Dr. Chiou-Hwa Yuh

Chiou-Hwa Yuh, Ph.D.

Investigator

Institute of Molecular and Genomic Medicine

chyuh@nhri.edu.tw

EDUCATION

Ph.D., Microbiology and Immunology, National Yang-Ming Medical College, Taipei, Taiwan (1992)
B.S., Biology, Fu-Jen Catholic University, Taipei, Taiwan (1987)

PROFESSIONAL EXPERIENCES

1992-1995      Research Fellow, California Institute of Technology, California, USA
1995-2001      Senior Research Fellow, California Institute of Technology, California, USA
1996-2001      Research Associate, Stowers Institute of Medical Research, Missouri, USA
2001-2002      Director, Transcription Factor Center, Beckman Institute, California Institute of Technology, California, USA
2002-2004      Member of the Professional Staff, Biology Division, California Institute of Technology, California, USA
2005-2015      Associate Investigator, Institute of Molecular and Genetic Medicine, National Health Research Institutes, Taiwan
2005-2006      Adjunct Assistant Professor, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan
2006-2015      Adjunct Associate Professor, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan
2007-2015      Joint Associate Professor, Department of the Biological Science & Technology, National Chiao Tung University, Taiwan
2013-present       Joint Associate Professor, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2015-present      Investigator, Institute of Molecular and Genomic Medicine, National Health Research Institute, Taiwan
2015-present      Joint Professor, Department of the Biological Science & Technology, National Chiao Tung University, Taiwan
2015-present      Adjunct Professor, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Taiwan

RESEARCH INTERESTS

Dr. Yuh is interested in gene regulation during development and carcinogenesis. Over the course of Dr. Yuh’s career in life science, she identified second enhancer (enhancer II) of hepatitis B virus and discovered the action mechanism of enhancer II and the core promoter of the HBV and received her Ph.D. from Institute of Microbiology and Immunology at National Yang-Ming Medical College, Taiwan in 1992. She published five international papers and one book chapter during five years. Dr. Yuh gained tremendous experience on the systematic approached of embryonic development and Gene Regulatory Networks (GRNs) in California Institute of Technology (Caltech) under the supervision of Dr. Eric Davidson. She decoded the regulatory circuits of endoderm specific gene in sea urchin, Endo16 and published the paper in Science on 1998, using computational algorisms to explain the transcription regulation. Dr. Yuh also participated on establishment of the Endomesoderm Gene Regulatory Network in sea urchin. Seventeen scientific high impact papers and three book chapters were published before she joined NHRI.

Dr. Yuh was recruited as an Associate Investigator by the DMGM of NHRI at December 31 of 2004, and started using zebrafish as model organism to decode the embryonic gene regulatory networks. Using a web-enabled GRN modeling tool (BioTapestry) to build an integrated model of the Endomesoderm Gene Regulatory Network in zebrafish, functional dissecting the important subcircuits in the endoderm networks by systematically approaches, she identified several interesting functional motifs that are important building blocks in zebrafish developmental GRNs, and published six papers on international well known journals such as Developmental Biology, BMC Developmental Biology and Birth Defects Research Part C.

For the translational research, Dr. Yuh had found the genes and pathways in development were dysregulated in cancer. She initiated the systematic analysis of hepatocellular carcinoma (HCC) in mouse model, and established transgenic zebrafish model. Dr. Yuh has identified five critical oncogenes from mouse model, verified using human HCC specimens, and confirmed in transgenic zebrafish. Dr. Yuh is currently interested in the mechanism of ribose-5-phosphate isomerase A (RPIA) in human hepatocellular carcinoma (HCC) and colorectal cancer. She is also studying the overexpression of alpha-mannosidase 1A1, 1A2, and 1B1 as well as down-regulation of alpha-mannosidase 1C1 during hepatocarcinogenesis.

For application, Dr. Yuh’s further develops the drug screening platform to identified novel small molecules which are effective in treatment HCC and lower toxicity compared to Sorafenib. Dr. Yuh’s lab have established high throughput anti-angiogenesis screening using fli1:EGFP transgenic fish. Dr. Yuh also have established xenotransplantation assay, for the anti-proliferation ability and anti-migration ability. We have tested the anti-HCC effects of those candidate drugs using adult transgenic fish with HCC, orbital injection or oral feeding of drugs for their anti-HCC effects. Using liver florescence zebrafish embryos, Dr. Yuh can examine their hepatoxicity, and also examine their embryonic toxicity. Therefore, the data proved that the zebrafish platform was an excellent model for identification of new anti-cancer drugs.

In cancer research, the unanswered questions and grand challenges are complexity of genomes and drug resistance, and long-term drug treatment to control cancer is a major challenge. After a period of targeting therapy, in about 2 to 3 months, eventually drug resistance occurs. From our previous patient-derived xenograft model of colorectal cancer zebrafish personalized drug screening, Dr. Yuh found that the drug inhibition lost along with tumor cell’s passage increases. This result prompted us to investigate the genomic evolution of drug resistance, and test new clinical available target therapies for the resistant tumors.

The toxicity of anti-cancer drugs is the biggest problem for cancer treatment; it may cause lots of side effect. Using liver specific fluorescence transgenic fish embryos, Dr. Yuh found 420S1 and Sorafenib will reduce liver RFP intensity and shrank liver size, however, the fish treated with 419S1 resembled the DMSO control. Therefore, the 419S1 may have less hepatotoxicity. With the integrated efforts and the advantage of zebrafish platform, Dr. Yuh can find more effective and safe drugs for anti-HCC.

In addition to her research, Dr. Yuh has been active in teaching and prompt Systems Biology in Taiwan. Dr. Yuh has been teaching Gene Regulatory Network and Systems Biology in National Tsing-Hua University, National Chiao Tung University, and National China Medical College.

HIGHLIGHTS OF RECENT RESEARCH

Endoderm Gene Regulatory Networks in zebrafish

fig 1 - Yuh

Many studies on the development of the liver in different model organisms have demonstrated that the mechanism of hepatogenesis is conserved in vertebrates. The identification of the genes and regulatory pathways involved in liver formation provides a basis for the diagnosis of liver diseases and therapeutic interventions. Liver derived from endoderm, Dr. Yuh therefore study the Gene Regulatory Networks (GRNs) of endoderm in order to understand the molecular mechanism of liver specific genes’ expression, eventually to derive some medical implications. Dr. Yuh has established the gene regulatory networks for zebrafish embryogenesis, functional dissecting the important subcircuits in the endoderm networks and published five papers.

Identification of the common regulators for hepatocellular carcinoma induced by hepatitis B virus X antigen in a mouse model

fig 2 - Yuh

Hepatitis B virus X antigen plays an important role in the development of human hepatocellular carcinoma (HCC). The key regulators controlling the temporal downstream gene expression for HCC progression remains unknown. Dr. Yuh took advantage of systems biology approach and analyzed the microarray data of the HBx transgenic mouse, identified five common regulator genes: EDN1, BMP7, BMP4, SPIB and SRC. Up-regulation of the common regulators was validated in the other independent HBx transgenic mouse lines. Using the human HCC samples, Dr. Yuh found EDN1, BMP4 and BMP7 were up-regulated in cirrhosis; BMP4, BMP7, and SRC were further up-regulated in hepatocellular or cholangiocellular carcinoma samples. Overexpression of the common regulators increases the cell viability, promotes migration and invasiveness, and enhances the colony formation ability in Hep3B cells. The validation of the gene expressions in the liver cancer of human patients and their cellular function assays suggests that the identified common regulators may serve as useful molecular targets for the early-stage diagnosis or therapy for HCC. The results have been publishing on Carcinogenesis. 2012 Jan; 33(1):209-219

Liver-specific expressions of HBx and src in the p53 mutant trigger hepatocarcinogenesis in zebrafish

fig 3 - Yuh

Hepatocarcinogenesis is a multistep process that starts from fatty liver and transitions to fibrosis and, finally, into cancer. Many etiological factors, including hepatitis B virus X antigen (HBx) and p53 mutations, have been implicated in hepatocarcinogenesis. However, potential synergistic effects between these two factors and the underlying mechanisms by which they promote hepatocarcinogenesis are still unclear. Dr. Yuh show that the synergistic action of HBx and p53 mutation triggers progressive hepatocellular carcinoma (HCC) formation via src activation in zebrafish. Liver-specific expression of HBx in wild-type zebrafish caused steatosis, fibrosis and glycogen accumulation. However, the induction of tumorigenesis by HBx was only observed in p53 mutant fish and occurred in association with the up-regulation and activation of the src tyrosine kinase pathway. Furthermore, the overexpression of src in p53 mutant zebrafish also caused hyperplasia, HCC, and sarcomatoid HCC, which were accompanied by increased levels of the signaling proteins p-erk, p-akt, myc, jnk1 and vegf. Increased expression levels of lipogenic factors and the genes involved in lipid metabolism and glycogen storage were detected during the early stages of hepatocarcinogenesis in the HBx and src transgenic zebrafish. The up-regulation of genes involved in cell cycle regulation, tumor progression and other molecular hallmarks of human liver cancer were found at later stages in both HBx and src transgenic, p53 mutant zebrafish. Dr. Yuh’s study demonstrates that HBx and src overexpression induced hepatocarcinogenesis in p53 mutant zebrafish. This phenomenon mimics human HCC formation and provides potential in vivo platforms for drug screening for therapies for human liver cancer. The results have been publishing on PLoS One 2013 Oct 9; 8(10):e76951.

HONORS & AWARDS

2018      Liver Disease Prevention Research Foundation Fellowship
2015      Liver Disease Prevention Research Foundation Fellowship
2014      Liver Disease Prevention Research Foundation Fellowship
2012      Liver Disease Prevention Research Foundation Fellowship
1995      Biology Divisional Fellowship, California Institute of Technology
1994      Gordon Ross Fellowship, California Institute of Technology
1993      Procter and Gamble Fellowship, California Institute of Technology
1991      First prize scholarship from Wang Ming-Ning Memorial Foundation, Taiwan
1984-1987      Ranked-First Scholarship Award, Fu-Jen Catholic University, Taiwan

SELECTED PUBLICATIONS

  1. Wu SY , Yang WY, Cheng CC, Hsiao MC, Tsai SL, Lin HK, Lin KH, Yuh CH*, Low Molecular Weight Fucoidan Prevents Radiation-Induced Fibrosis and Secondary Tumors in A Zebrafish Model, Cancers, 2020 June 16. 1608
  2. Sie ZL, Li RY, Sampurna BP, Hsu PJ, Liu SC, Wang HD, Huang CL*Yuh CH*, WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis, Cancers, 2020 Mar 2;12(3).
  3. Yang WY, Rao PS, Luo YC, Lin HK,  Huang SH, Yang JM*, Yuh CH*, Omics-based Investigation of Diet-induced Obesity Synergized with HBx, Src, and p53 Mutation Accelerating Hepatocarcinogenesis in Zebrafish Model, Cancers 2019 Nov., 11(12):1899
  4. Su ZL, Su CW, Huang YL, Yang WY, Sampurna BP, Ouchi T, Lee KL, Wu CS, Wang HD*, Yuh CH*, A novel AURKA mutant-induced early-onset severe hepatocarcinogenesis greater than wild-type via activating different pathways in zebrafish, Cancers (Basel). 2019 July 2;11(7). pii: E927
  5. Lin HS, Huang YL, Wang YS, Hsiao E, Hsu TA, Shiao HY, Jiaang WT, Sampurna BP, Lin KH, Wu MS, Lai GM, Yuh CH*, Identification of Novel Anti-Liver Cancer Small Molecules with Better Therapeutic Index than Sorafenib via Zebrafish Drug Screening Platform. Cancers (Basel). 2019 May 28;11(6). pii: E739
  6. Chou YT,  Chen LY, Tsai SL, Tu HC, Lu JW, Ciou SC, Wang HD*, Yuh CH*, Ribose-5-Phosphate Isomerase A (RPIA) Overexpression Promotes Liver Cancer Development in Transgenic Zebrafish via activation of ERK and β-catenin pathways, Carcinogenesis, 2019 May; 40(3): 461–473.
  7. Liu SC, Hsu T, Chang YS, Chung AK, Jiang SS, OuYang CN, Yuh CH, Hsueh C, Liu YP. Cytoplasmic LIF reprograms invasive mode to enhance NPC dissemination through YAP1-FAK/PXN signaling, Nature Communications, 2018 Nov., 9:5105
  8. Chou YT, Jiang JK, Yang MH, Lu JW, Lin HK, Wang HD*, Yuh CH*, Identification of a non-canonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain, PLoS Biology, 2018 Jan 16;16(1):e2003714
  9. Wu SY, Chou HY, Yuh CH, Mekuria SL, Kao YC, Tsai HC, Radiation-Sensitive Dendrimer-Based Drug Delivery System. Advanced Science, 2017 Oct, 1700339
  10. Tu HC, Hsiao YC, Yang WY, Tsai SL, Lin HK, Liao CY, Lu JW, Chou YT, Wang HD*, Yuh CH*, Up-Regulation of Golgi α-Mannosidase IA and Down-Regulation of Golgi α-Mannosidase IC Activates Unfolded Protein Response During Hepatocarcinogenesis, Hepatology Communications, 2017 Apr 19;1(3):230-247.

PATENT

  1. EARLY BIOMARKER FOR HEPATOCELLULAR CARCINOMA (早期階段檢測肝癌及預測肝癌轉移之方法), Taiwan Patent Number: I440855, 2014/06/11~2031/07/26 (granted), Horng-Dar Wang, Chiou-Hwa Yuh, Yung-Chun Hsiao, Yu-Ting Chou
  2. Method for inducing cancer cell apoptosis or inhibiting the cancer cell migration , United States Patent Application number 13/195,143, 2014/5/3 (granted), Horng-Dar Wang, Chiou-Hwa Yuh, Yu-Ting Chou, Shih-Ci Chou
  3. EARLY BIOMARKER FOR HEPATOCELLULAR CARCINOMA (Split application), United States Patent Application number 14/099,685, 2013/12/6(pending) , Horng-Dar Wang, Chiou-Hwa Yuh, Hsiao-Chen Tu, Yu-Ting Chou
  4. RPIA promote cancer cell apoptosis or inhibit migration (核酮糖五磷酸異構酶A促進癌細胞凋亡或抑制癌細胞轉移的方法), Taiwan Patent Number: I418361, 2013/12/11~2031/04/07 (granted), Horng-Dar Wang, Chiou-Hwa Yuh, Yu-Ting Chou, Shih-Ci Chou
  5. EARLY BIOMARKER FOR HEPATOCELLULAR CARCINOMA, United States Patent Application number 13/220,055, 2013/9/9 (granted), Horng-Dar Wang, Chiou-Hwa Yuh, Yung-Chun Hsiao, Yu-Ting Chou

Lab Members

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