Expression, Regulation, and Inhibition of Matriptase in Human B-cell Neoplasm

Abstract

Matriptase, a type II transmembrane serine protease, possesses potent oncogenic activity when an imbalance to its cognate inhibitor, hepatocyte activator inhibitor-1 (HAI-1), is established in a transgenic mouse model. The oncogenic activity of matriptase is in part attributed to its role in activation of other oncogenic molecules, such as urokinase plasminogen activator (uPA) and hepatocyte growth factor (HGF). These matriptase substrates play important roles in extracellular matrix-degrading, cellular motility, cell growth, and angiogenesis. All of these biological events are important for the development and progression of human cancers. While most of matriptase studies have been focused on epithelial and carcinoma cells in which HAI-1 plays a pivotal role in regulation and inhibition of matriptase, growing evidence showed that matriptase may be also important in blood malignancies. In this dissertation, I examined matriptase and HAI-1 expression in human blood tumor specimens and a variety of hematological cell lines. Significant imbalanced expression of matriptase to HAI-1 was determined in aggressive type B-cell malignancies in vitro and in vivo. In contrast, the protease was not detected in several indolent B-cell lymphomas and hyperactive B-cells residing in lymph nodes. The absence of HAI-1 expression in aggressive B-cell cancers has impact to the current dogma of matriptase-HAI-1 pairing in epithelial cells. Additionally, I discovered hypoxia initiated matriptase zymogen activation in blood tumors, producing inhibitor free, enzymatic matriptase to shed into extracellular milieu. Increased reactive oxygen species (ROSs) may be attributed to hypoxia-induced matriptase activation while the zymogen activation can be reduced by pre-treating cells with ROSs scavengers. To further define the roles of matriptase in the development and progression of B-cell tumors, stable matriptase knockdown populations were created in lymphoma and myeloma lines, respectively. The matriptase knockdown cells showed to negatively affect cell growth in vitro and colony formation in methylcellulose-based culture. Besides, in mice xenograft model, matriptase-deficient cells grew in significantly slow rate and formed less tumor volume than the control group. In summary, deregulated matriptase play important roles to affect the tumor microenvironment which is favoring the growth and progression of B-cell lymphoma and multiple myeloma.