Laboratory 

ext 5592
 
Curriculum Vitae
 
Publications
 

Other

 

Nan-Shan Chang, Ph.D

E-mail:changns@mail.ncku.edu.tw

TEL:06-2353535 ext 5268

FAX:06-2095845

 

Educations / Professional Experience

 

Educations

1974/9-1978/6

National Taiwan Normal Univ. Taipei, Taiwan,B.Sc., Biology

 

1980/8-1984/12

Medical Univ. of S. Carolina Charleston, S. Carolina, Ph.D., Immunology

   

 

Current Position

2010/08~

Director, Institute of Molecular Medicine, College of Medicine, National Cheng Kung University

 

2006/09~

Distinguished Professor,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University

 

1991/01~

Consultant, GlycoMed Research Incorporated, Hastings on Hudson, NY

 

1989/09~

Adjunct Associate Professor, Medical University of South Carolina, College of Dental Medicine

 
 
Professional Experience 1995/7-2005/12 Associate Scientist and Laboratory Director, Guthrie Research Institute, Laboratory of Molecular Immunology & Protein/Peptide Microsequencing Core Facility
  1989/7-1995/6 Assistant Scientist and Laboratory Director, Guthrie Research Institute, Laboratory of Molecular Immunology & Protein/Peptide Microsequencing Core Facility
  1996/3-2006/8 Adjunct Research Associate Professor, Upstate Medical University at Syracuse, Department of Immunology and Microbiology & Integrated Medicine
  1987/1-1989/6 Instructor, University of Massachusetts Medical Center, Department of Biochemistry
  1985/1-1986/12 Post Doctoral Fellow, The Samuel Roberts Noble Foundation, Immunology Section
  1982 Teaching Assistant of Dental Microbiology for one semester, Medical Univ. of South Carolina, Dept. of Basic & Clinical Immunology & Microbiology
  1978/7-1980/7 Teaching Assistant, National Taiwan Normal Univ., Department of Biology
  1977 winter Research Assistant, Tungkang Marine Laboratory, Tungkang, Taiwan

 

Expertise /Research Interests

 

Signal transductionApoptosis Signaling

   

 

My research group has been interested in elucidating the functional interactions between cancer cells and the innate immune system. How cancer cells evade immune attack and prevent death-inducing factors-initiated apoptosis has been our focus of research. To understand how cancer cells develop resistance to tumor necrosis factor (TNF), we have utilized functional cloning and microarray approaches to isolate genes, which may regulate cancer cell sensitivity to toxic cytokines. We have recently discovered a tumor suppressor WOX1 (also named WWOX or FOR), which enhances TNF function and is apparently involved in embryonic cell differentiation and cancer pathogenesis.

A. Our discovery of a candidate tumor suppressor WOX1 (WWOX/FOR) – Hyaluronan, hyaluronan synthases and hyaluronidases are associated with embryonic development and invasive progression of prostate and breast cancers. In year 2000, we and two other groups independently discovered a hyaluronidase-induced candidate tumor suppressor, named WW domain-containing oxidoreductase (WOX1/WWOX/FOR) (1). WOX1 enhances TNF cytotoxic function (1). Human WWOX gene, encoding WWOX/WOX1, is mapped to a fragile site on chromosome ch16q23.3-24.1. Approximately 30-50% of loss of heterozygosity (LOH) of WWOX gene has been found in breast, prostate and several types of cancers. WOX1 possesses a nuclear localization sequence (NLS), two N-terminal WW domains (containing conserved tryptophan residues) and a C-terminal short-chain alcohol dehydrogenase/reductase (ADH/SDR) domain (Fig. 1). We were the first laboratory to define the functional role of WOX1 in vitro (1,2). We show that WOX1 possesses dual functional roles in either inducing apoptosis or promoting cell survival and differentiation. Under genotoxic or apoptotic stress, WOX1 undergoes phosphorylation at tyrosine 33 (Tyr33) and translocation to the mitochondria and nuclei, and induces apoptosis in vitro and in vivo (Fig. 1). This phosphorylated WOX1 binds to p53, and both proteins induce apoptosis synergistically (1-8). In in vivo experiments, we have shown that Tyr33-phosphorylated WOX1 translocates to the mitochondria and nuclei during light-induced degeneration of photoreceptors in rat eyes, as determined by light and electron microscopy (5). Ectopic WOX1 suppresses growth of breast, lung and skin tumors in nude mice.

B. WOX1 is involved in embryonic differentiation and cancer progression to a pre-metastatic state – In contrast, under physiologic conditions, activated WOX1 supports cell survival. Significant up-regulation of phosphorylated-WOX1 and WOX2 is observed during the progression of prostate and breast cancers to a pre-metastatic state (3). We have recently shown that benign brain tumors, such as meningiomas, astrocytomas, glioblastomas and others have upregulated WOX1 expression (unpublished). These phosphorylated proteins are located mainly in the mitochondria. Similarly, a dramatically increased expression of WOX1, WOX2 and their Tyr33 phosphorylation occurs in proliferating normal human epidermal cells and in acute UVB-induced skin hyperplasia in hairless mice (6). Also, phosphorylated WOX1 and WOX2 are greatly upregulated in mitotic cells, up from prophase, metaphase to anaphase and down at telophase. Functional role of this regard is unknown and remains to be established. We believe that under physiologic conditions, WOX1 could promote cell cycle progression or act as a checkpoint protein during mitosis. Nonetheless, under stress conditions, WOX1 translocates to the nuclei to induce cell death.

Disappearance of WOX1 family proteins and their phosphorylated forms is observed in invasive or metastatic prostate, breast, and skin cancers (3,6). Suppression of WOX1 by siRNA dramatically enhances skin cancer cell growth and metastasis. We determined that downregulation of WOX1 and family proteins is shown in patients with cutaneous squamous cell carcinomas (SCCs), and the disappearance of WOX1 protein in SCCs is due, in part, to a translational blockade of WWOX mRNA to protein (6). We believe that cancer cells turn off WOX1 expression by a post-translational mechanism, so that they can avoid the apoptotic pressure from the overexpressed WOX1 and continue to proliferate.


Fig. 1. WOX1 and its splice variants. The predicted amino acid sequence (414 amino acids) of WOX1 (WWOXv1, or FOR2) possesses two N-terminal WW domains, a nuclear localization signal sequence (NLS), and a C-terminal short-chain alcohol dehydrogenase (ADH) domain. A mitochondria-targeting sequence in WOX1 was mapped within the ADH domain (amino acid #209-273) (1). There are at least 8 isoforms. Isoform WOX2 (WWOXv2; 41 kDa) is depicted. The C-terminal amino acid sequence of WOX2 is different from that of WOX1 (in red). A simulated structure of the first WW domain is shown. 1= 1st tryptophan; 2= Try33 phosphorylation site; 3= 2nd tryptophan. (These residues marked in yellow)

C. Short-term and future goals: transgenic and stem cells – We strongly believe the functional importance of WOX1 in biological processes in both normal and cancerous development (1-8). Our future research will direct toward molecular genetics, cancer stem cells, protein functions and gene therapy, with particular focus on WOX1 regulation of development of breast cancer stem cells and design of activated WOX1 peptides for cancer therapeutics. Our short-term and future goals regarding WOX1 are: 1) Establish WOX1-regulated signaling network leading to identification of breast cancer stem cells, and 2) Generate conditional knockin or knockout murine models for Wwox gene.

 

Honors & Awards

 
2011 Society for Experimental Biology and Medicine(SEBM)- Distinguished Scientist Award

2010

DOD Neurofibrometosis Research Award

2008

DOD Breast Cancer Concvept Award

 
Personal
  When I retire someday, I will write story books for kids, expanding the saga of Captain Hood and cloned monster.org…….Till then, my grandchildren will be my inspirations.