Lee, Ming-shyue

Biography

1992,B.Sc., Department of Agricultural Chemistry, National Taiwan University, Taipei, Taiwan 1994,M.S., Institute of Biological Chemistry, National Taiwan University, Taipei, Taiwan 2002, Ph.D., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE

Research Interest

Cell surface proteolysis plays an important role in a wide range of cellular activities including the degradation of extracellular matrix, blood coagulation, cell growth, differentiation, adhesion, migration, and apoptosis. Recently, the type II transmembrane serine proteases (TTSP) have received more attentions. It is evidenced that deregulation of the TTSPs contributes to many diseases; particularly implicated in tumor growth, invasion and metastasis. However, the physiological roles of these proteases and how the errant TTSPs malfunction in cancer malignancy are still unclear. Thus, it will be an important goal to understand the physiological functions of this group of proteases for developing therapeutic approaches against cancer and other diseases. Matriptase, a member of the type II transmembrane serine protease family, is expressed in a variety of epithelial-derived human tumors including prostate, breast, colon, stomach, and ovarian carcinomas. Similar to the matriptase expression in normal tissues, matriptase has not been found in the tumors of a stromal fibroblast origin. It has been shown that a tight correlation among matriptase, its substrate hepatocyte growth factor/scatter factor (HGF/SF), and the c-met receptor in a cohort of 330 node-negative breast carcinomas. Importantly, the high expression level of matriptase, c-met receptor, and HAI-1 is associated with poor patient outcome. In ovarian cancer, matriptase protein level is reduced in stages III and IV, compared to Stages I and II. However, the decrease of HAI-1 expression in advanced stage tumors is in a much greater degree than that of matriptase. The results suggest that in spite of decreased expression of matriptase in advanced cancer, an increase of the matriptase-to HAI-1 ratio may contributes to aberrant matriptase activation in cancer malignancy. The role that matriptase may play in tumor growth, cell motility, and progression is attributed to the activation of its known substrates uPA, HGF/SF, and possibly the G-protein-coupled receptor protease activated receptor (PAR-2). Matriptase-activated HGF or PAR-2 could promote tumor cell growth and survival through the c-Met receptor or the G-protein-coupled receptor signal pathway. Furthermore, HGF induces cell mobility and coordinates with the matriptase-activated uPA/plasmin system to facilitate breast cancer cell invasion by degrading ECM. These data indicate that matriptase could play a role in cancer invasion and metastasis via recruitment and activation of a major ECM-degrading protease system and a key cell mobility factor (HGF) at the surface of cancer cells. Steroid hormone androgens are required for the development and maintenance of both the male phenotype and reproductive organs, including the prostate. The normal prostate gland depends on the testicular androgen and functional androgen receptor (AR) to maintain its functional integrity. In the absence of androgen, the prostate epithelia undergo apoptosis, leading to tissue regression. Physiologically, androgens exert their biological functions via AR. Upon ligand stimulation, activated AR enters into the nucleus, binds to its target genes via an androgen-response element (ARE), which is involved in various cellular activities including cell proliferation and development. In the early stage of prostate cancer, androgens are required for the growth of cancer cells. However, in advanced or hormone-refractory prostate cancer, androgen requirements are reduced or eliminated, and androgen-dependent prostate cells retain the androgen-independent phenotype. However, the detailed molecular mechanisms of androgen actions on normal tissues and in the development of the steroid hormone-independent phenotype of human cancer remain largely unknown. In the future, our research focus will be on: (1) To test whether and how steroid hormones can induce matriptase activation (2) To examine if matripase plays a role in the progression of human prostate cancer. (3) To analyze if matriptase is also involved in the other types of cancer malignancy. (4) To delineate the roles of other TTSPs in human cancer development, progression, and metastasis.