Publications by authors named "Jong Kook Park"

44 Publications

Noncoding RNAs Associated with Therapeutic Resistance in Pancreatic Cancer.

Biomedicines 2021 Mar 7;9(3). Epub 2021 Mar 7.

Department of Biomedical Science, Hallym University, Chunchon 24252, Korea.

Therapeutic resistance is an inevitable impediment towards effective cancer therapies. Evidence accumulated has shown that the signaling pathways and related factors are fundamentally responsible for therapeutic resistance via regulating diverse cellular events, such as epithelial-to-mesenchymal transition (EMT), stemness, cell survival/apoptosis, autophagy, etcetera. Noncoding RNAs (ncRNAs) have been identified as essential cellular components in gene regulation. The expression of ncRNAs is altered in cancer, and dysregulated ncRNAs participate in gene regulatory networks in pathological contexts. An in-depth understanding of molecular mechanisms underlying the modulation of therapeutic resistance is required to refine therapeutic benefits. This review presents an overview of the recent evidence concerning the role of human ncRNAs in therapeutic resistance, together with the feasibility of ncRNAs as therapeutic targets in pancreatic cancer.
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http://dx.doi.org/10.3390/biomedicines9030263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998345PMC
March 2021

Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway.

Biomol Ther (Seoul) 2021 Jan 13. Epub 2021 Jan 13.

Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Republic of Korea.

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in HO-treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.
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http://dx.doi.org/10.4062/biomolther.2020.154DOI Listing
January 2021

The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer.

Int J Mol Sci 2021 Jan 10;22(2). Epub 2021 Jan 10.

Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea.

Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis. Multistep processes are involved in cancer metastasis. Accumulating evidence has shown that cancer cells acquire the capacity of anoikis resistance and anchorage-independent cell growth, which are critical prerequisite features of metastatic cancer cells. Multiple cellular factors and events, such as apoptosis, survival factors, cell cycle, EMT, stemness, autophagy, and integrins influence the anoikis resistance and anchorage-independent cell growth in cancer. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are dysregulated in cancer. They regulate cellular signaling pathways and events, eventually contributing to cancer aggressiveness. This review presents the role of miRNAs and lncRNAs in modulating anoikis resistance and anchorage-independent cell growth. We also discuss the feasibility of ncRNA-based therapy and the natural features of ncRNAs that need to be contemplated for more beneficial therapeutic strategies against cancer.
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http://dx.doi.org/10.3390/ijms22020627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827914PMC
January 2021

Tat‑aldose reductase prevents dopaminergic neuronal cell death by inhibiting oxidative stress and MAPK activation.

Int J Mol Med 2021 Feb 8;47(2):751-760. Epub 2020 Dec 8.

Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Republic of Korea.

Aldose reductase (AR) is known to detoxify aldehydes and prevent oxidative stress. Although AR exerts antioxidant effects, the role of AR in Parkinson's disease (PD) remains unclear. The objective of the present study was to investigate the protective effects of AR protein against 1‑methyl‑4‑phenylpyridinium (MPP+)‑induced SH‑SY5Y cell death and 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)‑induced PD in a mouse model using the cell permeable Tat‑AR fusion protein. The results revealed that when Tat‑AR protein was transduced into SH‑SY5Y cells, it markedly protected the cells against MPP+‑induced death and DNA fragmentation. It also reduced the activation of mitogen-activated protein kinase (MAPKs) and regulated the expression levels of Bcl‑2, Bax and caspase‑3. Immunohistochemical analysis revealed that when Tat‑AR protein was transduced into the substantia nigra (SN) of mice with PD, it markedly inhibited dopaminergic neuronal cell death. Therefore, Tat‑AR may be useful as a therapeutic protein for PD.
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http://dx.doi.org/10.3892/ijmm.2020.4812DOI Listing
February 2021

Three-Dimensional Imaging for Multiplex Phenotypic Analysis of Pancreatic Microtumors Grown on a Minipillar Array Chip.

Cancers (Basel) 2020 Dec 7;12(12). Epub 2020 Dec 7.

Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, Korea.

Three-dimensional (3D) culture of tumor spheroids (TSs) within the extracellular matrix (ECM) represents a microtumor model that recapitulates human solid tumors in vivo, and is useful for 3D multiplex phenotypic analysis. However, the low efficiency of 3D culture and limited 3D visualization of microtumor specimens impose technical hurdles for the evaluation of TS-based phenotypic analysis. Here, we report a 3D microtumor culture-to-3D visualization system using a minipillar array chip combined with a tissue optical clearing (TOC) method for high-content phenotypic analysis of microtumors. To prove the utility of this method, phenotypic changes in TSs of human pancreatic cancer cells were determined by co-culture with cancer-associated fibroblasts and M2-type tumor-associated macrophages. Significant improvement was achieved in immunostaining and optical transmission in each TS as well as the entire microtumor specimen, enabling optimization in image-based analysis of the morphology, structural organization, and protein expression in cancer cells and the ECM. Changes in the invasive phenotype, including cellular morphology and expression of epithelial-mesenchymal transition-related proteins and drug-induced apoptosis under stromal cell co-culture were also successfully analyzed. Overall, our study demonstrates that a minipillar array chip combined with TOC offers a novel system for 3D culture-to-3D visualization of microtumors to facilitate high-content phenotypic analysis.
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http://dx.doi.org/10.3390/cancers12123662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762293PMC
December 2020

Participation of MicroRNAs in the Treatment of Cancer with Phytochemicals.

Molecules 2020 Oct 14;25(20). Epub 2020 Oct 14.

Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea.

Cancer is a global health concern and one of the main causes of disease-related death. Even with considerable progress in investigations on cancer therapy, effective anti-cancer agents and regimens have thus far been insufficient. There has been compelling evidence that natural phytochemicals and their derivatives have potent anti-cancer activities. Plant-based anti-cancer agents, such as etoposide, irinotecan, paclitaxel, and vincristine, are currently being applied in medical treatments for patients with cancer. Further, the efficacy of plenty of phytochemicals has been evaluated to discover a promising candidate for cancer therapy. For developing more effective cancer therapy, it is required to apprehend the molecular mechanism deployed by natural compounds. MicroRNAs (miRNAs) have been realized to play a pivotal role in regulating cellular signaling pathways, affecting the efficacy of therapeutic agents in cancer. This review presents a feature of phytochemicals with anti-cancer activity, focusing mainly on the relationship between phytochemicals and miRNAs, with insights into the role of miRNAs as the mediators and the regulators of anti-cancer effects of phytochemicals.
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http://dx.doi.org/10.3390/molecules25204701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587345PMC
October 2020

Extracellular Vesicles (EVs) and Pancreatic Cancer: From the Role of EVs to the Interference with EV-Mediated Reciprocal Communication.

Biomedicines 2020 Aug 3;8(8). Epub 2020 Aug 3.

Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea.

Pancreatic cancer is malignant and the seventh leading cause of cancer-related deaths worldwide. However, chemotherapy and radiotherapy are-at most-moderately effective, indicating the need for new and different kinds of therapies to manage this disease. It has been proposed that the biologic properties of pancreatic cancer cells are finely tuned by the dynamic microenvironment, which includes extracellular matrix, cancer-associated cells, and diverse immune cells. Accumulating evidence has demonstrated that extracellular vesicles (EVs) play an essential role in communication between heterogeneous subpopulations of cells by transmitting multiplex biomolecules. EV-mediated cell-cell communication ultimately contributes to several aspects of pancreatic cancer, such as growth, angiogenesis, metastasis and therapeutic resistance. In this review, we discuss the role of extracellular vesicles and their cargo molecules in pancreatic cancer. We also present the feasibility of the inhibition of extracellular biosynthesis and their itinerary (release and uptake) for a new attractive therapeutic strategy against pancreatic cancer.
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http://dx.doi.org/10.3390/biomedicines8080267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459718PMC
August 2020

Tat-indoleamine 2,3-dioxygenase 1 elicits neuroprotective effects on ischemic injury.

BMB Rep 2020 Nov;53(11):582-587

Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea.

It is well known that oxidative stress participates in neuronal cell death caused production of reactive oxygen species (ROS). The increased ROS is a major contributor to the development of ischemic injury. Indoleamine 2,3-dioxygenase 1 (IDO-1) is involved in the kynurenine pathway in tryptophan metabolism and plays a role as an anti-oxidant. However, whether IDO-1 would inhibit hippocampal cell death is poorly known. Therefore, we explored the effects of cell permeable Tat-IDO-1 protein against oxidative stress-induced HT-22 cells and in a cerebral ischemia/reperfusion injury model. Transduced Tat-IDO-1 reduced cell death, ROS production, and DNA fragmentation and inhibited mitogen-activated protein kinases (MAPKs) activation in H2O2 exposed HT-22 cells. In the cerebral ischemia/ reperfusion injury model, Tat-IDO-1 transduced into the brain and passing by means of the blood-brain barrier (BBB) significantly prevented hippocampal neuronal cell death. These results suggest that Tat-IDO-1 may present an alternative strategy to improve from the ischemic injury. [BMB Reports 2020; 53(11): 582-587].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704220PMC
November 2020

Phenotypic Heterogeneity and Plasticity of Cancer Cell Migration in a Pancreatic Tumor Three-Dimensional Culture Model.

Cancers (Basel) 2020 May 21;12(5). Epub 2020 May 21.

Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul 06591, Korea.

Invasive cancer cell migration is a key feature of metastatic human pancreatic ductal adenocarcinoma (PDAC), yet the underlying mechanisms remain poorly understood. Here, we investigated modes of cancer cell invasion using two pancreatic cancer cell lines with differential epithelial-mesenchymal status, PANC-1 and BxPC-3, under 3D culture conditions. Multicellular tumor spheroids (TSs) were grown in a collagen matrix co-cultured with pancreatic stellate cells (PSCs) using microchannel chips. PANC-1 cells showed individual migration from TSs via invadopodium formation. BxPC-3 cells showed plasticity between collective and individual migration in either mesenchymal mode, with filopodium-like protrusions, or blebby amoeboid mode. These two cell lines showed significantly different patterns of extracellular matrix (ECM) remodeling, with MMP-dependent degradation in a limited area of ECM around invadopodia for PANC-1 cells, or MMP-independent extensive deformation of ECM for BxPC-3 cells. Cancer cell migration out of the collagen channel significantly increased by PSCs and directional cancer cell migration was mediated by fibronectin deposited by PSCs. Our results highlight the phenotypic heterogeneity and plasticity of PDAC cell migration and ECM remodeling under 3D culture conditions. This 3D co-culture model of pancreatic cancer cells and PSCs offers a useful tool for studying cancer cell migration and ECM remodeling to identify and develop potential molecular targets and anti-cancer agents against human PDAC.
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http://dx.doi.org/10.3390/cancers12051305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281339PMC
May 2020

Tat-Biliverdin Reductase A Exerts a Protective Role in Oxidative Stress-Induced Hippocampal Neuronal Cell Damage by Regulating the Apoptosis and MAPK Signaling.

Int J Mol Sci 2020 Apr 11;21(8). Epub 2020 Apr 11.

Department of Biomedical Science and Research, Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252, Korea.

Reactive oxygen species (ROS) is major risk factor in neuronal diseases including ischemia. Although biliverdin reductase A (BLVRA) plays a pivotal role in cell survival via its antioxidant function, its role in hippocampal neuronal (HT-22) cells and animal ischemic injury is not clearly understood yet. In this study, the effects of transducible fusion protein Tat-BLVRA on HO-induced HT-22 cell death and in an animal ischemia model were investigated. Transduced Tat-BLVRA markedly inhibited cell death, DNA fragmentation, and generation of ROS. Transduced Tat-BLVRA inhibited the apoptosis and mitogen activated protein kinase (MAPK) signaling pathway and it passed through the blood-brain barrier (BBB) and significantly prevented hippocampal cell death in an ischemic model. These results suggest that Tat-BLVRA provides a possibility as a therapeutic molecule for ischemia.
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http://dx.doi.org/10.3390/ijms21082672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215548PMC
April 2020

Luteolin-regulated MicroRNA-301-3p Targets Caspase-8 and Modulates TRAIL Sensitivity in PANC-1 Cells.

Anticancer Res 2020 Feb;40(2):723-731

Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea

Background/aim: MicroRNAs (miRNAs) play regulatory roles in pancreatic ductal adenocarcinoma (PDAC). However, it is still required to identify the function of miRNA-301-3p in pancreatic cancer cells.

Materials And Methods: Effects of luteolin on cell growth, TRAIL cytotoxicity, and miR-301-3p levels were evaluated. The role of miRNA-301-3p in regulating cell proliferation, target gene expression, and TRAIL cytotoxicity were studied.

Results: The levels of miR-301-3p were down-regulated in PANC-1 cells exposed to luteolin, which inhibits the growth of PANC-1 cells and sensitizes cells to TRAIL. The knockdown of miR-301-3p attenuates cell proliferation and enhances TRAIL cytotoxicity. In addition, caspase-8 was directly targeted by miR-301-3p.

Conclusion: Our findings unveil a critical biological function of miR-301-3p in regulating cell proliferation and elevating an antiproliferative effect of TRAIL on cancer cells. Our observation of miR-301-3p/caspase-8 relationship can also serve to clarify the role of miR-301-3p in other cancer types and related diseases.
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http://dx.doi.org/10.21873/anticanres.14003DOI Listing
February 2020

MicroRNA-22 negatively regulates LPS-induced inflammatory responses by targeting HDAC6 in macrophages.

BMB Rep 2020 Apr;53(4):223-228

Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chuncheon 24252, Korea.

Dysregulation of histone deacetylase 6 (HDAC6) can lead to the pathologic states and result in the development of various diseases including cancers and inflammatory diseases. The objective of this study was to elucidate the regulatory role of microRNA-22 (miR-22) in HDAC6-mediated expression of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated macrophages. LPS stimulation induced HDAC6 expression, but suppressed miR-22 expression in macrophages, suggesting possible correlation between HDAC6 and miR-22. Luciferase reporter assays revealed that 3'UTR of HDAC6 was a bona fide target site of miR-22. Transfection of miR-22 mimic significantly inhibited LPS-induced HDAC6 expression, while miR-22 inhibitor further increased LPS-induced HDAC6 expression. LPS-induced activation of NF-κB and AP-1 was inhibited by miR-22 mimic, but further increased by miR-22 inhibitor. LPS-induced expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 was inhibited by miR-22 mimic, but further increased by miR-22 inhibitor. Taken together, these data provide evidence that miR-22 can downregulate LPS-induced expression of proinflammatory cytokines via suppression of NF-κB and AP-1 axis by targeting HDAC6 in macrophages. [BMB Reports 2020; 53(4): 223-228].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196186PMC
April 2020

FIH-1 engages novel binding partners to positively influence epithelial proliferation via p63.

FASEB J 2020 01 25;34(1):525-539. Epub 2019 Nov 25.

Department of Dermatology, Northwestern University, Chicago, IL, USA.

Whereas much is known about the genes regulated by ΔNp63α in keratinocytes, how ΔNp63α is regulated is less clear. During studies with the hydroxylase, factor inhibiting hypoxia-inducible factor 1 (FIH-1), we observed increases in epidermal ΔNp63α expression along with proliferative capacity in a conditional FIH-1 transgenic mouse. Conversely, loss of FIH-1 in vivo and in vitro attenuated ΔNp63α expression. To elucidate the FIH-1/p63 relationship, BioID proteomics assays identified FIH-1 binding partners that had the potential to regulate p63 expression. FIH-1 interacts with two previously unknown partners, Plectin1 and signal transducer and activator of transcription 1 (STAT1) leading to the regulation of ΔNp63α expression. Two known interactors of FIH-1, apoptosis-stimulating of P53 protein 2 (ASPP2) and histone deacetylase 1 (HDAC1), were also identified. Knockdown of ASPP2 upregulated ΔNp63α and reversed the decrease in ΔNp63α by FIH-1 depletion. Additionally, FIH-1 regulates growth arrest and DNA damage-45 alpha (GADD45α), a negative regulator of ΔNp63α by interacting with HDAC1. GADD45α knockdown rescued reduction in ΔNp63α by FIH-1 depletion. Collectively, our data reveal that FIH-1 positively regulates ΔNp63α in keratinocytes via variety of signaling partners: (a) Plectin1/STAT1, (b) ASPP2, and (c) HDAC1/GADD45α signaling pathways.
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http://dx.doi.org/10.1096/fj.201901512RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956705PMC
January 2020

MicroRNA-Based Combinatorial Cancer Therapy: Effects of MicroRNAs on the Efficacy of Anti-Cancer Therapies.

Cells 2019 12 20;9(1). Epub 2019 Dec 20.

Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea.

The susceptibility of cancer cells to different types of treatments can be restricted by intrinsic and acquired therapeutic resistance, leading to the failure of cancer regression and remission. To overcome this problem, a combination therapy has been proposed as a fundamental strategy to improve therapeutic responses; however, resistance is still unavoidable. MicroRNA (miRNAs) are associated with cancer therapeutic resistance. The modulation of dysregulated miRNA levels through miRNA-based therapy comprising a replacement or inhibition approach has been proposed to sensitize cancer cells to other anti-cancer therapies. The combination of miRNA-based therapy with other anti-cancer therapies (miRNA-based combinatorial cancer therapy) is attractive, due to the ability of miRNAs to target multiple genes associated with the signaling pathways controlling therapeutic resistance. In this article, we present an overview of recent findings on the role of therapeutic resistance-related miRNAs in different types of cancer. We review the feasibility of utilizing dysregulated miRNAs in cancer cells and extracellular vesicles as potential candidates for miRNA-based combinatorial cancer therapy. We also discuss innate properties of miRNAs that need to be considered for more effective combinatorial cancer therapy.
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http://dx.doi.org/10.3390/cells9010029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016872PMC
December 2019

An In Vitro Protocol for Evaluating MicroRNA Levels, Functions, and Associated Target Genes in Tumor Cells.

J Vis Exp 2019 05 21(147). Epub 2019 May 21.

Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University;

MicroRNAs (miRNAs) are small regulatory RNAs which are recognized to modulate numerous intracellular signaling pathways in several diseases including cancers. These small regulatory RNAs mainly interact with the 3' untranslated regions (3' UTR) of their target messenger RNAs (mRNAs) ultimately resulting in the inhibition of decoding processes of mRNAs and the augmentation of target mRNA degradations. Based on the expression levels and intracellular functions, miRNAs are able to serve as regulatory factors of oncogenic and tumor-suppressive mRNAs. Identification of bona fide target genes of a miRNA among hundreds or even thousands of computationally predicted targets is a crucial step to discern the roles and basic molecular mechanisms of a miRNA of interest. Various miRNA target prediction programs are available to search possible miRNA-mRNA interactions. However, the most challenging question is how to validate direct target genes of a miRNA of interest. This protocol describes a reproducible strategy of key methods on how to identify miRNA targets related to the function of a miRNA. This protocol presents a practical guide on step-by-step procedures to uncover miRNA levels, functions, and related target mRNAs using the probe-based real-time polymerase chain reaction (PCR), sulforhodamine B (SRB) assay following a miRNA mimic transfection, dose-response curve generation, and luciferase assay along with the cloning of 3' UTR of a gene, which is necessary for proper understanding of the roles of individual miRNAs.
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http://dx.doi.org/10.3791/59628DOI Listing
May 2019

Cellular context-dependent interaction between cancer and stellate cells in hetero-type multicellular spheroids of pancreatic tumor.

Biochem Biophys Res Commun 2019 07 24;515(1):183-189. Epub 2019 May 24.

Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea; Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Heterotypic cell-cell interaction between cancer cells and pancreatic stellate cells (PSCs) within tumor microenvironment is considered as a key mechanism for epithelial-mesenchymal transition (EMT) that triggers disease progression and chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Hence, PSCs should be incorporated into in vitro co-culture models to maximize clinical relevance of data obtained using these models. In this study, we developed hetero-type spheroids of pancreatic cancer cells (ductal carcinoma cells PANC-1 and primacy sarcomatoid adenocarcinoma 36473 cells) and PSCs. Effect of PSC co-culture on the formation and growth of multicellular spheroids was cell-line dependent in that growth stimulation effect appeared in PANC-1/PSC spheroids, but not in 36473/PSC spheroids. Spatial distribution of PSCs within spheroids was also cell-line dependent. It was either confined to the center region (PANC-1) or evenly distributed (36473). Changes in expression levels of E-cadherin and vimentin revealed EMT induction in PANC-1/PSC hetero-type spheroids, but not in 36473/PSC spheroids. Gemcitabine sensitivity was increased partially by PSC co-culture. However, PSCs showed relative resistance to gemcitabine compared to PANC-1 cells in PANC-1/PSC spheroids. Overall, our hetero-type spheroid model can be used to study cancer-stroma interaction and their mechanism and evaluate anticancer drug activity. We demonstrated that stromal effect by PSC co-culture might be cellular context dependent with regard to growth stimulation and EMT induction. Hence, anti-stromal therapy should take these differences into consideration.
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http://dx.doi.org/10.1016/j.bbrc.2019.05.101DOI Listing
July 2019

MicroRNA-107 Targets IKBKG and Sensitizes A549 Cells to Parthenolide.

Anticancer Res 2018 Nov;38(11):6309-6316

Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea

Background/aim: Patients with advanced non-small cell lung cancer (NSCLC) frequently face a dismal prognosis because of lack of curative therapies. We, therefore, conducted a preclinical investigation of the therapeutic efficacy of microRNA-107 (miR-107).

Materials And Methods: The effects of miR-107 on cell proliferation and target gene expression were studied. Combinatorial effects of miR-107 and parthenolide were evaluated.

Results: Cell proliferation was repressed in A549 NSCLC cells transfected with miR-107. Inhibitor of nuclear factor kappa B kinase subunit gamma was directly targeted by miR-107. Overexpression of miR-107 in A549 cells sensitized them to parthenolide along with a marked reduction of cyclin-dependent kinase 2.

Conclusion: Our findings unveil an important biological function of miR-107 in regulating lung cancer cell proliferation and elevating an antiproliferative effect of parthenolide on lung cancer cells, suggesting that miR-107 could be beneficial benefit treatment for advanced NSCLC.
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http://dx.doi.org/10.21873/anticanres.12987DOI Listing
November 2018

Combinatorial Antitumor Activity of Oxaliplatin with Epigenetic Modifying Agents, 5-Aza-CdR and FK228, in Human Gastric Cancer Cells.

Biomol Ther (Seoul) 2018 Nov;26(6):591-598

Department of Biomedicine & Health Science, Graduate School, The Catholic University of Korea, Seoul 06591, Republic of Korea.

Epigenetic silencing is considered to be a major mechanism for loss of activity in tumor suppressors. Reversal of epigenetic silencing by using inhibitors of DNA methyltransferase (DNMT) or histone deacetylases (HDACs) such as 5-Aza-CdR and FK228 has shown to enhance cytotoxic activities of several anticancer agents. This study aims to assess the combinatorial effects of gene-silencing reversal agents (5-Aza-CdR and FK228) and oxaliplatin in gastric cancer cells, i.e., Epstein-Barr virus (EBV)-negative SNU-638 and EBV-positive SNU-719 cells. The doublet combinatorial treatment of 5-Aza-CdR and FK228 exhibited synergistic effects in both cell lines, and this was further corroborated by Zta expression induction in SNU-719 cells. Three drug combinations as 5-Aza-CdR/FK228 followed by oxaliplatin, however, resulted in antagonistic effects in both cell lines. Simultaneous treatment with FK228 and oxaliplatin induced synergistic and additive effects in SNU-638 and SNU-719 cells, respectively. Three drug combinations as 5-Aza-CdR prior to FK228/oxaliplatin, however, again resulted in antagonistic effects in both cell lines. This work demonstrated that efficacy of doublet synergistic combination using DNMT or HDACs inhibitors can be compromised by adding the third drug in pre- or post-treatment approach in gastric cancer cells. This implies that the development of clinical trial protocols for triplet combinations using gene-silencing reversal agents should be carefully evaluated in light of their potential antagonistic effects.
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http://dx.doi.org/10.4062/biomolther.2018.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254647PMC
November 2018

Effect of sodium stearoyl-2-lactylate supplementation on lactation performance, blood-biochemical profile, and economic efficacy of mid-lactation Holstein cows.

Asian-Australas J Anim Sci 2018 Sep 26;31(9):1458-1463. Epub 2018 Jul 26.

Division of Applied Life Science (BK21 Plus), Gyeongsang National University, IALS, Jinju 52825, Korea.

Objective: This study was done to evaluate the effect of sodium stearoyl-2-lactylate (SSL) supplementation in a total mixed ration (TMR) on the lactation performance, blood parameters, and economic efficacy of mid-lactation Holstein cows.

Methods: Twenty-four cows (body weight 647±11.7 kg) were randomly divided into 4 treatment groups, with six cows per group. The dietary treatments were as follows: basal diet (CON); CON+17.5 g of top dressed SSL (treatment [TRT] 0.05); CON+35 g of SSL (TRT 0.1); and CON+70 g of SSL (TRT 0.2) per 35 kg TMR.

Results: The highest level of SSL supplementation (TRT 0.2) significantly improved milk yield during the second period compared to the TRT 0.05 group (5 to 8 wks; 33.28 vs 31.09 kg/d), during the third period compared to both the CON and TRT 0.05 groups (p<0.05) (9 to 13 wks; 32.59 vs 30.64 and 30.01 kg/d) and during the overall experimental period compared to both the CON and TRT 0.05 groups (p<0.05) (1 to 13 wks; 33.43 vs 32.06 and 31.40 kg/d), respectively. No negative effects on hematological or biochemical parameters were observed due to SSL supplementation. Considering both the milk fat and protein content, the total milk price was set at 1,073.60 (TRT 0.05), 1,085.60 (TRT 0.1), 1,086.10 (TRT 0.2), and 1,064.20 (CON) won/L, with consequent total milk profits of -1.7%, 5.4%, and 3.5% for the TRT 0.05, TRT 0.1, and TRT 0.2 diet, respectively, compared to those in the CON diet.

Conclusion: The milk sales revenue related to SSL supplementation of the TRT 0.1 diet was increased by up to 5.4% compared to the milk sales revenue of the CON diet. Therefore, 0.1% SSL supplementation might be effective and profitable during the mid-lactation period of cows, without producing adverse effects.
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http://dx.doi.org/10.5713/ajas.18.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127564PMC
September 2018

Three Dimensional Mixed-Cell Spheroids Mimic Stroma-Mediated Chemoresistance and Invasive Migration in hepatocellular carcinoma.

Neoplasia 2018 08 4;20(8):800-812. Epub 2018 Jul 4.

Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Interactions between cancer cells and cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) play an important role in promoting the profibrotic microenvironment and epithelial-mesenchymal transition (EMT), resulting in tumor progression and drug resistance in hepatocellular carcinoma (HCC). In the present study, we developed a mixed-cell spheroid model using Huh-7 HCC cells and LX-2 stellate cells to simulate the in vivo tumor environment with respect to tumor-CAF interactions. Spheroids were cultured from cancer cells alone (monospheroids) or as a mixture (mixed-cell spheroids) in ultra-low-attachment plates. Compact, well-mixed, and stroma-rich mixed-cell spheroids were successfully established with heterotypic cell-cell contacts shown by the presence of gap junctions and desmosomes. Mixed-cell spheroids showed enhanced expression of collagen type-I (Col-I) and pro-fibrotic factors such as, transforming growth factor beta1 (TGF-β1), and connective tissue growth factor (CTGF) compared to the levels expressed in mono-spheroids. The EMT phenotype was evident in mixed-cell spheroids as shown by the altered expression of E-cadherin and vimentin. Differential drug sensitivity was observed in mixed-cell spheroids, and only sorafenib and oxaliplatin showed dose-dependent antiproliferative effects. Simultaneous treatment with TGF-β inhibitors further improved sorafenib efficacy in the mixed-cell spheroids, indicating the involvement of TGF-β in the mechanism of sorafenib resistance. In 3D matrix invasion assay, mixed-cell spheroids exhibited fibroblast-led collective cell movement. Overall, our results provide evidence that mixed-cell spheroids formed with Huh-7 and LX-2 cells well represent HCC tumors and their TME in vivo and hence are useful in studying tumor-stroma interactions as mechanisms associated with drug resistance and increased cell motility.
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http://dx.doi.org/10.1016/j.neo.2018.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034588PMC
August 2018

MicroRNAs Targeting Caspase-3 and -7 in PANC-1 Cells.

Int J Mol Sci 2018 Apr 16;19(4). Epub 2018 Apr 16.

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.

MicroRNAs (miRNAs), a critical part of the RNA silencing machinery, are known to play important regulatory roles in cancer. However, the consequence of miRNA deregulation in cancer is unknown for many miRNAs. Here, we define that miRNAs, miR-17-5p, miR-132-3p/-212-3p, and miR-337-3p are significantly up-regulated in the pancreatic ductal adenocarcinomas (PDAC) compared to the normal and benign tissues. Furthermore, by using PANC-1 cells, we demonstrate that overexpressed miR-337-3p and miR-17-5p/miR-132-3p/-212-3p can regulate executioner caspases-3 and -7, respectively. In addition, over-expression of miRNAs, especially miR-337-3p, attenuates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity in PANC-1 cells. Our findings unveil an important biological function for miRNAs up-regulated in PDAC in coordinately regulating caspases, potentially contributing to the malignant progression of PDAC.
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http://dx.doi.org/10.3390/ijms19041206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979519PMC
April 2018

In vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid.

J Biochem Mol Toxicol 2018 Jan 27;32(1). Epub 2017 Oct 27.

Department of Food Science and Biotechnology, Gwangju University, Gwangju 503-703, Republic of Korea.

We discovered recently in vitro and in vivo antithrombotic and cytotoxicity effects of ferulic acid. The cytotoxicity assays showed that ferulic acid (∼300 μg/mL) did not cause any significant toxicity on three cell lines, platelets, leukocytes, and erythrocytes. In vitro assays showed inhibitory effects of ferulic acid on thrombin (THR)- or collagen/epinephrine-stimulated platelet activation by inhibiting platelet aggregation, and decreasing clot retraction activity. The in vitro effect of ferulic acid on THR-stimulated platelet activation was proved by the decrease in the secretion of serotonin from the platelets. The anticoagulant effects of ferulic acid were confirmed by the prolongation of the intrinsic or/and extrinsic pathways and the delay of recalcification time in plasma coagulation. Ferulic acid had antithrombotic effect in acute thromboembolism model in vivo, and decreased the expression of α β /FIB and phosphorylation of AKT in THR-stimulated platelet activation in vivo, and their antithrombotic efficacies hold promise for therapeutic targeting in our ongoing studies.
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http://dx.doi.org/10.1002/jbt.22004DOI Listing
January 2018

Crosstalk between Signaling Pathways in Pemphigus: A Role for Endoplasmic Reticulum Stress in p38 Mitogen-Activated Protein Kinase Activation?

Front Immunol 2017 5;8:1022. Epub 2017 Sep 5.

Department of Genetics, Federal University of Paraná, Curitiba, Brazil.

Pemphigus consists of a group of chronic blistering skin diseases mediated by autoantibodies (autoAbs). The dogma that pemphigus is caused by keratinocyte dissociation (acantholysis) as a distinctive and direct consequence of the presence of autoAb targeting two main proteins of the desmosome-desmoglein (DSG) 1 and/or DSG3-has been put to the test. Several outside-in signaling events elicited by pemphigus autoAb in keratinocytes have been described, among which stands out p38 mitogen-activated protein kinase (p38 MAPK) engagement and its apoptotic effect on keratinocytes. The role of apoptosis in the disease is, however, debatable, to an extent that it may not be a determinant event for the occurrence of acantholysis. Also, it has been verified that compromised DSG trans-interaction does not lead to keratinocyte dissociation when p38 MAPK is inhibited. These examples of conflicting results have been followed by recent work revealing an important role for endoplasmic reticulum (ER) stress in pemphigus' pathogenesis. ER stress is known to activate the p38 MAPK pathway, and . However, this relationship has not yet been studied in the context of activated signaling pathways in pemphigus. Therefore, by reviewing and hypothetically connecting the role(s) of ER stress and p38 MAPK pathway in pemphigus, we highlight the importance of elucidating the crosstalk between all activated signaling pathways, which may in turn contribute for a better understanding of the role of apoptosis in the disease and a better management of this life-threatening condition.
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http://dx.doi.org/10.3389/fimmu.2017.01022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591886PMC
September 2017

Eyeing autophagy and macropinocytosis in the corneal/limbal epithelia.

Autophagy 2017 May 15;13(5):975-977. Epub 2017 Feb 15.

a Department of Dermatology, Feinberg School of Medicine , Northwestern University , Chicago , IL , USA.

Macroautophagy/autophagy is vital for cellular homeostasis and helps cells respond to various stress situations. Macropinocytosis enables cells to nonselectively engulf and take up large volumes of fluid and is known to supply amino acids to cells. The stem cell-enriched limbal epithelium has the machinery necessary to carry out both autophagy and macropinocytosis; however, both processes are relatively understudied in this tissue. We have demonstrated that these processes are linked via MIR103-MIR107, a microRNA family that is limbal epithelial-preferred. Loss of MIR103-MIR107 causes the accumulation of large vacuoles that originate, in part, from a dysregulation in macropinocytosis via activation of SRC-RAS signaling. We found that these vacuoles were autophagic in nature and retained in cells due to inappropriate regulation of end-stage autophagy. Specifically, MIR103-MIR107 regulates diacylglycerol-PRKC/protein kinase C and CDK5 (cyclin dependent kinase 5) signaling, which enables DNM1 (dynamin 1) to function in vacuole clearance.
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http://dx.doi.org/10.1080/15548627.2017.1287658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446053PMC
May 2017

Autophagy and Macropinocytosis: Keeping an Eye on the Corneal/Limbal Epithelia.

Invest Ophthalmol Vis Sci 2017 01;58(1):416-423

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.

Autophagy and macropinocytosis are processes that are vital for cellular homeostasis, and help cells respond to stress and take up large amounts of material, respectively. The limbal and corneal epithelia have the machinery necessary to carry out both processes; however, autophagy and macropinocytosis are relatively understudied in these two epithelia. In this Perspectives, we describe the basic principles behind macropinocytosis and autophagy, discuss how these two processes are regulated in the limbal and corneal epithelia, consider how these two processes impact on the physiology of limbal and corneal epithelia, and elaborate on areas of future research in autophagy and macropinocytosis as related to the limbal/corneal epithelia.
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http://dx.doi.org/10.1167/iovs.16-21111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270618PMC
January 2017

MicroRNAs-103/107 coordinately regulate macropinocytosis and autophagy.

J Cell Biol 2016 Dec 21;215(5):667-685. Epub 2016 Nov 21.

Department of Dermatology, Northwestern University, Chicago, IL 60611

Macropinocytosis, by which cells ingest large amounts of fluid, and autophagy, the lysosome-based catabolic process, involve vesicular biogenesis (early stage) and turnover (end stage). Much is known about early-stage events; however, our understanding of how the end stages of these processes are governed is incomplete. Here we demonstrate that the microRNA-103/107(miR-103/107) family, which is preferentially expressed in the stem cell-enriched limbal epithelium, coordinately regulates aspects of both these activities. Loss of miR-103/107 causes dysregulation of macropinocytosis with the formation of large vacuoles, primarily through up-regulation of Src, Ras, and Ankfy1. Vacuole accumulation is not a malfunction of early-stage autophagy; rather, miR-103/107 ensure proper end-stage autophagy by regulating diacylglycerol/protein kinase C and cyclin-dependent kinase 5 signaling, which enables dynamin to function in vacuole clearance. Our findings unveil a key biological function for miR-103/107 in coordinately suppressing macropinocytosis and preserving end-stage autophagy, thereby contributing to maintenance of a stem cell-enriched epithelium.
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http://dx.doi.org/10.1083/jcb.201604032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5146999PMC
December 2016

miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways.

FASEB J 2017 01 7;31(1):256-265. Epub 2016 Oct 7.

Department of Dermatology Northwestern University, Chicago, Illinois, USA;

Corneal avascularity is critical for achieving transparency necessary for proper transmission of light to the lens and visual acuity. Although much is known about angiogenesis and angiostasis, the precise regulation of these processes in the cornea is unclear. MicroRNA (miR)-184, the most abundant corneal epithelial miRNA, has been suggested to function in corneal angiostasis by altering VEGF signaling; however, the mechanism(s) underlying this regulation have not been addressed. Using a combination of in vitro and in vivo assays to evaluate angiogenesis, we demonstrated that human limbal epithelial keratinocytes (HLEKs) engineered to overexpress miR-184 secreted lower amounts of angiogenic mitogens. Human dermal microvascular cells exposed to conditioned medium from miR-184-overexpressing HLEKs were less proliferative and failed to seal linear scratch wounds. The in vivo Matrigel plug assay showed that conditioned medium from miR-184-expressing HLEKs elicited a lesser degree of neovascularization compared with controls. We found that miR-184 directly targets and represses the proangiogenic factors, friend of Gata 2 (FOG2), platelet-derived growth factor (PDGF)-β, and phosphatidic acid phosphatase 2b (PPAP2B). FOG2 regulates VEGF expression, whereas PDGF-β and PPAP2B regulate Akt activity. By attenuating both VEGF and Akt signaling, miR-184 acts as a broad-spectrum negative regulator of corneal angiogenesis.-Park, J. K., Peng, H., Yang, W., Katsnelson, J., Volpert, O., Lavker, R. M. miR-184 exhibits angiostatic properties via regulation of Akt and VEGF signaling pathways.
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http://dx.doi.org/10.1096/fj.201600746RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161520PMC
January 2017

Anti-invasion and anti-migration effects of miR-199a-3p in hepatocellular carcinoma are due in part to targeting CD151.

Int J Oncol 2016 Nov 2;49(5):2037-2045. Epub 2016 Sep 2.

College of Pharmacy, Ohio State University, Columbus, OH, USA.

Several studies have reported reduced miR-199a-3p expression in hepatocellular carcinoma (HCC). In an effort to discover important target genes for miR-199a-3p that may be related to HCC development or progression, we identified the tetraspanin, transmembrane glycoprotein CD151. Luciferase reporter assays and western blotting identified CD151 as a bona fide miR-199a-3p target gene. While CD151 protein was increased in the mesenchymal but not the epithelial HCC cell lines, CD151 knockdown with siRNA did not reduce HCC cell proliferation in either group of cells. miR-199a-3p reduced in vitro invasion and migration of CD151-positive HCC cells. Examination of the mRNA and protein expression in pairs of primary HCC tumors and adjacent benign tissues showed that not only was CD151 mRNA and protein increased in the tumors but also that an inverse correlation exists between the miR-199a-3p and CD151 RNA expression. We report that CD151 is a target of miR-199a-3p and that increased CD151 protein resulting from reduced miR-199a-3p could contribute to the development of metastatic HCC.
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http://dx.doi.org/10.3892/ijo.2016.3677DOI Listing
November 2016

A 3'UTR polymorphism marks differential KLRG1 mRNA levels through disruption of a miR-584-5p binding site and associates with pemphigus foliaceus susceptibility.

Biochim Biophys Acta 2016 10 14;1859(10):1306-13. Epub 2016 Jul 14.

Department of Genetics, Federal University of Paraná, Curitiba, PR 81531-980, Brazil. Electronic address:

Genetic variations mapping to 3' untranslated regions (3'UTRs) may overlap with microRNA (miRNA) binding sites, therefore potentially interfering with translation inhibition or messenger RNA (mRNA) degradation. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) located within the 3'UTRs of six candidate genes and predicted to interfere with miRNA ligation could account for disease-relevant differential mRNA levels. Focusing on pemphigus foliaceus (PF) - an autoimmune blistering skin condition with unique endemic patterns - we investigated whether nine 3'UTR SNPs from the CD1D, CTLA4, KLRD1, KLRG1, NKG7, and TNFSF13B genes differentially expressed in PF were disease-associated. The heterozygous genotype of the KLRG1 rs1805672 polymorphism was associated with increased predisposition to PF (A/G vs. A/A: P=0.038; OR=1.60), and a trend for augmented susceptibility was observed for carriers of the G allele (P=0.094; OR=1.44). In silico analyses suggested that rs1805672 G allele could disrupt binding of miR-584-5p, and indicated rs1805672 as an expression Quantitative Trait Locus (eQTL), with an effect on KLRG1 gene expression. Dual-luciferase assay showed that miR-584-5p mediated approximately 50% downregulation of the reporter gene's activity through the 3'UTR of KLRG1 harboring rs1805672 A allele (vs. miRNA-negative condition, P=0.006). This silencing relationship was lost after site-directed mutation to G allele (vs. miRNA-negative condition, P=0.391; vs. rs1805672 A allele, P=0.005). Collectively, these results suggest that a disease-associated SNP located within the 3'UTR of KLRG1 directly interferes with miR-584-5p binding, allowing for KLRG1 mRNA differential accumulation, which in turn may contribute to pathogenesis of autoimmune diseases, such as pemphigus.
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http://dx.doi.org/10.1016/j.bbagrm.2016.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997811PMC
October 2016

MicroRNAs Enhance Keratinocyte Proliferative Capacity in a Stem Cell-Enriched Epithelium.

PLoS One 2015 6;10(8):e0134853. Epub 2015 Aug 6.

Department of Dermatology, Northwestern University, Chicago, Illinois, United States of America.

MicroRNAs are critical regulators of stem cell behavior. The miR-103/107 family is preferentially expressed in the stem cell-enriched corneal limbal epithelium and plays an important role in coordinating several intrinsic characteristics of limbal epithelial stem cells. To elucidate further the mechanisms by which miRs-103/107 function in regulating limbal epithelial stem cells, we investigate the global effects of miRs-103/107 on gene expression in an unbiased manner. Using antagomirs-103/107, we knocked down endogenous miRs-103/107 in keratinocytes and conducted an mRNA profiling study. We show that miRs-103/107 target mitogen-activated protein kinase kinase kinase 7 (MAP3K7) and thereby negatively regulate the p38/AP-1 pathway, which directs epithelial cells towards a differentiated state. Pharmacological inhibition of p38 increases holoclone colony formation, a measure of proliferative capacity. This suggests that the negative regulation of p38 by miRs-103/107 contributes to enhanced proliferative capacity, which is a hallmark of stem cells. Since miRs-103/107 also promote increased holoclone colony formation by regulating JNK activation through non-canonical Wnt signaling, we believe that this microRNA family preserves "stemness" by mediating the crosstalk between the Wnt/JNK and MAP3K7/p38/AP-1 pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134853PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527697PMC
May 2016