Faculty Profile, National Health Research Institutes, Taiwan

Faculty Profiles


Ching-Tai Lin, Ph.D.

Assistant Investigator
National Institute of Cancer Research
linct@nhri.org.tw

EDUCATION

- Ph.D., Biochemistry, Mount Sinai Medical Center, New York, USA (1994)
- MBA, Acounting, Taiwan University, Taipei, Taiwan (2003)
- B.S., Chemistry, Tunghai University, Taichung, Taiwan (1984)

PROFESSIONAL EXPERIENCES

- Assistant Investigator, Institute of Cancer Research, National Health Research Institutes, Taipei, Taiwan (2001 - present)
- Research Associate, Division of Cancer Research, National Health Research Institutes, Taipei, Taiwan (1999-2001)
- Postdoctoral Fellow & Research Associate III, Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA (1994-1999)

RESEARCH INTERESTS

Analysis of molecular markers has become increasingly important in predicting chemosensitivity and targeted agents of cancer therapy. One of the most interesting examples has come from recent studies of the DNA mismatch repair (MMR) deficiency mediated drug resistance. MMR deficiency, which underlies hereditary non-polyposis colorectal cancer (HNPCC), has recently been linked to a number of sporadic human cancers as well. Deficiency in MMR renders cancer cells resistant to many clinically active chemotherapy agents, including cisplatin, adriamycin, and etoposide. Although the sample sizes are too small to get the final conclusion, investigation of MMR protein expression in tumors has revealed an inverse correlation with survival in breast and ovarian cancer and the poor response of patients with malignant glioma to temozolomide. Microsatellite instability (MSI) has been observed in various cancers, and reduced or lost expression of MMR protein(s) was also reported in those cancer cell lines. Thus far, no treatments have been reported to target MMR-deficient cells clinically. The long-term goal of research is to understand the molecular mechanisms underlying chemo-resistance of MMR deficiency toward various anti-cancer agents and to resolve the drug resistance problem. More specifically, the current research is aimed at whether MMR deficiency plays a major role in drug resistance of cancer chemotherapy and looking for the better treatment against MMR-deficient cancer cells specifically.

RESEARCH ACTIVITIES & ACCOMPLISHMENTS

Gene amplification has been demonstrated to occur during tumorigenesis, malignancy of cancer and emergence of drug resistance in eukaryotic cells. However, the molecular mechanism(s) underlying the process of gene amplification is still unclear. Analysis of the amplified genes has revealed the presence of giant inverted repeats in the forms of either circular inverted dimers (e.g. double-minute chromosomes in mammalian cells and H-circles in drug resistant Leishmania) or head-to-head linear arrays (e.g. homogeneous staining regions). Our studies have suggested that small inverted repeats may be the key genetic element in mediating the formation of giant inverted repeats. In addition, gene amplification in mammalian cells is strongly inhibited by the mismatch repair system suggesting the involvement of "homeologous" recombination between imperfect inverted repeats in gene amplification. It is the first report that shows DNA mismatch repair (MMR) system can suppress gene amplification. To further study the molecular mechanisms that MMR deficiency can lead to tumoregenesis and drug resistance, we used oncogenic action induced by phorbol ester. Although phorbol ester was known to activate protein kinase C (PKC) and exert numerous cellular effects including proliferation, apoptosis, and oncogenic transformation, how phorbol ester stimulates both apoptosis and tumor promotion is not clear. Here,induction of reactive oxygen species (ROS) by TPA is shown to be one of downstream effectors required but not sufficient. Strikingly, MMR-deficient cells are resistant to TPA-induced cell killing. Results suggest that deficiency in MMR could promote tumorigenesis by inhibiting apoptotic responses to ROS-mediated DNA damages as ROS are continuously produced as a byproduct of normal metabolism.

SELECTED PUBLICATIONS


  1. Lin, C.-T.*, Lin, W.-H., Lee, K.-D., Tzeng, P.-Y. DNA Mismatch Repair as an Effector for Promoting Phorbol Ester-induced Apoptotic DNA Damage and Cell Killing: Implications in Tumor Promotion. International Journal of Cancer, 2006 (in press).
  2. Chen, M.-F., Lin, C.-T., Chen, W.-C., Yang, C.-T., Chen, C.-C., Liao, S.-K., Liu, M.J., Lu, C.-H., Lee, K.-D.* (2006) The sensitivity of human mesenchymal stem cells to ionizing radiation. International Journal of Radiation Oncology, Biology, Physics, 2006 (in press).
  3. Lee, K-D., Kuo, K-C., Whang-Peng, J.*, Chung, Y-F, Lin, C-T., Chou, S-H., Chen, J-R., Chen, Y-P, Lee, and K-S.* In Vitro Hepatic Differentiation of Human Mesenchymal Stem Cells. Hepatology, 40, 1275-1284, 2004.
  4. Lin, C.-T., Lin, W.-H., Lyu, Y. L, and Whang-Peng, J. Inverted repeats as genetic elements for promoting DNA inverted duplication: implications in gene amplification. Nucleic Acids Res., 29, 3529-3538, 2001.
  5. Lin, C.-T., Lyu, Y. L., Xiao, H., Lin, W.-H., and Whang-Peng, J. Suppression of gene amplification and chromosomal DNA integration by the DNA mismatch repair system. Nucleic Acids Res., 29, 3304-3310, 2001.