• Korean Journal of Radiology
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• 제19권6호
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• pp.1130-1139
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• 2018

Objective: To compare the therapeutic efficacy between conventional transarterial chemoembolization (cTACE) and combined therapy using cTACE and radiofrequency ablation (RFA) in ultrasound (US)-invisible early stage hepatocellular carcinoma (HCC). Materials and Methods: From January 2008 to June 2016, 167 patients with US-invisible early stage HCCs were treated with cTACE alone (cTACE group; n = 85) or cTACE followed by immediate fluoroscopy-guided RFA targeting intratumoral iodized oil retention (combined group; n = 82). Procedure-related complications, local tumor progression (LTP), time to progression (TTP), and overall survival (OS) were compared between the two groups. Multivariate analyses were performed to identify prognostic factors. Results: There was no major complication in either group. The cTACE group showed higher 1-, 3-, and 5-year LTP rates than the combined group; i.e., 12.5%, 31.7%, and 37.0%, respectively, in the cTACE group; compared to 7.3%, 16.5%, and 16.5%, respectively, in the combined group; p = 0.013. The median TTP was 18 months in the cTACE group and 24 months in the combined group (p = 0.037). Cumulative 1-, 3-, and 5-year OS rates were 100%, 93.2%, and 87.7%, respectively, in the cTACE group and 100%, 96.6%, and 87.4%, respectively, in the combined group (p = 0.686). Tumor diameter > 20 mm and cTACE monotherapy were independent risk factors for LTP and TTP. Conclusion: Combined therapy using cTACE followed by fluoroscopy-guided RFA is a safe and effective treatment in US-invisible early stage HCCs. It provides less LTP and longer TTP than cTACE alone.

• 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.

• Journal of Microbiology and Biotechnology
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• 제32권10호
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• pp.1262-1274
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• 2022

Cholangiocarcinoma (CCA) is a complex and refractor type of cancer with global prevalence. Several barriers remain in CCA diagnosis, treatment, and prognosis. Therefore, exploring more biomarkers and therapeutic drugs for CCA management is necessary. CCA gene expression data was downloaded from the TCGA and GEO databases. KEGG enrichment, GO analysis, and protein-protein interaction network were used for hub gene identification. miRNA were predicted using Targetscan and validated according to several GEO databases. The relative RNA and miRNA expression levels and prognostic information were obtained from the GEPIA. The candidate drug was screened using pharmacophore-based virtual screening and validated by molecular modeling and through several in vitro studies. 301 differentially expressed genes (DEGs) were screened out. Complement and coagulation cascades-related genes (including AHSG, F2, TTR, and KNG1), and cell cycle-related genes (including CDK1, CCNB1, and KIAA0101) were considered as the hub genes in CCA progression. AHSG, F2, TTR, and KNG1 were found to be significantly decreased and the eight predicted miRNA targeting AHSG, F2, and TTR were increased in CCA patients. CDK1, CCNB1, and KIAA0101 were found to be significantly abundant in CCA patients. In addition, Molport-003-703-800, which is a compound that is derived from pharmacophores-based virtual screening, could directly bind to CDK1 and exhibited anti-tumor activity in cholangiocarcinoma cells. AHSG, F2, TTR, and KNG1 could be novel biomarkers for CCA. Molport-003-703-800 targets CDK1 and work as potential cell cycle inhibitors, thereby having potential for consideration for new chemotherapeutics for CCA.

• Molecules and Cells
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• 제45권8호
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• pp.550-563
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• 2022

Hepatocellular carcinoma (HCC) is an aggressive and incurable cancer. Although understanding of the molecular pathogenesis of HCC has greatly advanced, therapeutic options for the disease remain limited. In this study, we demonstrated that SETD5 expression is positively associated with poor prognosis of HCC and that SETD5 depletion decreased HCC cell proliferation and invasion while inducing cell death. Transcriptome analysis revealed that SETD5 loss downregulated the interferon-mediated inflammatory response in HCC cells. In addition, SETD5 depletion downregulated the expression of a critical glycolysis gene, PKM (pyruvate kinase M1/2), and decreased glycolysis activity in HCC cells. Finally, SETD5 knockdown inhibited tumor growth in xenograft mouse models. These results collectively suggest that SETD5 is involved in the tumorigenic features of HCC cells and that targeting SETD5 may suppress HCC progression.

• BMB Reports
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• 제55권10호
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• pp.506-511
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• 2022

Advanced hepatocellular carcinoma (HCC) is among the most challenging cancers to overcome, and there is a need for better therapeutic strategies. Among the different cancer drugs that have been used in clinics, sorafenib is considered the standard first-line drug for advanced HCC. Here, to identify a chemical compound displaying a synergistic effect with sorafenib in HCC, we screened a focused chemical library and found that MG149, a histone acetyltransferase inhibitor targeting the MYST family, exhibited the most synergistic anticancer effect with sorafenib on HCC cells. The combination of sorafenib and MG149 exerted a synergistic anti-proliferation effect on HCC cells by inducing apoptotic cell death. We revealed that cotreatment with sorafenib and MG149 aggravated endoplasmic reticulum (ER) stress to promote the death of HCC cells rather than adaptive cell survival. In addition, combined treatment with sorafenib and MG149 significantly increased the intracellular levels of unfolded proteins and reactive oxygen species, which upregulated ER stress. Collectively, these results suggest that MG149 has the potential to improve the efficacy of sorafenib in advanced HCC via the upregulation of cytotoxic ER stress.

• 한국융합학회논문지
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• 제13권1호
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• pp.161-166
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• 2022

HIF-2α는 저산소 조건에서 활성화되는 전사인자로 암, 대사증후군, 관절염, 간염 등의 발병 기전에서 핵심 역할을 한다고 보고된 바 있다. 이에 HIF-2α 저해제를 도출하고자 기존 약리활성 구조를 도입한 N'-arylisonicotinolyhydrazide를 골격으로 설정하고 화합물 라이브러리로부터 해당 화합물들을 선택하여 HIF-2α 저해활성을 측정하였다. 이를 위해 HRE-luciferase를 HTB-94세포에 transfection하고 아데노바이러스를 이용하여 HIF-2α를 세포 내로 도입하여 luciferase reporter gene assay를 수행하였다. 2-hydroxy-1-naphthyl 기를 포함한 화합물에서 저해활성이 발견됨에 따라 이 구조를 포함하는 골격을 다시 설정하고 해당 화합물들을 선정하여 활성을 측정하였다. 그 결과 HIF-2α 저해활성과 위양성 시험을 통하여 2 종의 HIF-2α 저해제를 도출하였다. 본 연구는 생물학과 화학의 융합연구로 수행되었으며 도출된 저해제는 후속 저해제 탐색 연구와 HIF-2α의 기능 연구에 활용될 수 있고 관련 질환의 치료제 개발에도 기여 할 것으로 사료된다.

• 디지털융복합연구
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• 제20권2호
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• pp.311-316
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• 2022

Tertomotide는 hTert의 일부분이며 항암 백신으로 개발된 펩타이드이나 임상시험과 동물실험에서 염증성 질환을 개선하는 활성이 다수 보고된 바 있다. 다양한 연구에서 발견된 항염활성에도 불구하고 약물성이 높지 않아 일반적인 항염약물로의 개발이 어렵다. 다양한 부위에서 일어나는 염증성 증상에 활용하기 위해서는 항염활성과 약물성이 동반되어야 하므로 구조의 개선이 필요하다. 본 연구에서는 tertomotide의 구조를 기반으로 12 종의 옥타펩타이드를 설계하고 항염증 활성을 측정하여 약물성이 개선된 tertomotide 유래의 항염 펩타이드를 도출하고자 하였다. 이를 위해 활성화된 단핵구에서 염증성 cytokine인 TNF-α의 분비에 미치는 영향을 측정하여 각 펩타이드의 항염 활성을 평가하였고 양성대조군으로 비교한 estradiol이나 tertomotide 이상의 항염활성을 가진 펩타이드를 도출하였다. 본 연구의 결과는 tertotmotide 유래 펩타이드들을 활용한 신규 항염증 소재 개발 연구에 도움이 될 것으로 예상되며, 항염증 활성 등의 생리활성이 있으나 약물성이 낮은 펩타이드에 대해 계산화학적 접근으로 구조를 변경하여 기능적 잠재력 있는 신규활성물질을 도출하는 융합연구의 좋은 예가 될 것으로 사료된다.

• International Journal of Stem Cells
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• 제16권3호
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• pp.315-325
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• 2023

Background and Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor characterized by its heterogeneity and high recurrence and lethality rates. Glioblastoma stem cells (GSCs) play a crucial role in therapy resistance and tumor recurrence. Therefore, targeting GSCs is a key objective in developing effective treatments for GBM. The role of Parathyroid hormone-related peptide (PTHrP) in GBM and its impact on GSCs remains unclear. This study aimed to investigate the effect of PTHrP on GSCs and its potential as a therapeutic target for GBM. Methods and Results: Using the Cancer Genome Atlas (TCGA) database, we found higher expression of PTHrP in GBM, which correlated inversely with survival. GSCs were established from three human GBM samples obtained after surgical resection. Exposure to recombinant human PTHrP protein (rPTHrP) at different concentrations significantly enhanced GSCs viability. Knockdown of PTHrP using target-specific siRNA (siPTHrP) inhibited tumorsphere formation and reduced the number of BrdU-positive cells. In an orthotopic xenograft mouse model, suppression of PTHrP expression led to significant inhibition of tumor growth. The addition of rPTHrP in the growth medium counteracted the antiproliferative effect of siPTHrP. Further investigation revealed that PTHrP increased cAMP concentration and activated the PKA signaling pathway. Treatment with forskolin, an adenylyl cyclase activator, nullified the antiproliferative effect of siPTHrP. Conclusions: Our findings demonstrate that PTHrP promotes the proliferation of patient-derived GSCs by activating the cAMP/PKA signaling pathway. These results uncover a novel role for PTHrP and suggest its potential as a therapeutic target for GBM treatment.

• BMB Reports
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• 제51권11호
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• pp.602-607
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• 2018

Aberrant expression of microRNAs (miRNAs) plays important roles in carcinogenesis and tumor progression. However, the expression and biological role of miR-301b in triple-negative breast cancer (TNBC) remains unclear. Here we aimed to evaluate the roles and mechanisms of miR-301b in TNBC cells. miR-301b expression was assessed in TNBC specimens and cell lines by quantitative Real-Time PCR (qRT-PCR). TNBC cells were transfected with miR-301b mimics, inhibitors or Cylindromatosis (CYLD) small interfering RNA (siRNA) using Lipofectamine 2000. The functional roles of miR-301b were determined by cell proliferation, colony formation, and apoptosis assays. Western blots and qRT-PCR were used to measure the expression of mRNAs and proteins in the cells. We found that miR-301b was upregulated in TNBC specimens and cell lines. Overexpression of miR-301b promoted cell proliferation in TNBC cells, while inhibited the apoptosis induced by 5-FU. CYLD was downregulated by miR-301b at both mRNA and protein levels in TNBC cells. Dual-luciferase report assay confirmed that miR-301b downregulated CYLD by direct interaction with the 3'-untranslated region(3'-UTR) of CYLD mRNA. $NF-{\kappa}B$ activation was mechanistically associated with miR-301b-mediated downregulation of CYLD. However, inhibition of miR-301b reversed all the effects of miR-301b. In conclusion, miR-301b plays an oncogenic role in TNBC possibly by downregulating CYLD and subsequently activating $NF-{\kappa}B$ p65, and this may provide a novel therapeutic approach for TNBC.

• 대한방사선치료학회지
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• 제28권2호
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• pp.131-137
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• 2016

목 적 : 자궁경부암 환자의 방사선 치료 시 다른 장기의 위치 변화 및 부작용을 줄이기 위해 방광의 체적을 일정하게 유지하도록 한 후 초음파를 이용하여 방광의 체적 변화를 측정하였다. 대상 및 방법 : 2015년 9월부터 12월까지 부산대학교병원에서 방사선 치료를 받은 환자 11명을 대상으로 하였다. 방광의 체적을 일정하게 유지하기 위하여 CT치료설계 전후, 모의치료 60분전에 500 cc의 물을 마시도록 설계되었다. 치료설계 전후, 모의치료, 치료계획 시 방광의 체적을 비교분석하였다. 결 과 : CT스캔상에서 측정한 방광의 평균 체적과 오차는 치료설계시와 비교한 결과 편차가 작다. CT치료설계시와 CT치료설계직후는 통계적으로 유의하며 상관관계가 있는 것으로 보이고 초음파를 이용하여 측정한 방광의 체적은 CT상에서의 체적보다 크다. 다만 CT치료설계시와 모의치료 시는 통계적으로 유의하지 않았다. 결 론 : 모의치료시 일정한 양의 물을 마시도록 지시한 것이 방광의 체적을 유지하는데 도움이 될수 있었다. 그러나 배변과 일정한 양의 물을 마시도록 지시하더라도 모의치료시 방광의 체적을 일정히 유지하는데는 어려움이 있었다. 또한 환자들이 지시에 따라 정확히 수행하는 여부가 중요하다.