis and metastasis, and suppresses antitumor hostimmune responses. Therefore, Stat3 has emerged as a promising molecular target for cancertherapies. In this study, we evaluated the Stat3-suppressive activity of 38 herbal medicinestraditionally used in Korea.Methods: Medicinal herb extracts in 70% ethanol were screened for their ability to suppressStat3 in the A549 human lung cancer cell line. A Stat3-responsive reporter assay system wasused to detect intracellular Stat3 activity in extract-treated cells, and Western blot analyseswere performed to measure the expression profiles of Stat3-regulated proteins.Results: Fifty percent of the 38 extracts possessed at least mild Stat3-suppressive activities(i.e., activity less than 75% of the vehicle control). Ethanol extracts of Bupleurum falcatumL., Taraxacum officinale Weber, Solanum nigrum L., Ulmus macrocarpa Hance, Euonymus alatusSieb., Artemisia capillaris Thunb., and Saururus chinensis (Lour.) Baill inhibited up to 75% of thevehicle control Stat3 activity level. A549 cells treated with these extracts also had reducedBcl-xL, Survivin, c-Myc, and Mcl-1 expression.Conclusion: Many medicinal herbs traditionally used in Korea contain Stat3 activity-suppressing substances. Because of the therapeutic impact of Stat3 inhibition, these resultscould be useful when developing novel cancer therapeutics from medicinal herbs.

• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.161-168
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• 2009

In the peripheral nerves, injury-induced cytokines and growth factors perform critical functions in the activation of both the MEK/ERK and JAK/STAT3 pathways. In this study, we determined that nerve injury-induced ERK activation was temporally correlated with STAT3 phosphorylation at the serine 727 residue. In cultured Schwann cells, we noted that ERK activation is required for the serine phosphorylation of STAT3 by neuropoietic cytokine interleukin-6 (IL-6). Serine phosphorylated STAT3 by IL-6 was transported into Schwann cell nuclei, thereby indicating that ERK may regulate the transcriptional activity of STAT3 via the induction of serine phosphorylation of STAT3. Neuregulin-1 (NRG) also induced the serine phosphorylation of STAT3 in an ERK-dependent fashion. In contrast with the IL-6 response, serine phosphorylated STAT3 induced by NRG was not detected in the nucleus, thus indicating the non-nuclear function of serine phosphorylated STAT3 in response to NRG. Finally, we determined that the inhibition of ERK prevented injury-induced serine phosphorylation of STAT3 in an ex-vivo explants culture of the sciatic nerves. Collectively, the results of this study show that ERK may be an upstream kinase for the serine phosphorylation of STAT3 induced by multiple stimuli in Schwann cells after peripheral nerve injury.

• 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.

• 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.