Proteolytic processing of laminin-332 by hepsin and matriptase and its role in prostate cancer progression

Abstract

Prostate cancer is the second most common form of cancer in men. Despite the alarming figures and decades of research, a cure still eludes prostate cancer patients. The morbidity associated with advanced prostate cancer is due to the metastasis of the primary tumor primarily to the bone. Hepsin is a gene that is over-expressed in more than 90% of human prostate cancer patients and thus assumes tremendous relevance in prostate cancer as a therapeutic target in the future. Similarly, matriptase is another gene that is over-expressed in prostate cancer patients. The expression of both genes positively correlates with the aggressiveness of human prostate tumors. Though both genes are known to be over-expressed in human prostate cancer, their mechanism of action is still unknown. Both hepsin and matriptase are within a category of genes known as proteases that have the potential ability to cleave or digest the matrix or nests (called basement membrane) that surrounds the tumor cells in a primary tumor and inhibits cells from escaping and eventually metastasizing. Tumor cells escape the primary tumor by interacting and digesting the basement membrane and travel through the blood stream to reach the bone environment. This study reveals the interaction between extracellular membrane component Ln-332, which is lost in prostate cancer and two type II transmembrane serine proteases, hepsin and matriptase that are consistently over-expressed in human prostate cancer cases. We have found in our study that hepsin and matriptase individually cleave or digest Laminin-332 and that this cleavage facilitates movement of human prostate cells in tissue culture. We found that in the tumor tissues of the prostate of hepsin overexpressing mice there is degradation of Ln-332. Furthermore, hepsin or matriptase overexpressing LNCaP prostate cancer cells also exhibited increased migration on Ln-332. Also, matriptase over-expression causes increased persistence of LNCap cells on Laminin-332. This cleavage of Ln-332 by hepsin and/or matriptase may play the critical mechanistic role for the spread of human prostate cancer thus assumes tremendous relevance in the field of prostate cancer research in finding a future therapeutic target.