• Molecules and Cells
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• 제44권10호
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• pp.710-722
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• 2021

Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment.

• Journal of Radiation Protection and Research
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• 제43권2호
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• pp.66-74
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• 2018

Background: Tumor response to anticancer therapies can much be influenced by microenvironmental factors. In this study, we determined the effect of these microenvironmental factors on DNA methylation using A549 human lung adenocarcinoma cell line. Materials and Methods: We subjected A549 cells to various conditions mimicking tumor microenvironment including hypoxia, acidosis (sodium lactate), oxidative stress ($H_2O_2$), bystander effect (supernatant from doxorubicin (Dox)-treated or irradiated cells), and immune cell infiltration (supernatant from THP-1 or Jurkat T cells). Genomic DNA was isolated from these cells and analyzed for DNA methylation. Clonogenic cell survival, gene expression, and metabolism were analyzed in cells treated with some of these conditions. Results and Discussion: We found that DNA methylation level was significantly decreased in A549 cells treated with conditioned media from Dox-treated cells or Jurkat T cells, or sodium lactate, indicating an active transcription. To determine whether the decreased DNA methylation affects radiation sensitivity, we exposed cells to these conditions followed by 6 Gy irradiation and found that cell survival was significantly increased by sodium lactate while it was decreased by conditioned media from Dox-treated cells. We further observed that cells treated with conditioned media from Dox-treated cells exhibited significant changes in expression of genes including BAX and FAS (involved in apoptosis), NADPH dehydrogenase (mitochondria), EGFR (cellular survival) and RAD51 (DNA damage repair) while sodium lactate increased cellular metabolism rather than changing the gene expression. Conclusion: Our results suggest that various tumor microenvironmental factors can differentially influence DNA methylation and hence radiosensitivity and gene expression in A549 cancer cells.

• Archives of Plastic Surgery
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• 제40권6호
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• pp.666-675
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• 2013

Background Stem cells are a unique cell population characterized by self-renewal and cellular differentiation capabilities. These characteristics, among other traits, make them an attractive option for regenerative treatments of tissues defects and for aesthetic procedures in plastic surgery. As research regarding the isolation, culture and behavior of stem cells has progressed, stem cells, particularly adult stem cells, have shown promising results in both translational and clinical applications. Methods The purpose of this review is to evaluate the applications of stem cells in the plastic surgery literature, with particular focus on the advances and limitations of current stem cell therapies. Different key areas amenable to stem cell therapy are addressed in the literature review; these include regeneration of soft tissue, bone, cartilage, and peripheral nerves, as well as wound healing and skin aging. Results The reviewed studies demonstrate promising results, with favorable outcomes and minimal complications in the cited cases. In particular, adipose tissue derived stem cell (ADSC) transplants appear to provide effective treatment options for bony and soft tissue defects, and non-healing wounds. ADSCs have also been shown to be useful in aesthetic surgery. Conclusions Further studies involving both the basic and clinical science aspects of stem cell therapies are warranted. In particular, the mechanism of action of stem cells, their interactions with the surrounding microenvironment and their long-term fate require further elucidation. Larger randomized trials are also necessary to demonstrate the continued safety of transplanted stem cells as well as the efficacy of cellular therapies in comparison to the current standards of care.

• Molecules and Cells
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• 제27권5호
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• pp.503-513
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• 2009

Proteoglycans located in basement membranes, the nanostructures underling epithelial and endothelial layers, are unique in several respects. They are usually large, elongated molecules with a collage of domains that share structural and functional homology with numerous extracellular matrix proteins, growth factors and surface receptors. They mainly carry heparan sulfate side chains and these contribute not only to storing and preserving the biological activity of various heparan sulfate-binding cytokines and growth factors, but also in presenting them in a more "active configuration" to their cognate receptors. Abnormal expression or deregulated function of these proteoglycans affect cancer and angiogenesis, and are critical for the evolution of the tumor microenvironment. This review will focus on the functional roles of the major heparan sulfate proteoglycans from basement membrane zones: perlecan, agrin and collagen XVIII, and on their roles in modulating cancer growth and angiogenesis.

• Molecules and Cells
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• 제43권11호
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• pp.945-952
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• 2020

Hypoxia induces the expression of several genes through the activation of a master transcription factor, hypoxia-inducible factor (HIF)-1α. This study shows that hypoxia strongly induced the expression of two carboxypeptidases (CP), CPA4 and CPE, in an HIF-1α-dependent manner. The hypoxic induction of CPA4 and CPE gene was accompanied by the recruitment of HIF-1α and upregulation in the active histone modification, H3K4me3, at their promoter regions. The hypoxic responsiveness of CPA4 and CPE genes was observed in human adipocytes, human adipose-derived stem cells, and human primary fibroblasts but not mouse primary adipocyte progenitor cells. CPA4 and CPE have been identified as secreted exopeptidases that degrade and process other secreted proteins and matrix proteins. This finding suggests that hypoxia changes the microenvironment of the obese hypoxic adipose tissue by inducing the expression of not only adipokines but also peptidases such as CPA4 and CPE.

• Molecules and Cells
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• 제24권1호
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• pp.1-8
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• 2007

Natural killer (NK) cells play a crucial role in innate immune system and tumor surveillance. NK cells are derived from $CD34^+$hematopoietic stem cells and undergo differentiation via precursor NK cells in bone marrow (BM) through sequential acquisition of functional surface receptors. During differentiation of NK cells, many factors are involved including cytokines, membrane factors and transcription factors as well as microenvironment of BM. NK cells express their own repertoire of receptors including activating and inhibitory receptors that bind to major histocompatibility complex (MHC) class I or class I-related molecules. The balance between activating and inhibitory receptors determines the function of NK cells to kill targets. Binding of NK cell inhibitory receptors to their MHC class I-ligand renders the target cells to be protected from NK cell-mediated cytotoxicity. Thus, NK cells are able to discriminate self from non-self through MHC class I-binding inhibitory receptor. Using intrinsic properties of NK cells, NK cells are emerging to apply as therapeutic agents against many types of cancers. Recently, NK cell alloactivity has also been exploited in killer cell immunoglobulin-like receptor mismatched haploidentical stem cell transplantation to reduce the rate of relapse and graft versus host disease. In this review, we discuss the basic mechanisms of NK cell differentiation, diversity of NK cell receptors, and clinical applications of NK cells for anti-cancer immunotherapy.

• Biomolecules & Therapeutics
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• 제26권1호
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• pp.10-18
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• 2018

Tumors are dynamic metabolic systems which highly augmented metabolic fluxes and nutrient needs to support cellular proliferation and physiological function. For many years, a central hallmark of tumor metabolism has emphasized a uniformly elevated aerobic glycolysis as a critical feature of tumorigenecity. This led to extensive efforts of targeting glycolysis in human cancers. However, clinical attempts to target glycolysis and glucose metabolism have proven to be challenging. Recent advancements revealing a high degree of metabolic heterogeneity and plasticity embedded among various human cancers may paint a new picture of metabolic targeting for cancer therapies with a renewed interest in glucose metabolism. In this review, we will discuss diverse oncogenic and molecular alterations that drive distinct and heterogeneous glucose metabolism in cancers. We will also discuss a new perspective on how aberrantly altered glycolysis in response to oncogenic signaling is further influenced and remodeled by dynamic metabolic interaction with surrounding tumor-associated stromal cells.

• IMMUNE NETWORK
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• 제14권6호
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• pp.265-276
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• 2014

The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy.

• Molecules and Cells
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• 제40권7호
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• pp.515-522
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• 2017

CD133, a pentaspan transmembrane glycoprotein, is generally used as a cancer stem cell marker in various human malignancies, but its biological function in cancer cells, especially in glioma cells, is largely unknown. Here, we demonstrated that forced expression of CD133 increases the expression of IL-$1{\beta}$ and its downstream chemokines, namely, CCL3, CXCL3 and CXCL5, in U87MG glioma cells. Although there were no apparent changes in cell growth and sphere formation in vitro and tumor growth in vivo, in vitro trans-well studies and in vivo tumor xenograft assays showed that neutrophil recruitment was markedly increased by the ectopic expression of CD133. In addition, the clinical relevance between CD133 expression and IL-$1{\beta}$ gene signature was established in patients with malignant gliomas. Thus, these results imply that glioma cells expressing CD133 are capable of modulating tumor microenvironment through the IL-$1{\beta}$ signaling pathway.

• 한국가시화정보학회지
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• 제19권1호
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• pp.74-80
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• 2021

Cells regulate their shapes and motility by sensing the cues from the internal and external microenvironment. Under different circumstances, microglia, the brain resident immune cells, undergo dynamic phenotypic changes, one of which is a remarkable periodic oscillatory migration in vitro. However, very little is known about the kinematic and dynamic perspectives of this oscillatory behavior. In this study, we tracked the changes in cell morphology and nuclear displacement, and visualized the forces using traction force microscopy (TFM). By correlation analyses, we confirmed that the lamellipodia formation preceded the nuclear translocation. Moreover, traction, developed following lamellipodia formation, was found to be localized and fluctuated at two ends of the oscillating cells. Taken together, our results imply that oscillatory microglial cells feature a viscoelastic migration, which will contribute to the field of cell mechanics.