• Tuberculosis and Respiratory Diseases
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• 제70권6호
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• pp.462-473
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• 2011

Background: Smoking is a risk factor for idiopathic pulmonary fibrosis (IPF), but the mechanism of the association remains obscure. There is evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. This study was to determine whether the administration of small interfering RNA (siRNA) targeting PAI-1 or PAI-1 inhibitor to the cigarette smoking extract (CSE)-exposed rat alveolar type II epithelial cells (ATII cells) limits the epithelial-mesenchymal transition (EMT). Methods: ATII cells were isolated from lung of SD-rat using percoll gradient method and cultured with 5% CSE. The EMT was determined from the ATII cells by measuring the real-time RT PCR and western blotting after the PAI-1 siRNA transfection to the cells and after administration of tiplaxtinin, an inhibitor of PAI-1. The effect of PAI-1 inhibitor was also evaluated in the bleomycin-induced rats. Results: PAI-1 was overexpressed in the smoking exposed ATII cells and was directly associated with EMT. The EMT from the ATII cells was suppressed by PAI-1 siRNA transfection or administration of tiplaxtinin. Signaling pathways for EMT by smoking extract were through the phosphorylation of SMAD2 and ERK1/2, and finally Snail expression. Tiplaxtinin also suppressed the pulmonary fibrosis and PAI-1 expression in the bleomycin-induced rats. Conclusion: Our data shows that CSE induces rat ATII cells to undergo EMT by PAI-1 via SMAD2-ERK1/2-Snail activation. This suppression of EMT by PAI-1 siRNA transfection or PAI-1 inhibitor in primary type II alveolar epithelial cells might be involved in the attenuation of bleomycin-induced pulmonary fibrosis in rats.

• Journal of Preventive Medicine and Public Health
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• 제30권2호
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• pp.369-380
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• 1997

Balb/c 마우스의 복강대식세포와 동종 마우스의 유선암에서 기원한 EMT-6 세포를 배양하는 조건에 여러 농도의 수은을 첨가하여 nitrite와 nitrite 생성의 변화를 관찰한 결과는 다음과 같다. 복강대식세포 및 EMT-6 세포가 생성하는 nitrite와 nitrate 양은 공히 배양시작 12시간 후에 생성량에 비해 24 시간 후에는 2배, 36시간 후에는 3배의 농도로 측정되었다. 이때 nitrite와 nitrate 농도 사이에 매우 밀접한 상관관계가 관찰되었다. 수음첨가에 따라 nitrite 및 nitrate 생성량은 용량 의존적 관계로 현저한 감소를 보이며, 24 시간 또는 36시간 후의 세포생존률도 역시 수은농도에 비례하여 감소되는데, 복강대식세포의 생존률 감소가 EMT-6 세포의 것에 비해 더욱 현저하였다. 이들 세포내에서 생성되는 ATP의 양은 복강세포의 경우 그 생존률과 비례하는 경향이었으나, EMT-6세포의 경우는 비교적 높은 생존률에도 불구하교 배양액내에 수은농도를 증가시킴에 따라 ATP생산은 현저히 감소하였다. 이상의 결과는 면역세포인 복강대식세포 뿐아니라 암세포인 EMT-6 세포에서도, L-arginine으로부터 nitric oxide를 생성하는 생화학적 반응이 수은에 의해 공히 억제될 수 있음을 보여준다. 한편 수은의 세포성 면역에 미치는 독성은 수은이 면역세포의 ATP생성과 관련한 에너지 대사과정의 장애을 초래하여 nitric oxide 생성에 필요한 반응에너지의 공급을 억제시키기 때문에 나타나는 현상으로 사료된다.

• BMB Reports
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• 제57권6호
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• pp.305-310
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• 2024

T-plastin (PLST), a member of the actin-bundling protein family, plays crucial roles in cytoskeletal structure, regulation, and motility. Studies have shown that the plastin family is associated with the malignant characteristics of cancer, such as circulating tumor cells and metastasis, by inducing epithelial-mesenchymal transition (EMT) in various cancer cells. However, the role of PLST in the EMT of human lung cancer cells remains unclear. In this study, we observed that PLST overexpression enhanced cell migratory and invasive abilities, whereas its downregulation resulted in their suppression. Moreover, PLST expression levels were associated with the expression patterns of EMT markers, including E-cadherin, vimentin, and Slug. Furthermore, the phosphorylation levels of focal adhesion kinase (FAK) and AKT serine/threonine kinase (AKT) were dependent on PLST expression levels. These findings indicate that PLST induces the migration and invasion of human lung cancer cells by promoting Slug-mediated EMT via the FAK/AKT signaling pathway.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3625-3630
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• 2013

Reactive oxygen species (ROS) are known to promote mesothelial carcinogenesis that is closely associated with asbestos fibers and inflammation. Epithelial to mesenchymal cell transition (EMT) is an important process involved in the progression of tumors, providing cancer cells with aggressiveness. The present study was performed to determine if EMT is induced by $H_2O_2$ in human malignant mesothelioma (HMM) cells. Cultured HMM cells were treated with $H_2O_2$, followed by measuring expression levels of EMT-related genes and proteins. Immunohistochemically, TWIST1 expression was confined to sarcomatous cells in HMM tissues, but not in epithelioid cells. Treatment of HMM cells with $H_2O_2$ promoted EMT, as indicated by increased expression levels of vimentin, SLUG and TWIST1, and decreased E-cadherin expression. Expression of stemness genes such as OCT4, SOX2 and NANOG was also significantly increased by treatment of HMM cells with $H_2O_2$. Alteration of these genes was mediated via activation of hypoxia inducible factor 1 alpha (HIF-$1{\alpha}$) and transforming growth factor beta 1 (TGF-${\beta}1$). Considering that treatment with $H_2O_2$ results in excess ROS, the present study suggests that oxidative stress may play a critical role in HMM carcinogenesis by promoting EMT processes and enhancing the expression of stemness genes.

• 한국식품과학회지
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• 제50권1호
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• pp.105-110
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• 2018

멜리틴은 봉독의 주요 성분 중 하나로 항염증과 항암활성 효과를 가지고 있다. 우리는 폐암세포에서 멜리틴이 EMT 억제를 통해 암세포 이동과 침투를 억제하는 사실을 확인하였다. 멜리틴은 EGF로 유도된 폐암 세포 이동과 침투를 억제하였을 뿐만 아니라 EMT와 관련된 단백질인 이카드헤린의 발현을 증가시켰으며, 바이멘틴과 피브로넥틴 발현은 감소시켰다. 또한 멜리틴에 의한 EMT조절 전사인자인 ZEB2, Slug, Snail의 발현을 확인한 결과 멜리틴 처리에 의해 농도의존적으로 발현이 감소하였다. 또한 작용 메커니즘을 확인하기 위해 mTOR와 FAK 메커니즘을 확인한 실험에서 EGF 처리에 의해 증가한 AKT, mTOR, p70S6K, 4EBP1의 인산화가 멜리틴 농도의존적으로 감소하였다. 그러나 FAK는 EGF에 의해 변화가 없었으며, EKR, JNK 메커니즘은 EGF 처리에 의해 인산화가 증가하였으나 멜리틴 처리에 의해 아무런 영향을 받지 않았다. 그러므로, 폐암세포의 세포 이동과 침투에 대한 멜리틴의 억제효과는 AKT/mTOR/P70S6K/4EBP1 기전 억제를 통해 EMT를 억제하여 세포 이동과 침투를 억제하는 것으로 보인다.

• Biomolecules & Therapeutics
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• 제25권6호
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• pp.625-633
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• 2017

Sphingosylphosphorylcholine (SPC) is one of the bioactive phospholipids that has many cellular functions such as cell migration, adhesion, proliferation, angiogenesis, and $Ca^{2+}$ signaling. Recent studies have reported that SPC induces invasion of breast cancer cells via matrix metalloproteinase-3 (MMP-3) secretion leading to WNT activation. Thrombospondin-1 (TSP-1) is a matricellular and calcium-binding protein that binds to a wide variety of integrin and non-integrin cell surface receptors. It regulates cell proliferation, migration, and apoptosis in inflammation, angiogenesis and neoplasia. TSP-1 promotes aggressive phenotype via epithelial mesenchymal transition (EMT). The relationship between SPC and TSP-1 is unclear. We found SPC induced EMT leading to mesenchymal morphology, decrease of E-cadherin expression and increases of N-cadherin and vimentin. SPC induced secretion of thrombospondin-1 (TSP-1) during SPC-induced EMT of various breast cancer cells. Gene silencing of TSP-1 suppressed SPC-induced EMT as well as migration and invasion of MCF10A cells. An extracellular signal-regulated kinase inhibitor, PD98059, significantly suppressed the secretion of TSP-1, expressions of N-cadherin and vimentin, and decrease of E-cadherin in MCF10A cells. ERK2 siRNA suppressed TSP-1 secretion and EMT. From online PROGgene V2, relapse free survival is low in patients having high TSP-1 expressed breast cancer. Taken together, we found that SPC induced EMT and TSP-1 secretion via ERK2 signaling pathway. These results suggests that SPC-induced TSP-1 might be a new target for suppression of metastasis of breast cancer cells.

• Journal of Microbiology and Biotechnology
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• 제32권6호
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• pp.792-799
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• 2022

As a vital problem in reproductive health, recurrent spontaneous abortion (RSA) affects about 1% of women. We performed this study with an aim to explore the molecular mechanism of interleukin-23 (IL-23) and find optimal or effective methods to improve RSA. First, ELISA was applied to evaluate the expressions of IL-23 and its receptor in HTR-8/SVneo cells after IL-23 treatment. CCK-8, TUNEL, wound healing and transwell assays were employed to assess the proliferation, apoptosis, migration and invasion of HTR-8/SVneo cells, respectively. Additionally, the expressions of apoptosis-, migration-, epithelial-mesenchymal transition- (EMT-) and p38 MAPK signaling pathway-related proteins were measured by western blotting. To further investigate the relationship between IL-23 and p38 MAPK signaling pathway, HTR-8/SVneo cells were treated for 1 h with p38 MAPK inhibitor SB239063, followed by a series of cellular experiments on proliferation, apoptosis, migration and invasion, as aforementioned. The results showed that IL-23 and its receptors were greatly elevated in IL-23-treated HTR-8/SVneo cells. Additionally, IL-23 demonstrated suppressive effects on the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells. More importantly, the molecular mechanism of IL-23 was revealed in this study; that is to say, IL-23 inhibited the proliferation, apoptosis, migration, invasion and EMT of IL-23-treated HTR-8/SVneo cells via activating p38 MAPK signaling pathway. In conclusion, IL-23 inhibits trophoblast proliferation, migration, and EMT via activating p38 MAPK signaling pathway, suggesting that IL-23 might be a novel target for the improvement of RSA.

• BMB Reports
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• 제57권6호
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• pp.273-280
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• 2024

Cancer cells metastasize to distant organs by altering their characteristics within the tumor microenvironment (TME) to effectively overcome challenges during the multistep tumorigenesis. Plasticity endows cancer cell with the capacity to shift between different morphological states to invade, disseminate, and seed metastasis. The epithelial-to-mesenchymal transition (EMT) is a theory derived from tissue biopsy, which explains the acquisition of EMT transcription factors (TFs) that convey mesenchymal features during cancer migration and invasion. On the other hand, adherent-to-suspension transition (AST) is an emerging theory derived from liquid biopsy, which describes the acquisition of hematopoietic features by AST-TFs that reprograms anchorage dependency during the dissemination of circulating tumor cells (CTCs). The induction and plasticity of EMT and AST dynamically reprogram cell-cell interaction and cell-matrix interaction during cancer dissemination and colonization. Here, we review the mechanisms governing cellular plasticity of AST and EMT during the metastatic cascade and discuss therapeutic challenges posed by these two morphological adaptations to provide insights for establishing new therapeutic interventions.

• 한국식품영양과학회지
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• 제43권1호
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• pp.47-54
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• 2014

본 연구는 녹차폴리페놀이 시스플라틴의 항암작용과 신장 독성에 미치는 영향을 유방암 세포(EMT6)와 암세포 이식마우스를 이용하여 in vitro와 in vivo 실험으로 관찰하였다. 배양한 EMT6 세포에서 녹차폴리페놀은 시스플라틴에 의한 세포 독성을 증가시켰다. 마우스에 EMT6 세포를 주사하여 유발된 종양의 크기가 시스플라틴군(CP)보다 시스플라틴+녹차폴리페놀군(CP+GTP)에서 유의하게 작았고, 종양조직 p53와 caspase-3 활성화가 시스플라틴군(CP)보다 시스플라틴+녹차폴리페놀군(CP+GTP)에서 유의하게 높았으며, 신장 GGT와 AP 활성은 시스플라틴군(CP)보다 시스플라틴+녹차폴리페놀군(CP+GTP)에서 유의하게 높았고, 신장 조직학적 소견에서 신세뇨관 확장과 괴사가 시스플라틴군(CP)보다 시스플라틴+녹차폴리페놀군(CP+GTP)에서 유의하게 낮았다. 이상의 결과 녹차폴리페놀은 EMT6 유방암 세포를 이용한 in vitro 및 in vivo 실험에서 시스플라틴의 항암작용을 증강시키면서 신장에 대한 독성 부작용은 감소시키는 효과가 있는 것으로 추측된다. 녹차폴리페놀의 시스플라틴 항암작용 증강과 신장 독성 억제 및 감소 효과는 시스플라틴에 의한 암 치료 시 화학요법제의 보조제로서 이용가치가 있는 것으로 생각되며, 항암화학요법제에 대한 보조제로의 개발을 위해서는 대규모 동물실험을 통한 효과 입증 및 부작용에 대한 실험과 임상연구가 뒷받침되어야 할 것으로 사료된다.

• BMB Reports
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• 제52권12호
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• pp.706-711
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• 2019

Cisplatin (Cis-DDP) is one of the most widely used anti-cancer drugs. It is applicable to many types of cancer, including lung, bladder, and breast cancer. However, its use is now limited because of drug resistance. p90 ribosomal S6 kinase (p90RSK) is one of the downstream effectors in the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathway and high expression of p90RSK is observed in human breast cancer tissues. Therefore, we investigated the role of p90RSK in the Cis-DDP resistance-related signaling pathway and epithelial-mesenchymal transition (EMT) in breast cancer cells. First, we discovered that MDA-MB-231 cells exhibited more Cis-DDP resistance than other breast cancer cells, including MCF-7 and BT549 cells. Cis-DDP increased p90RSK activation, whereas the inactivation of p90RSK using a small interfering RNA (siRNA) or dominant-negative kinase mutant plasmid overexpression significantly reduced Cis-DDP-induced cell proliferation and migration via the inhibition of matrix metallopeptidase (MMP)2 and MMP9 in MDA-MB-231 cells. In addition, p90RSK activation was involved in EMT via the upregulation of mRNA expression, including that of Snail, Twist, ZEB1, N-cadherin, and vimentin. We also investigated NF-κB, the upstream regulator of EMT markers, and discovered that Cis-DDP treatment led to NF-κB translocation in the nucleus as well as its promoter activity. Our results suggest that targeting p90RSK would be a good strategy to increase Cis-DDP sensitivity in triple-negative breast cancers.