Inhibition of the migration of human oral squamous cell carcinoma by lysyl oxidase pro-peptide

Abstract

PLEASE NOTE: This work is protected by copyright. Downloading is restricted to the BU community: please click Download and log in with a valid BU account to access. If you are the author of this work and would like to make it publicly available, please contact [email protected] (MSD) --Boston University, Henry M. Goldman School of Dental Medicine, 2013 (Department of Periodontology and Oral Biology).Includes bibliographic references: leaves 66-77.Squamous cell carcinoma of the oral cavity (SCC) is the sixth most common cancer worldwide and is associated with high morbidity and mortality [1-3]. Invasion and metastasis are perhaps the most challenging and important aspects of cancer progression, and metastasis is the most prevalent cause of death of patients with oral SCC [4]. Invasion occurs through the degradation of the basement membrane and the interstitial extracellular matrix (ECM) and is followed by migration of tumor cells into the adjacent tissue. Thus, cell migration is considered one of the earliest stages of metastasis; a better understanding of these early interactions between carcinoma, stromal cells and the ECM could lead to enhanced diagnostic and treatment protocols. Lysyl oxidase (LOX) enzyme catalyzes the final enzymatic step required for collagen and elastin cross-linking [5, 6]. LOX is synthesized as a 50 kDa secreted precursor, Pro-LOX, that is processed to the 32 kDa active enzyme (LOX) and to a 18 kDa propeptide (LOX-PP) [6, 7]. Expression of the LOX gene was found to inhibit the transforming activity of the ras oncogene and was hence named the “ras recession gene” (rrg) [8, 9]. Recently, it has been reported that LOX-PP but not LOX enzyme contains tumor suppressor activity [10, 11]. Expression of LOX-PP was found to inhibit growth and migration of breast [12, 13] and prostate cancer cells [14]. Similarly, LOX-PP was found to inhibit the invasive phenotype of lung and pancreatic cancer cells [15]. The MEK/ERK pathway, as well as the integrin signaling pathway, which leads to phosphorylation of the focal adhesion kinase (FAK) [13] have been identified as downstream targets of LOX-PP. [TRUNCATED