• Biomolecules & Therapeutics
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• v.27 no.1
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• pp.54-62
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• 2019

Cis-3-O-p-hydroxycinnamoyl ursolic acid (HCUA), a triterpenoid compound, was purified from Elaeagnus oldhamii Maxim. This traditional medicinal plant has been used for treating rheumatoid arthritis and lung disorders as well as for its anti-inflammation and anticancer activities. This study aimed to investigate the anti-proliferative and apoptotic-inducing activities of HCUA in oral cancer cells. HCUA exhibited anti-proliferative activity in oral cancer cell lines (Ca9-22 and SAS cells), but not in normal oral fibroblasts. The inhibitory concentration of HCUA that resulted in 50% viability was $24.0{\mu}M$ and $17.8{\mu}M$ for Ca9-22 and SAS cells, respectively. Moreover, HCUA increased the number of cells in the sub-G1 arrest phase and apoptosis in a concentration-dependent manner in both oral cancer cell lines, but not in normal oral fibroblasts. Importantly, HCUA induced p53-mediated transcriptional regulation of pro-apoptotic proteins (Bax, Bak, Bim, Noxa, and PUMA), which are associated with mitochondrial apoptosis in oral cancer cells via the loss of mitochondrial membrane potential. HCUA triggered the production of intracellular reactive oxygen species (ROS) that was ascertained to be involved in HCUA-induced apoptosis by the ROS inhibitors YCG063 and N-acetyl-L-cysteine. As a result, HCUA had potential antitumor activity to oral cancer cells through eliciting ROS-dependent and p53-mediated mitochondrial apoptosis. Overall, HCUA could be applicable for the development of anticancer agents against human oral cancer.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.2
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• pp.267-273
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• 2017

The p53-inducible gene 3 (PIG3), initially identified as a gene downstream of p53, plays an important role in the apoptotic process triggered by p53-mediated reactive oxygen species (ROS) production. Recently, several studies have suggested that PIG3 may play a role in various types of cancer. However, the functional significance of PIG3 in cancer remains unclear. Here, we found that PIG3 was highly expressed in human colon cancer cell lines compared to normal colon-derived fibroblasts. Therefore, we attempted to elucidate the functional role of PIG3 in colon cancer. PIG3 overexpression increases the colony formation, migration and invasion ability of HCT116 colon cancer cells. Conversely, these tumorigenic abilities were significantly decreased in in vitro studies with PIG3 knockdown HCT116 cells. PIG3 knockdown also attenuated the growth of mouse xenograft tumors. These results demonstrate that PIG3 is associated with the tumorigenic potential of cancer cells, both in vitro and in vivo, and could play a key oncogenic role in colon cancer.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.33 no.1
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• pp.11-19
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• 2007

This study was to evaluate the expression of vascular endothelial growth factor receptors (VEGFRs) in tumor and stromal cells of tougue squamous cell carcinoma (SCC). We also wanted to characterize the differences, from the angiogenic aspect, between cancer-associated stromal cells and non-malignant stromal cells. Paraffin-embedded tumor specimens from eleven patients with tongue SCCs were studied. Immunohistochemical staining for VEGFR-1,-2, and -3 was performed on the tumor cells, stromal fibroblasts and tumor-associated macrophages of the specimens. The expression of all 3 receptors was detected in the tumor cells themselves of the biopsy specimens. All 3 receptors were also expressed on stromal cells, except that VEGFR-2 was not expressed in stromal fibroblasts. In radical excision specimens, the staining intensity for VEGFR-1, -2 in the tumor cells and VEGFR-1,-3 in the tumor-associated macrophages was significantly lower than that in the biopsy specimens (P < 0.05). By using the general marker of fibroblast and macrophage, 5B5 and CD68, respectively, we performed double immunofluorescence staining for 5B5 and each VEGFR in the stromal fibroblasts and for CD68 and each VEGFR in the tumor-associated macrophages of the radical excision specimens. We used 4 cases of fibroma and 4 cases of chronic inflammation tissue as the controls. It was found that only each marker was expressed in the control group, however, 5B5/VEGFR-1 and 5B5/VEGFR-3 in the stromal fibroblasts, and CD68/VEGFR-1 and CD68/VEGFR-3 in the tumor-associated macrophages were double stained in the radical excision specimens. Although our study used small number of specimens, the results of our study showed that in tongue SCC, in association with the angiogenesis, the stromal cells showed the activated phenotype and this was different from the nonmalignant stromal cells.

• Genomics & Informatics
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• v.21 no.4
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• pp.48.1-48.8
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• 2023

Liver cancer is the fourth leading cause of death worldwide. Well-known risk factors include hepatitis B virus and hepatitis C virus, along with exposure to aflatoxins, excessive alcohol consumption, obesity, and type 2 diabetes. Genomic variants play a crucial role in mediating the associations between these risk factors and liver cancer. However, the specific variants involved in this process remain under-explored. This study utilized a bioinformatics approach to identify genetic variants associated with liver cancer from various continents. Single-nucleotide polymorphisms associated with liver cancer were retrieved from the genome-wide association studies catalog. Prioritization was then performed using functional annotation with HaploReg v4.1 and the Ensembl database. The prevalence and allele frequencies of each variant were evaluated using Pearson correlation coefficients. Two variants, rs2294915 and rs2896019, encoded by the PNPLA3 gene, were found to be highly expressed in the liver tissue, as well as in the skin, cell-cultured fibroblasts, and adipose-subcutaneous tissue, all of which contribute to the risk of liver cancer. We further found that these two SNPs (rs2294915 and rs2896019) were positively correlated with the prevalence rate. Positive associations with the prevalence rate were more frequent in East Asian and African populations. We highlight the utility of this population-specific PNPLA3 genetic variant for genetic association studies and for the early prognosis and treatment of liver cancer. This study highlights the potential of integrating genomic databases with bioinformatic analysis to identify genetic variations involved in the pathogenesis of liver cancer. The genetic variants investigated in this study are likely to predispose to liver cancer and could affect its progression and aggressiveness. We recommend future research prioritizing the validation of these variations in clinical settings.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.281-290
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• 2024

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis owing to its desmoplastic stroma. Therefore, therapeutic strategies targeting this tumor stroma should be developed. In this study, we describe the heterogeneity of cancer-associated fibroblasts (CAFs) and their diverse roles in the progression, immune evasion, and resistance to treatment of PDAC. We subclassified the spatial distribution and functional activity of CAFs to highlight their effects on prognosis and drug delivery. Extracellular matrix components such as collagen and hyaluronan are described for their roles in tumor behavior and treatment outcomes, implying their potential as therapeutic targets. We also discussed the roles of extracellular matrix (ECM) including matrix metalloproteinases and tissue inhibitors in PDAC progression. Finally, we explored the role of the adaptive and innate immune systems in shaping the PDAC microenvironment and potential therapeutic strategies, with a focus on immune cell subsets, cytokines, and immunosuppressive mechanisms. These insights provide a comprehensive understanding of PDAC and pave the way for the development of prognostic markers and therapeutic interventions.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.32 no.3
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• pp.209-215
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• 2006

Preoperative neoadjuvant chemotherapy using cisplatin and 5-FU is generally given in oral and maxillofacial cancer. At tissue level both inflammation and fibrosis occur after chemotherapy. The cellular changes mimic those of a granulating wound, with activated macrophages and fibroblasts replacing the malignant cells as they are erradicated. Stromal cells, together with extracellular matrix components, provide the microenvironment that is pivotal for tumor cell growth, invasion, and metastatic progression. Vascular endothelial growth factor(VEGF), an important regulator of angiogenesis in cancer, induces mitogenesis of vascular endothelial cells, and vascular permeabilization and microvessel formation in a tumor are associated with tumor nutrition and oxygenation. Also, they are associated with chemotherapeutic drug delivery. Oxygen delivery to tumor appears to rely on a network of microvessels, On the other hand, the tumor microvessel is clearly an important factor in chemotherapeutic drug delivery to cancer cells, and the efficacy of drug delivery can be high in richly vascularized tumors. So, this study was conducted to evaluate the effect of neoadjuvant chemotherapy on microvessel density from 11 patients with tongue cancers. Our results showed that neoadjuvant chemotherapy was seemed to decrease VEGF expression in tumor cells, however, it did not significantly alter VEGF expression in tumor-associated macrophages. Also, Neoadjuvant chemotherapy had little effect on the microvessel density using CD34, and tumor-associated macrophage level using CD68. Thus, tumorassociated macrophages seem to be the key factor associated with the maintenance of microvessel density after neoadjuvant chemotherapy in tongue cancer.

• Journal of Animal Science and Technology
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• v.52 no.6
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• pp.521-527
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• 2010

Fibroblast growth factor receptor 1 (FGFR1) plays roles in angiogenesis, wound healing, and embryonic development via the regulation of cell proliferation, differentiation, and survival. It is well known that ectopic expression of FGFR1 is associated with cancer development. To characterize the function of FGFR1 in the normal and cancer cell lines DF-1 and DT40, respectively, we performed FGFR1 knockdown by RNA interference. In the DT40 cells, FGFR1 knockdown induced upregulation of FGFR2 and FGFR3 expression, downregulation of pro-apoptosis-related genes, and upregulation of anti-apoptosis-related genes. However, in DF-1 cells, FGFR1 knockdown induced upregulation of pro-apoptosis-related genes and downregulation of anti-apoptosis-related genes. Our data suggest that repression of FGFR1 induced upregulation of other FGF receptors and anti-apoptosis-related genes in cancer cells and pro-apoptosis-related genes in normal cells.

• Journal of Ginseng Research
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• v.43 no.3
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• pp.431-441
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• 2019

Background: The efficacy of ginseng, the representative product of Korea, and its chemical effects have been well investigated. The ginsenoside RG3 has been reported to exhibit apoptotic, anticancer, and antidepressant-like effects. Methods: In this report, the putative effect of RG3 on several cellular function including cell survival, differentiation, development and aging process were evaluated by monitoring each specific marker. Also, mitochondrial morphology and function were investigated in ultraviolet (UV)-irradiated normal human dermal fibroblast cells. Results: RG3 treatment increased the expression of extracellular matrix proteins, growth-associated immediate-early genes, and cell proliferation genes in UV-irradiated normal human dermal fibroblast cells. And, RG3 also resulted in enhanced expression of antioxidant proteins such as nuclear factor erythroid 2-related factor-2 and heme oxygenase-1. In addition, RG3 affects the morphology of UV-induced mitochondria and plays a role in protecting mitochondrial dysfunction. Conclusioin: RG3 restores mitochondrial adenosine triphosphate (ATP) and membrane potential via its antioxidant effects in skin cells damaged by UV irradiation, leading to an increase in proteins linked with the extracellular matrix, cell proliferation, and antioxidant activity.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.8
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• pp.3817-3823
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• 2014

Background: The MDM2 oncogene, a negative regulator of p53, has a functional polymorphism in the promoter region (SNP309) that is associated with multiple kinds of cancers including non-melanoma skin cancer. SNP309 has been shown to associate with accelerated tumor formation by increasing the affinity of the transcriptional activator Sp1. It remains unknown whether there are other factors involved in the regulation of MDM2 transcription through a trans-regulatory mechanism. Methods: In this study, SNP309 was verified to be associated with overexpression of MDM2 in tumor cells. Bioinformatics predicts that the T to G substitution at SNP309 generates a stronger E2F1 binding site, which was confirmed by ChIP and luciferase assays. Results: E2F1 knockdown downregulates the expression of MDM2, which confirms that E2F1 is a functional upstream regulator. Furthermore, tumor cells with the GG genotype exhibited a higher proliferation rate than TT, correlating with cyclin D1 expression. E2F1 depletion significantly inhibits the proliferation capacity and downregulates cyclin D1 expression, especially in GG genotype skin fibroblasts. Notably, E2F1 siRNA effects could be rescued by cyclin D1 overexpression. Conclusion: Taken together, a novel modulator E2F1 was identified as regulating MDM2 expression dependent on SNP309 and further mediates cyclin D1 expression and tumor cell proliferation. E2F1 might act as an important factor for SNP309 serving as a rate-limiting event in carcinogenesis.

• Molecules and Cells
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• v.24 no.3
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• pp.409-415
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• 2007

The retinoblastoma (Rb) gene is one of the most important genes in cell cycle regulation and tumorigenesis. Homozygosity for a germ-line Rb mutation results in embryonic lethality and evokes developmental defects associated with inappropriate S-phase entry and high levels of apoptosis. Although Rb has been extensively studied, more target genes need to be identified and characterized to unravel the precise mechanism of Rb function. In order to identify Rb-regulated genes, we analyzed the gene expression profile of Rb-deficient mouse embryo fibroblasts (MEFs), and identified an unknown gene, RbEST47, that is transcriptionally upregulated in Rb-deficient MEFs. This gene is conserved from fruitfly to human. It is expressed in brain, lung, kidney, and testis, and is located on mouse chromosome 2. This region is syntenic to human chromosome 9q34.3, which frequently exhibits loss of heterozygosity in neoplastic diseases. RbEST47 was considerably down-regulated in immortalized cells, and showed cell cycle-dependent expression, suggesting important roles in S and/or G2.