• BMB Reports
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• 제54권12호
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• pp.608-613
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• 2021

Melanoma, the most serious type of skin cancer, exhibits a high risk of metastasis. Although chemotherapeutic treatment for metastatic melanoma improves disease outcome and patient survival, some patients exhibit resistance or toxicity to the drug treatment regime. OTUB1 is a deubiquitinating enzyme overexpressed in several cancers. In this study, we investigated the effects of inhibiting OTUB1 expression on melanoma-cell proliferation and viability and identified the underlying molecular mechanism of action of OTUB1. We did endogenous OTUB1 knockdown in melanoma cells using short interfering RNA, and assessed the resulting phenotypes via MTT assays, Western blotting, and cell-cycle analysis. We identified differentially expressed genes between OTUB1-knockdown cells and control cells using RNA sequencing and confirmed them via Western blotting and reverse transcription polymerase chain reaction. Furthermore, we investigated the involvement of apoptotic and cell survival signaling pathways upon OTUB1 depletion. OTUB1 depletion in melanoma cells decreased cell viability and caused simultaneous accumulation of cells in the sub-G1 phase, indicating an increase in the apoptotic-cell population. RNA sequencing of OTUB1-knockdown cells revealed an increase in the levels of the apoptosis-inducing protein TRAIL. Additionally, OTUB1-knockdown cells exhibited increased sensitivity to PLX4032, a BRAF inhibitor, implying that OTUB1 and BRAF act collectively in regulating apoptosis. Taken together, our findings show that OTUB1 induces apoptosis of melanoma cells in vitro, likely by upregulating TRAIL, and suggest that approaches targeting OTUB1 can be developed to provide novel therapeutic strategies for treating melanoma.

• 생명과학회지
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• 제26권2호
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• pp.259-264
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• 2016

암전이는 현재까지 적당한 치료제가 거의 없었기 때문에 암에 의한 사망의 주요한 원인 중의 하나로 인식되고 있다. 최근 본 연구팀은 마늘 추출물과 순수분리한 성분에 대한 암전이 억제 시험 결과 마늘의 추출물 또는 성분이 암전이를 억제시켰으며, 역학조사에서도 마늘을 많이 섭취한 사람은 암의 발생을 억제시키는 것으로 보고되어 있다, 본 연구의 암전이 실험에서는 C57BL/6 mouse의 꼬리 정맥에 melanoma B16F10세포를 주사하여 폐에 전이를 유도하였다. 암세포 주사 1일 후에 마늘의 헥산 추출물 50, 100 및 200 mg/kg body weight를 2일 간격으로 21일 동안 구강투여 한 다음 암전이 억제효과를 조사하였다. GHE를 처리하지 않은 대조구에서는 폐에서 암 colony가 97.4±30.2으로 대량 생성되었다. GHE를 50, 100 및 200 mg/kg의 농도로 경구투여시에 암전이 빈도는 각각 6.93, 46.80 및 50.53% 억제하였다. 또한 100 mg/kg body weight 경구투여 시에는 폐로 암전이 억제율이 약 53% 이상으로 매우 높았다. 폐에서 melanoma cell colony의 발생율과 면적은 마늘 헥산 추출물의 농도가 높을수록 감소하였다. 결론적으로 C57BL/6 mice의 암전이 모델에서 마늘 헥산추출물의 구강투여는 폐에 암전이를 억제시켰으나, 향후 그 기작에 대한 연구가 수행되어야 할 것으로 생각된다.

• Journal of Chest Surgery
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• 제32권9호
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• pp.840-843
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• 1999

저자는 심장의 우심실내에 입구와 출구를 막는 커다란 전이성 흑색종 1례를 수술치험하였기에 보고한다. 49세 여자환자로 호흡곤란과 전신부종의 증상을 보였다. 심초음파상 우심실내에 커다란 종괴와 심낭액을 보 였다. 심폐 체외순환후 심실내 종괴를 제거하였고, 악성 흑색종으로 판명되었다. 환자는 수술후 30일 현재 양호하다.

• 대한세포병리학회:학술대회논문집
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• 대한세포병리학회 1992년도 제6차 춘계학술대회 초록집
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• pp.16.2-17
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• 1992

• 한국발생생물학회지:발생과생식
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• 제25권2호
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• pp.93-104
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• 2021

Cutaneous melanoma is a fatal disease for patients with distant metastasis. Metformin is the most widely used anti-diabetic drug, and proved to suppress cell proliferation and metastasis in diverse cancers including melanoma. We previously reported that MEK inhibitor trametinib increases the expression of epithelial-mesenchymal transition (EMT) regulators and melanoma cell motility, which are suppressed by addition of metformin in A375 melanoma cells. To confirm our findings further, we first evaluated the effect of metformin in combination with another MEK inhibitor binimetinib on cell viability in G361 melanoma cells. We then investigated whether binimetinib affects the expression of EMT regulators and cell motility. We finally monitored the effect of metformin on binimetinib-induced cell migration. Cell viability assay showed that combination index (CI) value at ED₅₀ is 0.80, suggesting synergy for the combination of metformin with binimetinib. Our results also revealed that binimetinib increased the expression of EMT regulators such as integrin αV, fibronectin and slug, which correlate well with the enhanced cell migration in wound healing assay. Metformin, on the contrary, suppressed the expression of sparc, integrin αV, fibronectin and N-cadherin with the reduced cell motility. The combination treatment showed that metformin counteracts the binimetinib-induced increase of cell motility. Overall, these results suggest that metformin with binimetinib might be useful as a potential therapeutic adjuvant against cell survival and metastatic activity in melanoma patients.

• Natural Product Sciences
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• 제18권2호
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• pp.89-96
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• 2012

Ligularia stenocephala has been used as a traditional medicine for the treatment of asthma, arthritis, jaundice, and hyperpiesia. In this study, we investigated the anti-metastatic and hypnotic effects of the methanolic extract of L. stenocephala (MLS). Gelatin zymographic analysis revealed that MLS suppresses matrix metalloproteinase-2 (MMP-2) and MMP-9 activities in B16F10 cells. The gene expressions of MMPs were also down-regulated by MLS treatment in a dose-dependent manner. In addition, cancer cell invasion and migration were attenuated by MLS via suppression of NF-${\kappa}B$ activation. The in vivo lung metastasis of B16F10 melanoma cells was also inhibited by the treatment of MLS. These findings show that MLS has anti-metastatic properties, and, therefore, it might be applicable as a valuable anti-metastatic agent.

• Journal of Korean Neurosurgical Society
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• 제54권2호
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• pp.107-111
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• 2013

Objective : We investigated the effectiveness of stereotactic gamma knife Radiosurgery (GKR) for radioresistant brain metastases with the impact upon histology. Methods : Between April 2004 and May 2011, a total of 23 patients underwent GKR for 67 metastatic brain tumors from 12 renal cell cancers, 5 sarcomas and 6 melanomas. The mean age was 56 years (range, 18 to 79 years). Most of the patients were classified as the Radiation Therapy Oncology Group recursive partitioning analysis class II (91.3%). The synchronous metastasis was found in 6 patients (26.1%) and metachronous metastasis in 17 patients (73.9%). We analyzed the local control rate, intracranial progression-free survival (PFS) and overall survival (OS). Results : The mean tumor volume for GKR was 2.24 cc and the mean prescription dose was 19.4 Gy (range, 10 to 24) to the tumor margin. Out of metachronous metastases, the median duration to intracranial metastasis was 3.3 years in renal cell cancer (RCC), 2.4 years in melanoma and 1.1 years in sarcoma (p=0.012). The total local control rate was 89.6% during the mean 12.4 months follow-up. The six-month and one-year local control rate was 90.2% and 83% respectively. Depending on the pathology, the control rate of RCC was 95.7%, sarcoma 91.3% and melanoma 80.5% during the follow-up. The common cause of local failure was the tumor bleeding in melanoma. The median PFS and OS were 5.2 and 8.4 months in RCC patients, 6.5 and 9.8 months in sarcoma, and 3.8 and 5.1 months in melanoma. Conclusion : The GKR can be one of the effective management options for the intracranial metastatic tumors from the radioresistant tumors. The melanoma showed a poor local control rate compared to other pathologies because of the hemorrhage.

• 동의생리병리학회지
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• 제21권1호
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• pp.204-208
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• 2007

Chaga mushroom extract is well known as immune modulator and anti-cancer agent. However, the molecular mechanism by which Chaga exerts cell cycle arrest and apoptosis of cancer cells is poorly understood. In this study, we demonstrated anti-proliferative effects of Chaga extract on murine melanoma B16 cells. Chaga extract dose-dependently inhibited cell growth along with the arrest of G0/G1 phase and the induction of apoptotic cell death. Treatment with Chaga extract resulted in a decrease of cyclin E, cyclin D1, cdk 2, cdk 4 expression levels. Furthermore, in vivo inoculation study of B16 melanoma cells into Balb/c mice Chaga extract markedly suppressed the metastatic growth of tumor cells (6 folds, p<0.05,). These results indicate that Chaga mushroom extract induces apoptosis of B16 melanoma cells through arrest of G0/G1 phase in cell cycle.

• 한국동물위생학회지
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• 제39권3호
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• pp.199-204
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• 2016

A 16 year-old female grey pony was presented to Animal and Plant Quarantine agency for diagnosis in Feb 2, 2015. At necropsy, multiple pigmented masses, likely melanomas, were detected peri-anally and under the tail. Further metastatic spread to the spleen, liver, lung and lymph nodes was also identified. Histopathologically, anaplastic and pleomorphic melanocytes were observed in the mass. By immunohistochemistry, PNL2, S100 and PGP 9.5 protein were detected, but Melan A was not expressed in the neoplastic melanocytes. Based on the pathological and immunohistochemical examination, we diagnosed this case as malignant melanoma in a grey pony. To the authors' knowledge, this is the first report of equine malignant melanoma in republic of Korea.

• Genomics & Informatics
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• 제19권1호
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• pp.2.1-2.10
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• 2021

BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy.