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Dive into the research topics where Simon Weonsang Ro is active.

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Featured researches published by Simon Weonsang Ro.


Hepatology | 2008

Surface markers for the murine oval cell response.

Craig Dorrell; Laura Erker; Kelsea M. Lanxon-Cookson; Stephanie L. Abraham; Tristan Victoroff; Simon Weonsang Ro; Pamela S. Canaday; Philip R. Streeter; Markus Grompe

The biology of progenitor activation in the liver is of considerable medical and scientific interest. The powerful genetic tools available for the mouse make it an ideal model system to study this complex process involving many different cell types. However, reagents for the isolation and study of distinct hepatic subpopulations have been quite limited compared to those available for hematopoietic cells. To produce cell surface reactive reagents more specific for the oval cell response, we generated a new collection of monoclonal antibodies by immunization of Fischer rats with enzymatically dispersed nonparenchymal cells from the livers of adult mice treated with 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine. Each of the resulting antibodies recognized a surface antigen present on a liver cell subset and permitted the viable isolation of the associated subpopulation by fluorescence‐activated cell sorting. Differential activity was observed on normal liver cells and at different stages of oval cell activation, indicating potential utility for progenitor cell identification. The subdivision of liver cells using these tools should facilitate the study of the biology of ductal and periductal hepatic cell types, including progenitors. Conclusion: A new panel of surface reactive monoclonal antibodies to support investigation of the murine oval cell response has been developed. (HEPATOLOGY 2008.)


Proceedings of the National Academy of Sciences of the United States of America | 2001

Methylation patterns and mathematical models reveal dynamics of stem cell turnover in the human colon

Simon Weonsang Ro; Bruce Rannala

To understand the normal aging process, as well as the role of cellular aging in diseases such as cancer, it is essential to understand the process of somatic cell development and renewal. Stem cells are undifferentiated cells, normally residing in a specific location (a niche) within a tissue. Stem cells are capable of producing a variety of somatic cell types needed for periodic tissue renewal and tissue regeneration after injury. To accomplish this, stem cells produce intermediate progenitors, called transit amplifying (TA) cells, that can divide rapidly and differentiate into various types of tissue cells. Because stem cells are the only cells capable of continuous tissue renewal, the population of stem cells must be maintained. It is still largely a mystery how stem cells maintain their numbers. Two competing models have been proposed (1, 2) (Fig. 1). The deterministic model proposes that a small number of stem cells reside in a niche, each generating exactly one stem cell and one TA cell at each (asymmetrical) cell division. The daughter TA cell leaves the niche to proliferate for tissue renewal while the daughter stem cell remains in the niche; each stem cell is “immortal” under this model. The stochastic model proposes that many stem cells exist in a niche with each stem cell division producing either two, one, or zero stem cells (and either zero, one, or two proliferating TA cells, respectively). This leads to “drift” in the numbers of descendents of each stem cell lineage over time. Eventually, a single common ancestral stem cell exists from which all stem cells in a niche are descended. The stem cell population is most likely to persist (under the stochastic model) if the probability that a stem cell division produces either two stem cells, or zero stem cells, is equal. In this …


EMBO Reports | 2004

A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation

Simon Weonsang Ro; Bruce Rannala

The investigation of cell lineages and clonal organization in tissues is facilitated by techniques that allow labelling of clonal cell lineages. Here, we describe a novel transgenic mouse that allows clonal cell lineages to be traced in virtually any tissue. A green fluorescent cell lineage is generated by a random mutation at an enhanced green fluorescent protein gene that carries a premature stop codon, ensuring clonality. The transgenic system allows efficient detection of mutations and stem‐cell fate mapping in the epidermis using live mice, as well as in the kidney and liver post‐mortem. Cell lineages that descended from single epidermal stem cells were found to be capable of generating three adjacent corneocytes using the system, providing evidence for horizontal migration of epidermal cells between epidermal proliferative units (EPUs), in contrast to the classical EPU model. The transgenic mouse system is expected to provide a novel tool for stem‐cell lineage studies.


Experimental Dermatology | 2005

Evidence from the stop-EGFP mouse supports a niche-sharing model of epidermal proliferative units.

Simon Weonsang Ro; Bruce Rannala

Abstract:  The classical model of epidermal proliferative units (EPUs) postulates that each EPU is composed of a single column of corneocytes plus epidermal cells directly below the column and is maintained by a single stem cell within the unit. Using the stop‐enhanced green fluorescent protein (stop‐EGFP) transgenic mouse system, we previously showed epidermal stem cell clonal lineages could produce multiple adjacent corneocytes (i.e. epidermal cells belonging to multiple adjacent EPUs), contradicting the classical EPU model. One possible problem with our earlier study was that N‐ethyl‐N‐nitrosourea (ENU) was used to generate mutations for clonal analysis. This could alter the normal environment of the epidermal tissue and might lead to an artificial expansion of stem cell clonal lineages. In this study, we replicate our earlier findings using untreated stop‐EGFP mice and relying on spontaneous mutations to generate clonal cell lineages. We propose an alternative to the classical EPU model to explain the dynamic nature of epidermal proliferation. Our niche‐sharing model of EPUs allows epidermal cells to horizontally migrate among EPUs, so that multiple stem cells cooperatively maintain a larger proliferative compartment.


Journal of Hepatology | 2016

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

Sook In Chung; Hyuk Moon; Hye Lim Ju; Kyung Joo Cho; Do Young Kim; Kwang Hyub Han; Jung Woo Eun; Suk Woo Nam; Silvia Ribback; Frank Dombrowski; Diego F. Calvisi; Simon Weonsang Ro

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.


Liver International | 2014

Inhibition of tumour angiogenesis and growth by small hairpin HIF‐1α and IL‐8 in hepatocellular carcinoma

Sung Hoon Choi; Oh Joon Kwon; Jun Yong Park; Do Young Kim; Sang Hoon Ahn; Seung Up Kim; Simon Weonsang Ro; Kyung Sik Kim; Jeon Han Park; Seungtaek Kim; Chae-Ok Yun; Kwang Hyub Han

Hypoxia‐inducible factor‐1α (HIF‐1α), a key transcription factor in the cellular response to hypoxia, and interleukin 8 (IL‐8), a key mediator of angiogenesis, are important in cancerous tumour growth. In this study, we evaluated the effects of HIF‐1α and IL‐8 knockdown on angiogenesis and tumour growth in hepatocellular carcinoma (HCC).


Proceedings of the National Academy of Sciences of the United States of America | 2017

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

Young Eun Kim; Wantae Kim; Yonghee Song; Jeong-Rae Kim; Kyungjoo Cho; Hyuk Moon; Simon Weonsang Ro; Eunjeong Seo; Yeon-Mi Ryu; Seung-Jae Myung; Eek-hoon Jho

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.


Scientific Reports | 2015

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

Hye Lim Ju; Diego F. Calvisi; Hyuk Moon; Sinhwa Baek; Silvia Ribback; Frank Dombrowski; Kyung Joo Cho; Sook In Chung; Kwang Hyub Han; Simon Weonsang Ro

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.


Hepatology Research | 2015

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

Sinhwa Baek; Kyung Joo Cho; Hye Lim Ju; Hyuk Moon; Sung Hoon Choi; Sook In Chung; Jun Yong Park; Ki Hong Choi; Do Young Kim; Sang Hoon Ahn; Kwang Hyub Han; Simon Weonsang Ro

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.


Hepatology | 2018

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

Qingyu Shen; Jung Woo Eun; K.-W. Lee; Hyung Seok Kim; Hee Doo Yang; Sang Yean Kim; Eun Kyung Lee; Taemook Kim; Keunsoo Kang; Seongchan Kim; Dal-Hee Min; Soon-Nam Oh; Young-Joon Lee; Hyuk Moon; Simon Weonsang Ro; Won Sang Park; Jung Young Lee; Suk Woo Nam

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).

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Bruce Rannala

University of California

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