Role of TMPRSS2 in the progression of prostate cancer cells

• Main Authors: Cheng-Chung Huang, 黃正忠
• Other Authors: 李明學
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/68768438964142790106

碩士 === 國立臺灣大學 === 生物化學暨分子生物學研究所 === 98 === Prostate cancer is one of the most common cancers among men in the western countries. In Taiwan, the incidence of prostate cancer has been rising to the seventh leading cause of cancer-related death, partly due to westernized life style and diets. Human prostate cancer usually undergoes several alterations to progress to advanced stages with androgen-independence and/or high metastasis. The molecular mechanisms for the progression are still not well understood. Recently, it has been proposed that deregulation of cell surface proteolysis is strongly involved in cancer cell invasion and metastasis. In this study, we are interested in addressing the role of an androgen-regulated, membrane-anchored serine protease TMPRSS2 in the progression of prostate cancer cells, since a decreased expression of TMPRSS2 was shown in advanced prostate cancer. To explore the role of TMPRSS2 in prostate cancer, a monoclonal antibody (AL-20) against the protease was successfully generated by constructing the cDNA fragment encoding the extracellular region of TMPRSS2 inserted into a mammalian secretory vector with a His tag and purifying the fusion proteins as an antigen. With three androgen-independent prostate cancer cells (DU145, PC-3 and LNCaP C-81 cells) and an androgen-sensitive LNCaP C-33 cell, our data showed that the protein levels of TMPRSS2 were decreased in those cells with androgen-independence and highly invasive potentials. Moreover, a reduction of TMPRSS2 expression by shRNA approaches increased prostate cancer cell proliferation, but decreased the expression of androgen receptor (AR) and prostate-specific antigen (PSA). Furthermore, our data showed that TMPRSS2 was important for Dihydrotestosterone (DHT) -induced matriptase activation, PSA production and prostate cancer cell growth. On the other hand, down regulation of TMPRSS2 during the progression of prostate cancer cells decreased matriptase activation and increased the protein level of EGFR, leading to enhancement of EGF sensitivity for growth stimulation. Taken together, this study indicates that a decrease/loss of TMPRSS2 expression may play a role in the progression of prostate cancer cells, at least in part via increasing cell growth and EGF sensitivity. Key words: TMPRSS2; prostate cancer; androgen receptor; EGFR; matriptase; prostasin.