• Journal of Life Science
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• v.33 no.11
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• pp.950-955
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• 2023

Cell division is an essential process for the survival and development of living organisms. It is critical that duplicated chromosomes are properly segregated into daughter cells during mitosis. The centrosome is the core organelle that forms the microtubule-organizing center (MTOC), which generates the microtubules that make up the mitotic spindle during cell division. The centrosome is also involved in cell signaling and motility. In normal cells, there is one centrosome in G1 that replicates into two in the S phase and matures through G2. During the M phase, duplicated centrosomes move to both ends of the cell, and spindle microtubules that are generated from MTOC move the chromosome to both ends. The cells then split into two to complete the cell division. However, a phenomenon called centrosome amplification (CA), in which the number of centrosomes is higher than normal, is common in cancer cells and can lead to chromosome instability (CIN). This paper discusses the process of centrosome replication and the role of PLK4 in this process. The possible consequences of centrosome amplification and how the PLK4 inhibitor may be able to treat certain types of cancer cells, such as breast cancer and neuroblastoma, will also be discussed.

• Genomics & Informatics
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• v.21 no.4
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• pp.44.1-44.10
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• 2023

Tumor hypoxia, oxygen deprivation state, occurs in most cancers and promotes angiogenesis, enhancing the potential for metastasis. The vascular endothelial growth factor (VEGF) family genes play crucial roles in tumorigenesis by promoting angiogenesis. To investigate the malignant processes triggered by hypoxia-induced angiogenesis across pan-cancers, we comprehensively analyzed the relationships between the expression of VEGF family genes and hypoxic microenvironment based on integrated bioinformatics methods. Our results suggest that the expression of VEGF family genes differs significantly among various cancers, highlighting their heterogeneity effect on human cancers. Across the 33 cancers, VEGFB and VEGFD showed the highest and lowest expression levels, respectively. The survival analysis showed that VEGFA and placental growth factor (PGF) were correlated with poor prognosis in many cancers, including kidney renal cell and liver hepatocellular carcinoma. VEGFC expression was positively correlated with glioma and stomach cancer. VEGFA and PGF showed distinct positive correlations with hypoxia scores in most cancers, indicating a potential correlation with tumor aggressiveness. The expression of miRNAs targeting VEGF family genes, including hsa-miR-130b-5p and hsa-miR-940, was positively correlated with hypoxia. In immune subtypes analysis, VEGFC was highly expressed in C3 (inflammatory) and C6 (transforming growth factor β dominant) across various cancers, indicating its potential role as a tumor promotor. VEGFC expression exhibited positive correlations with immune infiltration scores, suggesting low tumor purity. High expression of VEGFA and VEGFC showed favorable responses to various drugs, including BLU-667, which abrogates RET signaling, an oncogenic driver in liver and thyroid cancers. Our findings suggest potential roles of VEGF family genes in malignant processes related with hypoxia-induced angiogenesis.

• IMMUNE NETWORK
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• v.23 no.2
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• pp.15.1-15.17
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• 2023

Innate lymphoid cells (ILCs) are critical immune-response mediators. Although they largely reside in mucosal tissues, the kidney also bears substantial numbers. Nevertheless, kidney ILC biology is poorly understood. BALB/c and C57BL/6 mice are known to display type-2 and type-1 skewed immune responses, respectively, but it is unclear whether this extends to ILCs. We show here that indeed, BALB/c mice have higher total ILCs in the kidney than C57BL/6 mice. This difference was particularly pronounced for ILC2s. We then showed that three factors contributed to the higher ILC2s in the BALB/c kidney. First, BALB/c mice demonstrated higher numbers of ILC precursors in the bone marrow. Second, transcriptome analysis showed that compared to C57BL/6 kidneys, the BALB/c kidneys associated with significantly higher IL-2 responses. Quantitative RT-PCR also showed that compared to C57BL/6 kidneys, the BALB/c kidneys expressed higher levels of IL-2 and other cytokines known to promote ILC2 proliferation and/or survival (IL-7, IL-33, and thymic stromal lymphopoietin). Third, the BALB/c kidney ILC2s may be more sensitive to the environmental signals than C57BL/6 kidney ILC2s since they expressed their transcription factor GATA3 and the IL-2, IL-7, and IL-25 receptors at higher levels. Indeed, they also demonstrated greater responsiveness to IL-2 than C57BL/6 kidney ILC2s, as shown by their greater STAT5 phosphorylation levels after culture with IL-2. Thus, this study demonstrates previously unknown properties of kidney ILC2s. It also shows the impact of mouse strain background on ILC2 behavior, which should be considered when conducting research on immune diseases with experimental mouse models.

• Biomolecules & Therapeutics
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• v.21 no.2
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• pp.107-113
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• 2013

Plasminogen activator inhibitor-1 (PAI-1) is a member of serine protease inhibitor family, which regulates the activity of tissue plasminogen activator (tPA). In CNS, tPA/PAI-1 activity is involved in the regulation of a variety of cellular processes such as neuronal development, synaptic plasticity and cell survival. To gain a more insights into the regulatory mechanism modulating tPA/PAI-1 activity in brain, we investigated the effects of proteasome inhibitors on tPA/PAI-1 expression and activity in rat primary astrocytes, the major cell type expressing both tPA and PAI-1. We found that submicromolar concentration of MG132, a cell permeable peptide-aldehyde inhibitor of ubiquitin proteasome pathway selectively upregulates PAI-1 expression. Upregulation of PAI-1 mRNA as well as increased PAI-1 promoter reporter activity suggested that MG132 transcriptionally increased PAI-1 expression. The induction of PAI-1 downregulated tPA activity in rat primary astrocytes. Another proteasome inhibitor lactacystin similarly increased the expression of PAI-1 in rat primary astrocytes. MG132 activated MAPK pathways as well as PI3K/Akt pathways. Inhibitors of these signaling pathways reduced MG132-mediated upregulation of PAI-1 in varying degrees and most prominent effects were observed with SB203580, a p38 MAPK pathway inhibitor. The regulation of tPA/PAI-1 activity by proteasome inhibitor in rat primary astrocytes may underlie the observed CNS effects of MG132 such as neuroprotection.

• Journal of Life Science
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• v.25 no.8
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• pp.947-952
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• 2015

Prostate apoptosis response-4 (Par-4) was originally identified in androgen-independent prostate cancer cells undergoing apoptosis. Par-4 is ubiquitously expressed in normal cells and tissues, but it is downregulated in several types of cancers. Par-4 is a 38 kDa tumor suppressor protein encoded by the PARW gene. Par-4 promotes apoptosis in a variety of cancerous cells, but not in normal cells. In this review, we focused on the structure, expression and function of Par-4 in apoptotic signaling pathway. Functional domains of Par-4 include two nuclear localization sequences (NLS), a leucine zipper (LZ) domain, a nuclear export sequence (NES) and selective for apoptosis in cancer cell (SAC) domain. Many studies have underlined the importance of Par-4 in preventing cancer development. The activity of Par-4 is differently regulated by localization of intracellular and extracellular Par-4. Intracellular Par-4 inhibits Akt- and NF-κB-mediated cell survival pathways and downregulates Bcl-2 expression. Extracellular Par-4 activates the extrinsic apoptotic pathway by binding to cell surface receptor GRP78, a stress response protein that is in the endoplasmic reticulum (ER). Endogenous Par-4 sensitizes cancer cells to various apoptotic stimuli, while exogenous Par-4 enhances SAC domain-dependent apoptosis in cancer cells, but not normal cells. Therefore, Par-4 is an attractive target for cancer therapy.

• Korean Journal of Veterinary Research
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• v.43 no.2
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• pp.211-218
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• 2003

Human ovarian cancerous cells survive in a way that they trigger the nucleotide excision repair (NER) or double-strand DNA repair (dsDNA) repair mechanism to show resistance to anticancer drugs and activate many kinds of repair protein, thus removing damaged DNAs. Two experiments on the PA-1 human ovarian teratocareinoma cell line that hardly has any expression of epidermal growth factor receptor (EGFR) were conducted in the study; first, EGF-R was transfected and its receptor was obtained. The receptor was investigated in terms of its mutual relations with many kinds of protein concerning NER or dsDNA repair. Second, it was examined what kind impact cisplatin and adriamycin had on the effects of EGF-R over the PA-1 cell line lacking EGF-R. When being administered with cisplatin and adriamycin, Hey and Hey C2 cell lines showed a high level of resistance while PA-1 cell line a high level of sensitivity. Hey and Hey C2 cell lines that are resistant against anticancer drugs exhibited a high level of EGF-R expression while PA-1 cell line that is sensitive to them did a much lower level of the expression. When PA-1 cell line was transfected for the expression of DNA adduct and EGF-R, it showed a higher level of resistance compared to the control group. There was no difference in the expression of DNA repair proteins (DNA- dependent protein kinase, Ku70, and Ku80) between Hey and the PA-1 cell lines. The results indicate that the Hey cell line that is resistant against cisplatin and adriamycin works along the signaling system responding to the changes of EGF-R while the PA-1 cell line that is sensitive to both of them does to the lack of EGF-R.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.16
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• pp.6813-6823
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• 2015

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive of human brain tumors and has a stunning progression with a mean survival of one year from the date of diagnosis. High cell proliferation, angiogenesis and/or necrosis are histopathological features of this cancer, which has no efficient curative therapy. This aggressiveness is associated with particular heterogeneity of the tumor featuring multiple genetic and epigenetic alterations, but also with implications of aberrant signaling driven by growth factors. The transforming growth factor ${\beta}$ ($TGF{\beta}$) superfamily is a large group of structurally related proteins including $TGF{\beta}$ subfamily members Nodal, Activin, Lefty, bone morphogenetic proteins (BMPs) and growth and differentiation factor (GDF). It is involved in important biological functions including morphogenesis, embryonic development, adult stem cell differentiation, immune regulation, wound healing and inflammation. This superfamily is also considered to impact on cancer biology including that of GBM, with various effects depending on the member. The $TGF{\beta}$ subfamily, in particular, is overexpressed in some GBM types which exhibit aggressive phenotypes. This subfamily impairs anti-cancer immune responses in several ways, including immune cells inhibition and major histocompatibility (MHC) class I and II abolishment. It promotes GBM angiogenesis by inducing angiogenic factors such as vascular endothelial growth factor (VEGF), plasminogen activator inhibitor (PAI-I) and insulinlike growth factor-binding protein 7 (IGFBP7), contributes to GBM progression by inducing metalloproteinases (MMPs), "pro-neoplastic" integrins (${\alpha}v{\beta}3$, ${\alpha}5{\beta}1$) and GBM initiating cells (GICs) as well as inducing a GBM mesenchymal phenotype. Equally, Nodal promotes GICs, induces cancer metabolic switch and supports GBM cell proliferation, but is negatively regulated by Lefty. Activin promotes GBM cell proliferation while GDF yields immune-escape function. On the other hand, BMPs target GICS and induce differentiation and sensitivity to chemotherapy. This multifaceted involvement of this superfamily in GBM necessitates different strategies in anti-cancer therapy. While suppressing the $TGF{\beta}$ subfamily yields advantageous results, enhancing BMPs production is also beneficial.

• BMB Reports
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• v.48 no.2
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• pp.68-80
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• 2015

G protein-coupled receptors (GPCRs) are a large class of transmembrane receptors categorized into five distinct families: rhodopsin, secretin, adhesion, glutamate, and frizzled. They bind and regulate 80% of all hormones and account for 20-50% of the pharmaceuticals currently on the market. Hundreds of GPCRs integrate and coordinate the functions of individual cells, mediating signaling between various organs. GPCRs are crucial players in tumor progression, adipogenesis, and inflammation. Several studies have also confirmed their central roles in embryonic development and stem cell maintenance. Recently, GPCRs have emerged as key players in the regulation of cell survival, proliferation, migration, and self-renewal in pluripotent (PSCs) and cancer stem cells (CSCs). Our study and other reports have revealed that the expression of many GPCRs is modulated during the generation of induced PSCs (iPSCs) or CSCs as well as during CSC sphere formation. These GPCRs may have crucial roles in the regulation of self-renewal and other biological properties of iPSCs and CSCs. This review addresses the current understanding of the role of GPCRs in stem cell maintenance and somatic reprogramming to PSCs or CSCs.

• Reproductive and Developmental Biology
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• v.36 no.3
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• pp.173-181
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• 2012

Sphingosine-1-phosphate (S1P) has a many function involved proliferation, differentiation and survival of many cells. In this study, to investigate whether S1P improve the developmental competence of porcine embryos, 50 nM of S1P were supplemented during in vitro maturation (with EGF or without EGF) medium and/or in vitro culture (IVC) medium. Addition of S1P was significantly increased the rate of oocytes reaching metaphase II (MII) compared to the control (83.5 vs. 64.1%) in without EGF medium, but not with EGF medium (89.5 vs. 84.6%). When treated with $1{\mu}M$ of N1N-dimethylsphingosine (DMS), a sphingosine kinase inhibitor which is blocked endogenous generation of S1P, the meiotic progression rates to MII stage (without EGF: 45.2 and with EGF: 66.7%) were significantly decreased and degeneration rates (without EGF: 51.2 and with EGF: 30.1%) were increased in both medium compared to control group during IVM periods. Also, the rates of blastocyst formation was significantly increased in the S1P treated group compared to control group (29.0 vs. 19.2%) of EGF supplemented medium, whereas there were no effect in the EGF free medium (9.0 vs. 10.5%). After 12 h IVM, the phosphorylation of ERK1 and ERK2, which is major signaling pathway of MAP kinase, were increased in the S1P group than that of control or DMS group. When supplemented of S1P during IVC, the rates of blastocyst formation and total cell number (30.2% and 40.6) were significantly increased in S1P-treated group compared with control (20.1% and 32.5), DMS (12.3% and 25.1), and S1P plus DMS group (24.7% and 33.6). The percentage of apoptosis nuclei in the S1P group was significantly decreased than other groups. Also, the rates of blastocyst formation (26.7 vs. 14%) and total cell number (42.8 vs. 32.5) were significantly increased in the S1P group than those of control group when S1P added during the entire IVM and IVC periods. Taken together, our results indicate that S1P supplementation in IVM and/or IVC medium affects beneficial effect of meiotic maturation and subsequent developmental competence of porcine embryos.

• BMB Reports
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• v.50 no.9
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• pp.460-465
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• 2017

Polycystic kidney disease (PKD) is one of the most common inherited disorders, involving progressive cyst formation in the kidney that leads to renal failure. FK506 binding protein 12 (FK506BP) is an immunophilin protein that performs multiple functions, including regulation of cell signaling pathways and survival. In this study, we determined the roles of PEP-1-FK506BP on cell proliferation and cyst formation in PKD cells. Purified PEP-1-FK506BP transduced into PKD cells markedly inhibited cell proliferation. Also, PEP-1-FK506BP drastically inhibited the expression levels of p-Akt, p-p70S6K, p-mTOR, and p-ERK in PKD cells. In a 3D-culture system, PEP-1-FK506BP significantly reduced cyst formation. Furthermore, the combined effects of rapamycin and PEP-1-FK506BP on cyst formation were markedly higher than the effects of individual treatments. These results suggest that PEP-1-FK506BP delayed cyst formation and could be a new therapeutic strategy for renal cyst formation in PKD.