Publications by authors named "Ki Taek Nam"

97 Publications

Olig2 regulates p53-mediated apoptosis, migration and invasion of melanoma cells.

Sci Rep 2021 Apr 8;11(1):7778. Epub 2021 Apr 8.

Department of Genetic Engineering and Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University, Yongin, 17104, Republic of Korea.

Melanoma is a disease with a high recurrence rate and poor prognosis; therefore, the need for targeted therapeutics is steadily increasing. Oligodendrocyte transcription factor2 (Olig2) is a basic helix-loop-helix transcription factor that is expressed in the central nervous system during embryonic development. Olig2 is overexpressed in various malignant cell lines such as lung carcinoma, glioma and melanoma. Olig2 is known as a key transcription factor that promotes tumor growth in malignant glioma. However, the role of Olig2 in melanoma is not well characterized. We analyzed the role of Olig2 in apoptosis, migration, and invasion of melanoma cells. We confirmed that Olig2 was overexpressed in melanoma cells and tissues. Reduction of Olig2 increased apoptosis in melanoma cells by increasing p53 level and caspase-3/-7 enzyme activity. In addition, downregulation of Olig2 suppressed migration and invasion of melanoma cells by inhibiting EMT. Reduction of Olig2 inhibited expression of MMP-1 and the enzyme activity of MMP-2/-9 induced by TGF-β. Moreover, Olig2 was involved in the downstream stages of MEK/ERK and PI3K/AKT, which are major signaling pathways in metastatic progression of melanoma. In conclusion, this study demonstrated the crucial roles of Olig2 in apoptosis, migration, and invasion of melanoma and may help to further our understanding of the relationship between Olig2 and melanoma progression.
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http://dx.doi.org/10.1038/s41598-021-87438-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032681PMC
April 2021

Skin irritation and inhalation toxicity of biocides evaluated with reconstructed human epidermis and airway models.

Food Chem Toxicol 2021 Apr 15;150:112064. Epub 2021 Feb 15.

College of Pharmacy, Ewha Womans University, Seoul, 03760, Republic of Korea. Electronic address:

Biocides are widely used in household products. Humans are exposed to biocides through dermal, inhalational, and oral routes. However, information on the dermal and inhalational toxicity of biocides is limited. We evaluated the effects of biocides on the skin and airways using the reconstructed human epidermis model KeraSkin™ and the airway model SoluAirway™. We determined the irritancy of 11 commonly used biocides (1,2-benzisothiazol-3(2H)-one [BIT], 2-phenoxyethanol [PE], zinc pyrithione, 2-bromo-2-nitropropane-1,3-diol, 3-iodoprop-2-ynyl N-butylcarbamate [IPBC], 2-octyl-1,2-thiazol-3-one, 2,2-dibromo-2-cyanoacetamide, 4-chloro-3-methylphenol [CC], 2-phenylphenol, deltamethrin, and 4,5-dichloro-2-octyl-1,2-thiazol-3-one) in the KeraSkin™ and SoluAirway™ by viability and histological examinations. BIT and CC were found to cause skin irritation at the approved concentrations or at the concentration close to approved limit while the others were non-irritants within the approved concentration. These results were confirmed via histology, wherein skin irritants induced erosion, vacuolation, and necrosis of the tissue. In the SoluAirway™, most of the biocides decreased cell viability even within the approved limits, except for PE, IPBC, and deltamethrin, suggesting that the airway may be more vulnerable to biocides than the skin. Taken together, our result indicates that some biocides can induce toxicity in skin and airway. Further studies on the dermal and inhalational toxicity of biocides are warranted.
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http://dx.doi.org/10.1016/j.fct.2021.112064DOI Listing
April 2021

Local Toxicity of Biocides after Direct and Aerosol Exposure on the Human Skin Epidermis and Airway Tissue Models.

Toxics 2021 Feb 3;9(2). Epub 2021 Feb 3.

College of Pharmacy, Ewha Womans University, Seoul 03760, Korea.

Biocides are commonly used as spray- or trigger-type formulations, thus dermal and respiratory exposure to biocide aerosol is unavoidable. However, little is known about the impact of aerosolization on the local toxicity of biocides on the skin or the airway. We compared the local toxicity of biocides after direct or aerosol exposure on reconstructed human skin epidermis and upper airway models. Three biocides, 1,2-benzisothiazol-3(2H)-one (BIT), 2-phenoxyethanol (PE), and 2-phenylphenol (OPP), most widely used in the market were selected. When the biocide was treated in aerosols, toxicity to the skin epidermis and upper airway tissue became significantly attenuated compared with the direct application as determined by the higher tissue viabilities. This was further confirmed in histological examination, wherein the tissue damages were less pronounced. LC-MS/MS and GC/MS analysis revealed that concentrations of biocides decreased during aerosolization. Importantly, the toxicity of biocides treated in 3 μm (median mass aerodynamic diameter (MMAD)) aerosols was stronger than that of 5 μm aerosol, suggesting that the aerosol particle size may affect biocide toxicity. Collectively, we demonstrated that aerosolization could affect the local toxicity of biocides on the skin epidermis and the upper airway.
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http://dx.doi.org/10.3390/toxics9020029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913294PMC
February 2021

Ex Vivo Live Full-Thickness Porcine Skin Model as a Versatile In Vitro Testing Method for Skin Barrier Research.

Int J Mol Sci 2021 Jan 11;22(2). Epub 2021 Jan 11.

College of Pharmacy, Ewha Womans University, Seodaemungu, Seoul 03760, Korea.

Since the European Union (EU) announced their animal testing ban in 2013, all animal experiments related to cosmetics have been prohibited, creating a demand for alternatives to animal experiments for skin studies. Here, we investigated whether an ex vivo live porcine skin model can be employed to study the safety and skin barrier-improving effects of hydroxyacids widely used in cosmetics for keratolytic peels. Glycolic acid (1-10%), salicylic acid (0.2-2%), and lactobionic acid (1.2-12%) were used as representative substances for α-hydroxyacid (AHA), β-hydroxyacid (BHA), and polyhydroxyacid (PHA), respectively. When hydroxyacids were applied at high concentrations on the porcine skin every other day for 6 days, tissue viability was reduced to 50-80%, suggesting that the toxicity of cosmetic ingredients can be evaluated with this model. Based on tissue viability, the treatment scheme was changed to a single exposure for 20 min. The protective effects of a single exposure of hydroxyacids on skin barrier function were evaluated by examining rhodamine permeability and epidermal structural components of barrier function using immunohistochemistry (IHC) and immunofluorescence (IF) staining. Lactobionic acid (PHAs) improved skin barrier function most compared to other AHAs and BHAs. Most importantly, trans-epidermal water loss (TEWL), an important functional marker of skin barrier function, could be measured with this model, which confirmed the significant skin barrier-protective effects of PHAs. Collectively, we demonstrated that the ex vivo live full-thickness porcine skin model can be an excellent alternative to animal experiments for skin studies on the safety and efficacy of cosmetic ingredients.
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http://dx.doi.org/10.3390/ijms22020657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827261PMC
January 2021

Evaluation of skin phototoxicity of transdermally administered pharmaceuticals in Sprague-Dawley rats.

Lab Anim Res 2020 Nov 19;36(1):42. Epub 2020 Nov 19.

Toxicological Evaluation and Research Department, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, 28159, Republic of Korea.

Some drugs cause phototoxicity in humans when exposed to light, thus there is a need for an in vivo phototoxicity test to evaluate them. However, an in vivo phototoxicity test method to evaluate this has not been established. This study aimed to establish an in vivo phototoxicity test method for transdermally administered drugs. For this, we evaluated the phototoxicity using Sprague-Dawley (SD) rats for transdermal administered drugs and we studied the appropriate UVA dose using 8-methoxypsalen, which is a well-known phototoxic drug. We found that a UVA dose of 15 J/cm was dose and time dependent response compared to other UVA doses. We performed the Minimum Erythema Dose (MED) test because UVB can cause skin irritation by itself and selected 0.01 J/cm as an appropriate dose of UVB. Using the selected UVA and UVB doses, we performed a phototoxicity study of 6 pharmaceutical drugs, which included phototoxic and non-phototoxic drugs. As a result of the phototoxicity test, 100% accuracy was obtained when compared with previous studies. In addition, we performed histopathology to confirm the new findings. We found that histopathology can be used as an additional indicator of phototoxicity test for transdermally administered drugs.
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http://dx.doi.org/10.1186/s42826-020-00074-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678087PMC
November 2020

Depletion of Adipocyte Leads to Lipodystrophy and Metabolic Dysregulation.

Diabetes 2021 01 12;70(1):182-195. Epub 2020 Oct 12.

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

/ is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.
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http://dx.doi.org/10.2337/db19-1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881852PMC
January 2021

Elevated GCN5 expression confers tamoxifen resistance by upregulating AIB1 expression in ER-positive breast cancer.

Cancer Lett 2020 12 25;495:145-155. Epub 2020 Sep 25.

Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, 03722, South Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, South Korea. Electronic address:

Approximately 70% of breast cancers are estrogen receptor (ER)-positive and treated with endocrine therapy. A commonly used treatment agent, tamoxifen, shows high efficacy for improving prognosis. However, approximately one-third of patients treated with tamoxifen develop resistance to this drug. Here, we investigated the function of general control non-derepressible 5 (GCN5) and its downstream effectors in tamoxifen-resistant (TamR) breast cancer. TamR-MCF7 breast cancer cells maintained high GCN5 levels due to its attenuated proteasomal degradation. GCN5 overexpression upregulated amplified in breast cancer 1 (AIB1) expression, resulting in decreased p53 stability and tamoxifen resistance. Conversely, the sensitivity of GCN5-AIB1-overexpressing MCF7 cells to tamoxifen was restored by forced p53 expression. An in vivo study demonstrated a positive correlation between GCN5 and AIB1 and their contribution to tamoxifen resistance. We concluded that GCN5 promotes AIB1 expression and tamoxifen resistance in breast cancer by reducing p53 levels, suggesting the utility of GCN5 and its downstream effectors as therapeutic targets to either prevent or overcome tamoxifen resistance in breast cancer.
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http://dx.doi.org/10.1016/j.canlet.2020.09.017DOI Listing
December 2020

Orally Administered 6:2 Chlorinated Polyfluorinated Ether Sulfonate (F-53B) Causes Thyroid Dysfunction in Rats.

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

Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Osong, Chungcheongbuk-do 28159, Korea.

The compound 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), a replacement for perfluorooctanesulfonate (PFOS) in the electroplating industry, has been widely detected in numerous environmental matrices, human sera, and organisms. Due to regulations that limit PFOS use, F-53B use is expected to increase. Therefore, in this study, we performed a subchronic oral toxicity study of F-53B in Sprague Dawley (SD) rats. F-53B was administered orally once daily to male and female rats for 28 days at doses of 5, 20, and 100 mg/kg/day. There were no toxicologically significant changes in F-53B-treated rats, except in the thyroid gland. However, F-53B slightly reduced the serum concentrations of thyroid hormones, including triiodothyronine and thyroxine, compared with their concentrations in the vehicle group. F-53B also induced follicular hyperplasia and was associated with increased thyroid hormone biosynthesis-associated protein expression. These results demonstrate that F-53B is a strong regulator of thyroid hormones in SD rats as it disrupts thyroid function. Thus, caution should be exercised in the industrial application of F-53B as an alternative for PFOS.
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http://dx.doi.org/10.3390/toxics8030054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560397PMC
August 2020

Employment of cytology for in vitro skin irritation test using a reconstructed human epidermis model, Keraskin™.

Toxicol In Vitro 2020 Dec 8;69:104962. Epub 2020 Aug 8.

College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address:

Skin irritation tests using reconstructed human epidermis (RhE) employ viability as an endpoint, but color interference or borderline results are often problematic. We examined whether the cytology of cells from treated RhE could determine skin irritancy. Six chemicals (three irritants; DnP, 1-B, PH, three non-irritants; DP, APA, HS) were evaluated in a RhE, Keraskin™. DP, HS, and PH were clearly classified with viability, but DnP, 1-B, and APA were often falsely determined, due to borderline values falling near the cutoff, 50%. In histology, the tissues treated with DnP, 1-B, and PH showed erosion of the stratum corneum, vacuolization, and necrosis in the basal layer. DP- and HS-treated tissues showed relatively normal morphology but APA induced necrosis similar to irritants. Cytology revealed that DnP, 1-B or PH depleted cells and induced irregular and abnormal cell shapes. In contrast, relatively regular and normal shapes and clear distinction between the nucleus and cytoplasm was observed for DP, APA and HS. To further confirm it, additional 10 substances, including false positives from OECD TG 439, were tested. Overall (16 substances in total), cytology: total area predicted the skin irritancy of test chemicals with the highest accuracy (87.5%) followed by cytology: cell count (81.3%), histology (75%) and viability (68.8%), confirming the utility of cytology as an alternative endpoint in the skin irritation test using RhE.
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http://dx.doi.org/10.1016/j.tiv.2020.104962DOI Listing
December 2020

Differential manifestation of ocular phenotypes in TALEN-mediated p19 knockout FVB/N and C57BL/6J mouse lines.

Genes Genomics 2020 09 25;42(9):1023-1033. Epub 2020 Jul 25.

Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.

Background: p19, primarily known as a tumor suppressor, has also been reported to play an essential role in normal development of mouse eyes. Consistently, lack of p19 has been associated with ocular defects, but the mixed background of the knockout (KO) mouse strain used raised a concern on the accuracy of the phenotypes observed in association with the targeted gene due to genetic heterogeneity.

Object: We carried out a study to investigate into the effect of genetic background on the manifestation of p19 KO associated phenotypes.

Methods: We characterized the phenotypes of novel p19 KO mouse lines generated in FVB/N and C57BL/6J using a transcription activator-like effector nuclease (TALEN) system in comparison to the reported phenotypes of three other p19-deficient mouse lines generated using homologous recombination.

Results: Ninety-five percent of FVB/N-p19 KO mice showed ocular opacity from week 4 after birth which worsened rapidly until week 6, while such abnormality was absent in C57BL/6J-p19 KO mice up to the age of 26 weeks. Histopathological analysis revealed retrolental masses and dysplasia in the retinal layer in FVB/N-p19 KO mice from week 4. Besides these, both strains developed normally from birth to week 26 without increased tumorigenesis except for a subcutaneous tumor found in a C57BL/6J-p19 KO mouse.

Conclusion: Our findings demonstrated surprisingly variable manifestation of p19-linked phenotypes between FVB/N and C57BL/6J mice, and furthermore between our mouse lines and the established lines, indicating a critical impact of genetic background on functional study of genes using gene targeting strategies in mice.
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http://dx.doi.org/10.1007/s13258-020-00959-zDOI Listing
September 2020

The position of the target site for engineered nucleases improves the aberrant mRNA clearance in in vivo genome editing.

Sci Rep 2020 03 6;10(1):4173. Epub 2020 Mar 6.

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.

Engineered nucleases are widely used for creating frameshift or nonsense mutations in the target genes to eliminate gene functions. The resulting mRNAs carrying premature termination codons can be eliminated by nonsense-mediated mRNA decay. However, it is unclear how effective this process would be in vivo. Here, we found that the nonsense-mediated decay was unable to remove the mutant mRNAs in twelve out of sixteen homozygous mutant mice with frameshift mutations generated using engineered nucleases, which is far beyond what we expected. The frameshift mutant proteins translated by a single nucleotide deletion within the coding region were also detected in the p53 mutant mice. Furthermore, we showed that targeting the exons present downstream of the exons with a start codon or distant from ATG is relatively effective for eliminating mutant mRNAs in vivo, whereas the exons with a start codon are targeted to express the mutant mRNAs. Of the sixteen mutant mice generated, only four mutant mice targeting the downstream exons exhibited over 80% clearance of mutant mRNAs. Since the abnormal products, either mutant RNAs or mutant proteins, expressed by the target alleles might obscure the outcome of genome editing, these findings will provide insights in the improved performance of engineered nucleases when they are applied in vivo.
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http://dx.doi.org/10.1038/s41598-020-61154-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060192PMC
March 2020

spp.-fermented chicken meat for dogs.

J Anim Sci Technol 2020 Jan 31;62(1):84-93. Epub 2020 Jan 31.

Department of Animal Science and Technology, Konkuk University, Seoul 05029, Korea.

An experiment was conducted to evaluate spp.-fermented chicken meat as a snack for dogs. The fermented or non-fermented snacks used in this study were prepared through the following process; meat mixtures containing 52.8% MDCM, 35.2% chicken breast meat (CBM) and 9.7% corn starch were inoculated with or without spp., incubated at 37°C for 24 h and then sterilized at 121°C for 20 min. During the 24-h fermentation, the pH of fermented chicken snack dropped rapidly with concomitant increase in number of lactic acid bacteria. The nutritional composition was not altered by fermentation. pepsin nitrogen digestibility was higher ( < 0.05) in the fermented snack compared with the non-fermented snack. Upon storage at room temperature for 14 days, bacteria grew slowly in fermented vs. non-fermented snack samples. In a palatability trial, dogs preferred non-fermented over fermented snack food. In 12-d-long feeding trial, fecal ammonia content was lowered, but fecal lactic acid content was increased in dogs fed the fermented vs. non-fermented snack food. Our study shows that the fermented MDCM-based snack exhibited good preservability upon storage, and improved nitrogen digestibility and fecal characteristics in dogs.
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http://dx.doi.org/10.5187/jast.2020.62.1.84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008127PMC
January 2020

Ccrn4l as a pre-dose marker for prediction of cisplatin-induced hepatotoxicity susceptibility.

Free Radic Biol Med 2020 02 3;148:128-139. Epub 2020 Jan 3.

Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea. Electronic address:

Clinical cisplatin use is often limited by its drug-induced liver injury (DILI). Particularly, individual differences in susceptibility to DILI can cause life-threatening medical conditions. This study aimed to uncover the inherent genetic factors determining individual variations in hepatotoxicity susceptibility. Rats were subjected to liver biopsy and a 3-week postoperative recovery period before cisplatin administration. At 2 days post-treatment with cisplatin, the rats exhibited histopathological and serum biochemical alterations in the liver, and changes in hydrogen peroxide and cytochrome P450-2E1 levels. Based on these results of liver-related biochemical markers, 32 rats were grouped into the susceptible (top five) and resistant (bottom five) groups. Using RNA-sequencing, we compared gene expressions in the liver pre-biopsied from these two groups before cisplatin treatment and found 161 differently expressed genes between the Susceptible and Resistant groups. Among them, the clock-controlled Ccrn4l responsible for 'rhythmic process' was identified as a common gene downregulated inherently prior to drug exposure in both cisplatin- and acetaminophen-sensitive animals. Additionally, low Ccrn4l levels before cisplatin treatment in the Susceptible group were maintained even after treatment, with decreased antioxidants, increased nitration, and apoptosis. The relationship of Ccrn4l with catalase and mitochondrial RNAs in the liver was confirmed by correlation of their hepatic levels among individuals and similar patterns of circadian variation in their mRNA expression. Remarkably, Ccrn4l knockdown promoted cisplatin-induced mitochondrial dysfunction in WB-F344 cells with antioxidant catalase and apoptosis-related Bax changes. Inherent individual hepatic Ccrn4l level might be a novel factor affecting cisplatin-induced hepatotoxicity susceptibility, possibly through regulation of mitochondrial and antioxidant functions.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.01.003DOI Listing
February 2020

Biallelic Deletion of in Mice Leads to Anophthalmia and Severe Eye Malformation.

Int J Mol Sci 2019 Dec 5;20(24). Epub 2019 Dec 5.

Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

Peroxidasin (PXDN) is a unique peroxidase containing extracellular matrix motifs and stabilizes collagen IV networks by forming sulfilimine crosslinks. PXDN gene knockout in () and results in the demise at the embryonic and larval stages. PXDN mutations lead to severe eye disorders, including microphthalmia, cataract, glaucoma, and anterior segment dysgenesis in humans and mice. To investigate how PXDN loss of function affects organ development, we generated knockout mice by deletion of exon 1 and its 5' upstream sequences of the gene using the CRISPR/Cas9 system. Loss of both PXDN expression and collagen IV sulfilimine cross-links was detected only in the homozygous mice, which showed completely or almost closed eyelids with small eyes, having no apparent external morphological defects in other organs. In histological analysis of eye tissues, the homozygous mice had extreme defects in eye development, including no eyeballs or drastically disorganized eye structures, whereas the heterozygous mice showed normal eye structure. Visual function tests also revealed no obvious functional abnormalities in the eyes between heterozygous mice and wild-type mice. Thus, these results suggest that PXDN activity is essential in eye development, and also indicate that a single allele of gene is sufficient for eye-structure formation and normal visual function.
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http://dx.doi.org/10.3390/ijms20246144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941041PMC
December 2019

Knockdown of Pyruvate Kinase M2 Inhibits Cell Proliferation, Metabolism, and Migration in Renal Cell Carcinoma.

Int J Mol Sci 2019 Nov 10;20(22). Epub 2019 Nov 10.

School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.

Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. However, the molecular mechanism underlying the function of PKM2 in renal cancer is undetermined. Here, we reveal the overexpression of PKM2 in the proximal tubule of renal tumor tissues from 70 cases of patients with renal carcinoma. The functional role of PKM2 in human renal cancer cells following small-interfering RNA-mediated knockdown, which retarded 786-O cell growth was examined. Targeting PKM2 affected the protein kinase B (AKT)/mechanistic target of the rapamycin 1 (mTOR) pathway, and downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, and other downstream signaling key proteins. PKM2 knockdown changed glycolytic metabolism, mitochondrial function, adenosine triphosphate (ATP) level, and intracellular metabolite formation and significantly reduced 786-O cell migration and invasion. Acridine orange and monodansylcadaverine staining, immunocytochemistry, and immunoblotting analyses revealed the induction of autophagy in renal cancer cells following PKM2 knockdown. This is the first study to indicate PKM2/AKT/mTOR as an important regulatory axis mediating the changes in the metabolism of renal cancer cells.
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http://dx.doi.org/10.3390/ijms20225622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887957PMC
November 2019

Rab25 Deficiency Perturbs Epidermal Differentiation and Skin Barrier Function in Mice.

Biomol Ther (Seoul) 2019 Nov;27(6):553-561

Severance Biomedical Science Institute and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.

Rab25, a member of the Rab11 small GTPase family, is central to achieving cellular polarity in epithelial tissues. Rab25 is highly expressed in epithelial cells of various tissues including breast, vagina, cervix, the gastrointestinal tract, and skin. Rab25 plays key roles in tumorigenesis, mainly by regulating epithelial differentiation and proliferation. However, its role in skin physiology is relatively unknown. In this study, we demonstrated that Rab25 knock-out (KO) mice show a skin barrier dysfunction with high trans-epidermal water loss and low cutaneous hydration. To examine this observation, we investigated the histology and epidermal differentiation markers of the skin in Rab25 KO mice. Rab25 KO increased cell proliferation at the basal layer of epidermis, whereas the supra-basal layer remained unaffected. Ceramide, which is a critical lipid component for skin barrier function, was not altered by Rab25 KO in its distribution or amount, as determined by immunohistochemistry. Notably, levels of epidermal differentiation markers, including loricrin, involucrin, and keratins (5, 14, 1, and 10) increased prominently in Rab25 KO mice. In line with this, depletion of Rab25 with single hairpin RNA increased the expression of differentiation markers in a human keratinocyte cell line, HaCaT. Transcriptomic analysis of the skin revealed increased expression of genes associated with skin development, epidermal development, and keratinocyte differentiation in Rab25 KO mice. Collectively, these results suggested that Rab25 is involved in the regulation of epidermal differentiation and proliferation.
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http://dx.doi.org/10.4062/biomolther.2019.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824620PMC
November 2019

Commensal-derived metabolites govern Vibrio cholerae pathogenesis in host intestine.

Microbiome 2019 09 14;7(1):132. Epub 2019 Sep 14.

Department of Microbiology and Immunology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu Seoul, Seoul, 03722, Korea.

Background: Recent evidence suggests that the commensal microbes act as a barrier against invading pathogens and enteric infections are the consequences of multi-layered interactions among commensals, pathogens, and the host intestinal tissue. However, it remains unclear how perturbations of the gut microbiota compromise host infection resistance, especially through changes at species and metabolite levels.

Results: Here, we illustrate how Bacteroides vulgatus, a dominant species of the Bacteroidetes phylum in mouse intestine, suppresses infection by Vibrio cholerae, an important human pathogen. Clindamycin (CL) is an antibiotic that selectively kills anaerobic bacteria, and accordingly Bacteroidetes are completely eradicated from CL-treated mouse intestines. The Bacteroidetes-depleted adult mice developed severe cholera-like symptoms, when infected with V. cholerae. Germ-free mice mono-associated with B. vulgatus became resistant to V. cholerae infection. Levels of V. cholerae growth-inhibitory metabolites including short-chain fatty acids plummeted upon CL treatment, while levels of compounds that enhance V. cholerae proliferation were elevated. Furthermore, the intestinal colonization process of V. cholerae was well-simulated in CL-treated adult mice.

Conclusions: Overall, we provide insights into how a symbiotic microbe and a pathogenic intruder interact inside host intestine. We identified B. vulgatus as an indigenous microbial species that can suppress intestinal infection. Our results also demonstrate that commensal-derived metabolites are a critical determinant for host resistance against V. cholerae infection, and that CL pretreatment of adult mice generates a simple yet useful model of cholera infection.
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http://dx.doi.org/10.1186/s40168-019-0746-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744661PMC
September 2019

Sexually dimorphic leanness and hypermobility in p16/CDKN2A-deficient mice coincides with phenotypic changes in the cerebellum.

Sci Rep 2019 08 1;9(1):11167. Epub 2019 Aug 1.

Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.

p16/CDKN2A is a tumor suppressor that critically regulates the cell cycle. Indeed, p16 deficiency promotes tumor formation in various tissues. We now report that p16 deficiency in female mice, but not male mice, induces leanness especially in old age, as indicated by lower body weight and smaller white adipose tissue, although other major organs are unaffected. Unexpectedly, the integrity, number, and sizes of adipocytes in white adipose tissue were unaffected, as was macrophage infiltration. Hence, hypermobility appeared to be accountable for the phenotype, since food consumption was not altered. Histological analysis of the cerebellum and deep cerebellar nuclei, a vital sensorimotor control center, revealed increased proliferation of neuronal cells and improved cerebellum integrity. Expression of estrogen receptor β (ERβ) and PCNA also increased in deep cerebellar nuclei, implying crosstalk between p16 and ERβ. Furthermore, p16 deficiency expands LC3B cells and GFAP astrocytes in response to estrogen. Collectively, the data suggest that loss of p16 induces sexually dimorphic leanness in female mice, which appears to be due to protection against cerebellar senescence by promoting neuronal proliferation and homeostasis via ERβ.
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http://dx.doi.org/10.1038/s41598-019-47676-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671985PMC
August 2019

Intrinsic expression of viperin regulates thermogenesis in adipose tissues.

Proc Natl Acad Sci U S A 2019 08 24;116(35):17419-17428. Epub 2019 Jul 24.

Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea;

Viperin is an interferon (IFN)-inducible multifunctional protein. Recent evidence from high-throughput analyses indicates that most IFN-inducible proteins, including viperin, are intrinsically expressed in specific tissues; however, the respective intrinsic functions are unknown. Here we show that the intrinsic expression of viperin regulates adipose tissue thermogenesis, which is known to counter metabolic disease and contribute to the febrile response to pathogen invasion. Viperin knockout mice exhibit increased heat production, resulting in a reduction of fat mass, improvement of high-fat diet (HFD)-induced glucose tolerance, and enhancement of cold tolerance. These thermogenic phenotypes are attributed to an adipocyte-autonomous mechanism that regulates fatty acid β-oxidation. Under an HFD, viperin expression is increased, and its function is enhanced. Our findings reveal the intrinsic function of viperin as a novel mechanism regulating thermogenesis in adipose tissues, suggesting that viperin represents a molecular target for thermoregulation in clinical contexts.
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http://dx.doi.org/10.1073/pnas.1904480116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717265PMC
August 2019

Sequential Protein-Responsive Nanophotosensitizer Complex for Enhancing Tumor-Specific Therapy.

ACS Nano 2019 06 7;13(6):6702-6710. Epub 2019 Jun 7.

Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Chemistry and Molecular Medicine , Hunan University , Changsha 410082 , China.

A major challenge in cancer treatment is the development of effective tumor-specific therapeutic methods that have minimal side effects. Recently, a photodynamic therapy (PDT) technique using activatable photosensitizers (aPSs) has shown great potential for cancer-specific treatment. Here, we develop a sequential protein-responsive aPS (PcC4-MSN-O1) that is based on zinc(II) phthalocyanine derivative (PcC4)-entrapped mesoporous silica nanoparticles (MSNs) and a wrapping DNA (O1) as a biogate. Inside the nanostructure of PcC4-MSN-O1, PcC4 shows self-quenching photoactivity. However, when PcC4-MSN-O1 sequentially reacts with telomerase and albumin, its photoactivity is dramatically turned on. Therefore, PcC4-MSN-O1 displays selective phototoxicity against cancer cells ( e.g., HeLa) over normal cells ( e.g., HEK-293). Following systemic PcC4-MSN-O1 administration, there is an obvious accumulation in HeLa tumors of xenograft-bearing mice, and laser irradiation clearly induces the inhibition of tumor growth. Moreover, the time-modulated activation process in tumors and the relatively fast excretion of PcC4-MSN-O1 indicate its advantages in reducing potential side effects.
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http://dx.doi.org/10.1021/acsnano.9b01100DOI Listing
June 2019

Loss of Rab25 promotes the development of skin squamous cell carcinoma through the dysregulation of integrin trafficking.

J Pathol 2019 10 18;249(2):227-240. Epub 2019 Jul 18.

Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.

Rab25 can function as both a tumor suppressor and a tumor promoter across different tissues. This study sought to clarify the role of Rab25 as a tumor suppressor in skin squamous cell carcinoma (SCC). Rab25 loss was closely associated with neoplastic transition in both humans and mice. Rab25 loss was well correlated with increased cell proliferation and poor differentiation in human SCC. While Rab25 knockout (KO) in mice did not induce spontaneous tumor formation, it did significantly accelerate tumor generation and promote malignant transformation in a mouse two-stage skin carcinogenesis model. Xenografting of a Rab25-deficient human keratinocyte cell line, HaCaT, also elicited neoplastic transformation. Notably, Rab25 deficiency led to dysregulation of integrins β1, β4, and α6, which matched well with increased epidermal proliferation and impaired desmosome-tight junction formation. Rab25 deficiency induced impairment of integrin recycling, leading to the improper expression of integrins. In line with this, significant attenuation of integrin β1, β4, and α6 expression was identified in human SCCs where Rab25 was deficient. Collectively, these results suggest that loss of Rab25 promotes the development and neoplastic transition of SCC through dysregulation of integrin trafficking. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5311DOI Listing
October 2019

RAE1 mediated ZEB1 expression promotes epithelial-mesenchymal transition in breast cancer.

Sci Rep 2019 02 27;9(1):2977. Epub 2019 Feb 27.

Department of Anatomy, Embryology Laboratory, Yonsei University College of Medicine, Seoul, 03722, Korea.

Breast cancer metastasis accounts for most of the deaths from breast cancer. Since epithelial-mesenchymal transition (EMT) plays an important role in promoting metastasis of cancer, many mechanisms regarding EMT have been studied. We previously showed that Ribonucleic acid export 1 (RAE1) is dysregulated in breast cancer and its overexpression leads to aggressive breast cancer phenotypes by inducing EMT. Here, we evaluated the functional capacity of RAE1 in breast cancer metastasis by using a three-dimensional (3D) culture system and xenograft models. Furthermore, to investigate the mechanisms of RAE1-driven EMT, in vitro studies were carried out. The induction of EMT with RAE1-overexpression was confirmed under the 3D culture system and in vivo system. Importantly, RAE1 mediates upregulation of an EMT marker ZEB1, by binding to the promoter region of ZEB1. Knockdown of ZEB1 in RAE1-overexpressing cells suppressed invasive and migratory behaviors, accompanied by an increase in epithelial and a decrease in mesenchymal markers. Taken together, these data demonstrate that RAE1 contributes to breast cancer metastasis by regulating a key EMT-inducing factor ZEB1 expression, suggesting its potential as a therapeutic target.
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http://dx.doi.org/10.1038/s41598-019-39574-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393568PMC
February 2019

Development of novel biocompatible thermosensitive anti-adhesive agents using human-derived acellular dermal matrix.

PLoS One 2019 22;14(2):e0212583. Epub 2019 Feb 22.

Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.

Postoperative adhesion is a natural phenomenon that occurs in damaged tissue cells. Several anti-adhesion agents are currently used, but there is no leading-edge product with excellent adhesion-preventive effects. The purpose of this study was to develop ideal anti-adhesive agents using human-derived acellular dermal matrix (ADM). We developed 5 new biocompatible thermosensitive anti-adhesion barriers (AABs) using micronized human-derived ADM, hyaluronic acid, and temperature-sensitive and biocompatible synthesized polymers. The biocompatibility, anti-adhesion effect, and biodegradability of these AABs were compared with those of commercial thermosensitive anti-adhesion agents. No cytotoxic effects were observed in vitro and in vivo. Animal testing of adhesion resistance confirmed that the adhesion area, strength, and grade of AAB03 were statistically superior to those of the control group. Factors related to adhesion formation, such as lymphocytes, macrophages, microvessels, and collagen fiber density, were observed using specific staining methods; the results confirmed that AAB03 group exhibited significantly lower macrophage counts, microvessel density, and collagen fiber density than the control groups. Furthermore, AAB03 was completely absorbed by 6 weeks. Thus, AAB03 has the potential to be used as a high-performance anti-adhesion agent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212583PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386309PMC
November 2019

Enrichment of Short-Chain Ceramides and Free Fatty Acids in the Skin Epidermis, Liver, and Kidneys of db/db Mice, a Type 2 Diabetes Mellitus Model.

Biomol Ther (Seoul) 2019 02 8;27(5):457-465. Epub 2019 Feb 8.

Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.

Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains (<C26) occurred in the skin epidermis (16NS, 18NS, 24NS, 16NDS, 18NDS, 20NDS, 22NDS, 24NDS, C16:1FA, C18:2FA, and C18:1FA) and the liver (16NS, 18NS, 20NS, 24:1NS, 18NDS, 20NDS, 22NDS, C16:1FA, C18:2FA, C18:1FA), whereas those with very long chains were not affected. In the kidney, only slight increases (<3 fold) were observed for 16NS, 18NS, 20NS, 26NDS, C26FA, and C22:1FA. Consistently, LXRα/β and PPARγ, nuclear receptors promoting lipid synthesis, lipid synthesis enzymes such as elongases 1, 4, and 6, and fatty acid synthase and stearoyl-CoA desaturase were highly expressed in the skin and livers of the db/db mice. Collectively, our study demonstrates an extensive alteration in the skin and systemic lipid profiles of db/db mice, which could contribute to the development of skin disorders in DM.
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http://dx.doi.org/10.4062/biomolther.2018.214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720538PMC
February 2019

CRISPR/Cas9-mediated knockout of causes hemolytic anemia with splenomegaly in C57BL/6 mice.

Lab Anim Res 2018 Dec 31;34(4):302-310. Epub 2018 Dec 31.

Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea.

CD47 (integrin-associated protein), a multi-spanning transmembrane protein expressed in all cells including red blood cells (RBCs) and leukocytes, interacts with signal regulatory protein α (SIRPα) on macrophages and thereby inhibits phagocytosis of RBCs. Recently, we generated a novel C57BL/6J knockout ( hereafter) mouse line by employing a CRISPR/Cas9 system at Center for Mouse Models of Human Disease, and here report their hematological phenotypes. On monitoring their birth and development, mice were born viable with a natural male-to-female sex ratio and normally developed from birth through puberty to adulthood without noticeable changes in growth, food/water intake compared to their age and sex-matched wild-type littermates up to 26 weeks. Hematological analysis revealed a mild but significant reduction of RBC counts and hemoglobin in 16 week-old male mice which were aggravated at the age of 26 weeks with increased reticulocyte counts and mean corpuscular volume (MCV), suggesting hemolytic anemia. Interestingly, anemia in female mice became evident at 26 weeks, but splenomegaly was identified in both genders of mice from the age of 16 weeks, consistent with development of hemolytic anemia. Additionally, helper and cytotoxic T cell populations were considerably reduced in the spleen, but not in thymus, of mice, suggesting a crucial role of CD47 in proliferation of T cells. Collectively, these findings indicate that our mice have progressive hemolytic anemia and splenic depletion of mature T cell populations and therefore may be useful as an model to study the function of CD47.
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http://dx.doi.org/10.5625/lar.2018.34.4.302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333621PMC
December 2018

Disruption of the gene in mice using CRISPR/Cas9 promotes body weight reduction and gastric tumorigenesis.

Lab Anim Res 2018 Dec 31;34(4):257-263. Epub 2018 Dec 31.

Department of Biochemistry, College of Life Science and Biotechnology and Yonsei Laboratory Animal Research Center, Yonsei University, Seoul, Korea.

Trefoil factor 1 (, also known as pS2) is strongly expressed in the gastrointestinal mucosa and plays a critical role in the differentiation of gastric glands. Since approximately 50% of all human gastric cancers are associated with decreased expression, it is considered a tumor suppressor gene. deficiency in mice results in histological changes in the antral and pyloric gastric mucosa, with severe hyperplasia and dysplasia of epithelial cells, resulting in the development of antropyloric adenoma. Here, we generated -knockout (KO) mice, without a neomycin resistant (Neo) cassette, using the clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRSIPR/Cas9) system. Though our -KO mice showed phenotypes very similar to the previous embryonic stem (ES)-cell-based KO mice, they differed from the previous reports in that a reduction in body weight was observed in males. These results demonstrate that these newly established -KO mice are useful tools for investigating genetic and environmental factors influencing gastric cancer, without the effects of artificial gene insertion. Furthermore, these findings suggest a novel hypothesis that expression influences gender differences.
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http://dx.doi.org/10.5625/lar.2018.34.4.257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333602PMC
December 2018

CRISPR/Cas9-mediated knockout of causes systemic lymphopenia with hypoplastic lymphoid organs in FVB mice.

Lab Anim Res 2018 Dec 31;34(4):166-175. Epub 2018 Dec 31.

Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, Korea.

Recombination activating gene-2 () plays a crucial role in the development of lymphocytes by mediating recombination of T cell receptors and immunoglobulins, and loss of causes severe combined immunodeficiency (SCID) in humans. knockout mice created using homologous recombination in ES cells have served as a valuable immunodeficient platform, but concerns have persisted on the specificity of -related phenotypes in these animals due to the limitations associated with the genome engineering method used. To precisely investigate the function of , we recently established a new knockout FVB mouse line () manifesting lymphopenia by employing a CRISPR/Cas9 system at Center for Mouse Models of Human Disease. In this study, we further characterized their phenotypes focusing on histopathological analysis of lymphoid organs. mice showed no abnormality in development compared to their WT littermates for 26 weeks. At necropsy, gross examination revealed significantly smaller spleens and thymuses in mice, while histopathological investigation revealed hypoplastic white pulps with intact red pulps in the spleen, severe atrophy of the thymic cortex and disappearance of follicles in lymph nodes. However, no perceivable change was observed in the bone marrow. Moreover, our analyses showed a specific reduction of lymphocytes with a complete loss of mature T cells and B cells in the lymphoid organs, while natural killer cells and splenic megakaryocytes were increased in mice. These findings indicate that our mice show systemic lymphopenia with the relevant histopathological changes in the lymphoid organs, suggesting them as an improved -related immunodeficient model.
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http://dx.doi.org/10.5625/lar.2018.34.4.166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333597PMC
December 2018

In Vivo Albumin Traps Photosensitizer Monomers from Self-Assembled Phthalocyanine Nanovesicles: A Facile and Switchable Theranostic Approach.

J Am Chem Soc 2019 01 2;141(3):1366-1372. Epub 2019 Jan 2.

Department of Chemistry and Nano Science , Ewha Womans University , Seoul 03760 , Republic of Korea.

Albumin is a promising candidate as a biomarker for potential disease diagnostics and has been extensively used as a drug delivery carrier for decades. In these two directions, many albumin-detecting probes and exogenous albumin-based nanocomposite delivery systems have been developed. However, there are only a few cases demonstrating the specific interactions of exogenous probes with albumin in vivo, and nanocomposite delivery systems usually suffer from tedious fabrication processes and potential toxicity of the complexes. Herein, we demonstrate a facile "one-for-all" switchable nanotheranostic (NanoPcS) for both albumin detection and cancer treatment. In particular, the in vivo specific binding between albumin and PcS, arising from the disassembly of injected NanoPcS, is confirmed using an inducible transgenic mouse system. Fluorescence imaging and antitumor tests on different tumor models suggest that NanoPcS has superior tumor-targeting ability and the potential for time-modulated, activatable photodynamic therapy.
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http://dx.doi.org/10.1021/jacs.8b12167DOI Listing
January 2019

Di-2-ethylhexylphthalate promotes thyroid cell proliferation and DNA damage through activating thyrotropin-receptor-mediated pathways in vitro and in vivo.

Food Chem Toxicol 2019 Feb 10;124:265-272. Epub 2018 Dec 10.

Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea. Electronic address:

Phthalates are being suggested to be associated with altered thyroid function and proliferative changes, but detailed mechanisms remain unclear. Here, we examined the effects of di-(2-ethylhexyl) phthalate (DEHP) on DNA damage and proliferation in thyroid using thyroid carcinoma cell line, 8505C, in vitro and the rats orally treated with DEHP at 0, 0.3, 3, 30 and 150 mg/kg for 90 days from post-natal day 9 in vivo. Exposure to DHEP (1-50 μM) induced cellular proliferation, as evidenced by increased cell viability and DNA synthesis. Activation of γH2AX, a sensitive biomarker for DNA damage was observed following the exposure to DHEP (from 5 to 50 μM) with increased comet tail moment (5-100 μM) in comet assay, reflecting that DNA damage also occurred. When upstream signaling was examined, both thyrotropin receptor (TSHR)-ERK1/2 axis and TSHR-AKT axis were activated with upregulation of Pax8, a master transcriptional factor for thyroid differentiation and proliferation. Thyroid tissue from juvenile rats orally exposed to DEHP also confirmed DNA damage responses and the activation of TSHR signaling, which was evident from 0.3 to 3 mg/kg respectively. Notably, deletion of TSHR through siRNA attenuated these DEHP-induced events in vitro. Collectively these results suggest that DEHP induces DNA damage and cellular proliferation in thyroid, which appears to be from TSHR activation, providing an important insight into endocrine disrupting activities of phthalates on thyroid.
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http://dx.doi.org/10.1016/j.fct.2018.12.010DOI Listing
February 2019

Expression of LRIG1, a Negative Regulator of EGFR, Is Dynamically Altered during Different Stages of Gastric Carcinogenesis.

Am J Pathol 2018 12 21;188(12):2912-2923. Epub 2018 Sep 21.

Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a transmembrane protein that antagonizes epidermal growth factor receptor signaling in epithelial tissues. LRIG1 is down-regulated in various epithelial cancers, including bladder, breast, and colorectal cancer, suggesting that it functions as a tumor suppressor. However, its role in gastric carcinogenesis is not well understood. Here, we investigated the changes in LRIG1 expression during the stages of gastric cancer. We used a DMP-777-induced spasmolytic polypeptide-expressing metaplasia mouse model and a tissue array of human gastric cancer lesions. The effects of LRIG1 knockdown were also assessed using the human gastric cancer cell line SNU638 in a xenograft model. LRIG1 expression varied over the course of gastric carcinogenesis, increasing in spasmolytic polypeptide-expressing metaplasia lesions but disappearing in intestinal metaplasia and cancer lesions, and the increase was concurrent with the up-regulation of epidermal growth factor receptor. In addition, LRIG1 knockdown promoted the tumorigenic potential in vitro, which was manifested as increased proliferation, invasiveness, and migration as well as increased tumor size in vivo in the xenograft model. Furthermore, LRIG1 expression was determined to be a positive prognostic biomarker for the survival of gastric cancer patients. Collectively, our findings indicate that LRIG1 expression is closely related wto gastric carcinogenesis and may play a vital role as a tumor suppressor through the modulation of epidermal growth factor receptor activity.
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http://dx.doi.org/10.1016/j.ajpath.2018.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334257PMC
December 2018