Hyuk Moon

Phase studies of SrOAl2O3 by emission signatures of Eu2+ and Eu3+

Phase transformation sequences of SrOAl2O3 have been investigated at 1000 and 1250 °C through XRD technique along with emission signatures of Eu2+ and Eu3+. Two phases, i.e., [Sr3Al2O6] and [SrAl2O4], have been observed at 1000 °C as stable phases. These phases were found to be transformed into [SrAl2O4] at 1250 °C.

Tunable Color Emission in a Zn1−xCdxGa2O4 Phosphor and Solid Solubility of CdGa2O4 in ZnGa2O4

Abstract Tunable color emission was achieved through forming solid solution between ZnGa 2 O 4 and CdGa 2 O 4 , i.e., Zn 1−x Cd x Ga 2 O 4 . The solid solubility limit of CdGa 2 O 4 in ZnGa 2 O 4 was found to be 0.6 mole fraction. Thus, solid solution can exist in 0 ≤ x ≤ 0.6 compositions in the Zn 1−x Cd x Ga 2 O 4 . Emission color was tunable between 352 and 520 nm in Zn 1−x Cd x Ga 2 O 4 (0 ≤ x ≤ 0.6). Our approach has demonstrated an innovative way of tuning color through the formation of solid solution between CdGa 2 O 4 and ZnGa 2 O 4

Dependence of the structural and the optical properties of ZnGa2O4 phosphors on the mixture molar ratio of ZnO and Ga2O3

Abstract Dependence of the structural and the optical properties of ZnGa 2 O 4 phosphors on the mixture molar ratio of ZnO and Ga 2 O 3 were investigated by using X-ray diffraction (XRD) and cathodoluminescence (CL) measurements. While the lattice constants of the ZnGa 2 O 4 phosphors obtained from the XRD curves varied dramatically with changing the excess amount of the ZnO, those did not change significantly with increasing the excess amount of the Ga 2 O 3 . The CL spectra exhibited the dominant emission peak in the ZnGa 2 O 4 shifted to the longer wavelength with increasing the amount of the ZnO excess and that the peak position of the emission was not independent on the variation quantity of the Ga 2 O 3 excess. This result indicates that the ZnO excess in the ZnGa 2 O 4 phosphors has a limit solubility and that the Ga 2 O 3 excess is not soluble in the ZnGa 2 O 4 phosphors.

Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model

BACKGROUND & AIMS Liver fibrosis is an increasing health concern worldwide and a major risk factor for hepatocellular carcinoma (HCC). Although the involvement of Hedgehog signaling in hepatic fibrosis has been known for some time, the causative role of activated Hedgehog signaling in liver fibrosis has not been verified in vivo. METHODS Using hydrodynamics-based transfection, a transgenic mouse model has been developed that expresses Sonic Hedgehog (SHH), a ligand for Hedgehog signaling, in the liver. Levels of hepatic fibrosis and fibrosis-related gene expression were assessed in the model. Hepatic expression of SHH was induced in a murine model for hepatocellular adenoma (HCA) and tumor development was subsequently investigated. RESULTS The transgenic mice revealed SHH expression in 2-5% of hepatocytes. Secreted SHH activated Hedgehog signaling in numerous cells of various types in the tissues. Hepatic expression of SHH led to fibrosis, activation of hepatic stellate cells, and an upregulation of various fibrogenic genes. Liver injury and hepatocyte apoptosis were observed in SHH mice. Persistent expression of SHH for up to 13months failed to induce tumors in the liver; however, it promoted liver tumor development induced by other oncogenes. By employing a HCA model induced by P53(R172H) and KRAS(G12D), we found that the SHH expression promoted the transition from HCA to HCC. CONCLUSIONS SHH expression in the liver induces liver fibrosis with concurrent activation of hepatic stellate cells and fibrogenic genes. It can also enhance hepatocarcinogenesis induced by other oncogenes.

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

Significance The Hippo pathway restricts cell proliferation and plays key roles in organ size control and tissue homeostasis. The crucial step of this pathway is the regulation of the transcriptional coactivators YAP/TAZ by LATS1/2 kinases. We report in the present study that deubiquitinase YOD1 acts as a positive regulator of YAP/TAZ in controlling organ size. The significance of our study is the discovery of a regulatory mechanism for the Hippo pathway: high cell density miR-21−YOD1−ITCH−LATS signaling cascade, which is parallel to a previously known high cell density MST1/2−LATS signaling cascade. Data from harnessing a mouse model that allowed inducible human YOD1 expression in mouse liver and liver cancer patients suggest mechanistic insights to expand our understanding about regulation of the Hippo pathway. Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination−deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.

Transgenic mouse model expressing P53 R172H , luciferase, EGFP, and KRAS G12D in a single open reading frame for live imaging of tumor

Genetically engineered mouse cancer models allow tumors to be imaged in vivo via co-expression of a reporter gene with a tumor-initiating gene. However, differential transcriptional and translational regulation between the tumor-initiating gene and the reporter gene can result in inconsistency between the actual tumor size and the size indicated by the imaging assay. To overcome this limitation, we developed a transgenic mouse in which two oncogenes, encoding P53R172H and KRASG12D, are expressed together with two reporter genes, encoding enhanced green fluorescent protein (EGFP) and firefly luciferase, in a single open reading frame following Cre-mediated DNA excision. Systemic administration of adenovirus encoding Cre to these mice induced specific transgene expression in the liver. Repeated bioluminescence imaging of the mice revealed a continuous increase in the bioluminescent signal over time. A strong correlation was found between the bioluminescent signal and actual tumor size. Interestingly, all liver tumors induced by P53R172H and KRASG12D in the model were hepatocellular adenomas. The mouse model was also used to trace cell proliferation in the epidermis via live fluorescence imaging. We anticipate that the transgenic mouse model will be useful for imaging tumor development in vivo and for investigating the oncogenic collaboration between P53R172H and KRASG12D.

Analysis of miRNA expression patterns in human and mouse hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC), one of the most common malignancies in adults displays aberrant miRNA expression during its pathogenesis. We assessed expression of miRNA in surgically resected human HCC of an early stage and murine HCC with a high malignancy in order to find miRNA overexpressed in HCC regardless of tumor stage and underlying etiology. Further, the role of the deregulated miRNA in HCC pathogenesis was investigated.

BANF1, PLOD3, SF3B4 as Early-stage Cancer Decision Markers and Drivers of Hepatocellular Carcinoma

An accurate tool enabling early diagnosis of hepatocellular carcinoma (HCC) is clinically important, since early detection of HCC markedly improves survival. We aimed to investigate the molecular markers underlying early progression of HCC that can be detected in precancerous lesions. We designed a gene selection strategy to identify potential driver genes by integrative analysis of transcriptome and clinicopathologic data of human multi-stage HCC tissues including precancerous lesions, lowand high-grade dysplastic nodules. The gene selection process was guided by detecting the selected molecules in both HCC and precancerous lesion. Using various computational approaches, we selected 10 gene elements as a candidate and, through immunohistochemical staining, showed that BANF1, PLOD3 and SF3B4 are HCC decision markers with superior capability to diagnose early-stage HCC in a large cohort of HCC patients, as compared to the currently popular trio of HCC diagnostic markers: glypican 3, glutamine synthetase, and heat-shock protein 70. Targeted inactivation of BANF1, PLOD3 and SF3B4 inhibits in vitro and in vivo liver tumorigenesis by selectively modulating EMT and cell cycle proteins. Treatment of nanoparticles containing siRNAs of the three genes suppressed liver tumor incidence as well as tumor growth rates in spontaneous mouse HCC model. We also demonstrated that SF3B4 overexpression triggers SF3b complex to splice tumor suppressor KLF4 transcript to non-functional skipped exon transcripts. This contributes to malignant transformation and growth of hepatocyte via transcriptional inactivation of p27 and simultaneously activation of Slug genes. Conclusion: The findings suggest novel molecular markers of BANF1, PLOD3 and SF3B4 indicating early-stage HCC in precancerous lesion, and also suggest drivers for understanding the development of hepatocarcinogenesis. Page 3 of 71 Hepatology Hepatology This article is protected by copyright. All rights reserved.An accurate tool enabling early diagnosis of hepatocellular carcinoma (HCC) is clinically important, given that early detection of HCC markedly improves survival. We aimed to investigate the molecular markers underlying early progression of HCC that can be detected in precancerous lesions. We designed a gene selection strategy to identify potential driver genes by integrative analysis of transcriptome and clinicopathological data of human multistage HCC tissues, including precancerous lesions, low‐ and high‐grade dysplastic nodules. The gene selection process was guided by detecting the selected molecules in both HCC and precancerous lesion. Using various computational approaches, we selected 10 gene elements as a candidate and, through immunohistochemical staining, showed that barrier to autointegration factor 1 (BANF1), procollagen‐lysine, 2‐oxoglutarate 5‐dioxygenase 3 (PLOD3), and splicing factor 3b subunit 4 (SF3B4) are HCC decision markers with superior capability to diagnose early‐stage HCC in a large cohort of HCC patients, as compared to the currently popular trio of HCC diagnostic markers: glypican 3, glutamine synthetase, and heat‐shock protein 70. Targeted inactivation of BANF1, PLOD3, and SF3B4 inhibits in vitro and in vivo liver tumorigenesis by selectively modulating epithelial‐mesenchymal transition and cell‐cycle proteins. Treatment of nanoparticles containing small‐interfering RNAs of the three genes suppressed liver tumor incidence as well as tumor growth rates in a spontaneous mouse HCC model. We also demonstrated that SF3B4 overexpression triggers SF3b complex to splice tumor suppressor KLF4 transcript to nonfunctional skipped exon transcripts. This contributes to malignant transformation and growth of hepatocyte through transcriptional inactivation of p27Kip1 and simultaneously activation of Slug genes. Conclusion: The findings suggest molecular markers of BANF1, PLOD3, and SF3B4 indicating early‐stage HCC in precancerous lesion, and also suggest drivers for understanding the development of hepatocarcinogenesis. (Hepatology 2018;67:1360‐1377).

Comparison of liver oncogenic potential among human RAS isoforms.

Mutation in one of three RAS genes (i.e., HRAS, KRAS, and NRAS) leading to constitutive activation of RAS signaling pathways is considered a key oncogenic event in human carcinogenesis. Whether activated RAS isoforms possess different oncogenic potentials remains an unresolved question. Here, we compared oncogenic properties among RAS isoforms using liver-specific transgenesis in mice. Hydrodynamic transfection was performed using transposons expressing short hairpin RNA downregulating p53 and an activated RAS isoform, and livers were harvested at 23 days after gene delivery. No differences were found in the hepatocarcinogenic potential among RAS isoforms, as determined by both gross examination of livers and liver weight per body weight ratio (LW/BW) of mice expressing HRASQ61L, KRAS4BG12V and NRASQ61K. However, the tumorigenic potential differed significantly between KRAS splicing variants. The LW/BW ratio in KRAS4AG12V mice was significantly lower than in KRAS4BG12V mice (p < 0.001), and KRAS4AG12V mice lived significantly longer than KRRAS4BG12V mice (p < 0.0001). Notably, tumors from KRAS4AG12V mice displayed higher expression of the p16INK4A tumor suppressor when compared with KRAS4BG12V tumors. Forced overexpression of p16INK4A significantly reduced tumor growth in KRAS4BG12V mice, suggesting that upregulation of p16INK4A by KRAS4AG12V presumably delays tumor development driven by the latter oncogene.

Enhancement of the phase stability in ZnGa2O3.994Se0.006: Li+, Mn2+ phosphors

Abstract The degradation behavior of ZnGa 2 O 3.994 Se 0.006 : Li, Mn caused by thermal annealing and acceleration voltage was investigated. Thermal degradation of ZnGa 2 O 3.994 Se 0.006 : Li, Mn initiated from the volatilization of Se, whereas, commercial green phosphor, ZnS: Cu, Al, transformed from ZnS to ZnO. The cathodoluminescence measurements showed that the saturation characteristics of the luminance of ZnGa 2 O 3.994 Se 0.006 : Li, Mn at higher voltage were a little better than that of commercial green phosphor (ZnS: Cu, Al). These results indicate that the phase stability of ZnGa 2 O 3.994 Se 0.006 : Li, Mn in both thermal and acceleration voltage dependent degradations is superior to that of ZnS: Cu, Al.