Data from Human Kallikrein 8 Protease Confers a Favorable Clinical Outcome in Non–Small Cell Lung Cancer by Suppressing Tumor Cell Invasiveness

Abstract

<div>Abstract<p>The human <i>kallikrein 8</i> (<i>KLK8</i>) gene, a member of the human tissue kallikrein gene family, encodes a serine protease. The <i>KLK8</i> protein (hK8) is known to be a favorable prognostic marker in ovarian cancer, but the biological basis of this is not understood. We found that overexpressing the <i>KLK8</i> gene in highly invasive lung cancer cell lines suppresses their invasiveness. This role in invasiveness was further confirmed by the fact that inhibition of endogenous <i>KLK8</i> expression with a specific short hairpin RNA reduced cancer cell invasiveness. <i>In situ</i> degradation and cell adhesion assays showed that proteins produced from <i>KLK8</i> splice variants modify the extracellular microenvironment by cleaving fibronectin. DNA microarray experiments and staining of cells for actin filaments revealed that the degradation of fibronectin by hK8 suppresses integrin signaling and retards cancer cell motility by inhibiting actin polymerization. In addition, studies in a mouse model coupled with the detection of circulating tumor cells by quantitative PCR for the human <i>Alu</i> sequence showed that <i>KLK8</i> suppresses tumor growth and invasion <i>in vivo</i>. Finally, studies of clinical specimens from patients with non–small cell lung cancer showed that the time to postoperative recurrence was longer for early-stage patients (stages I and II) with high <i>KLK8</i> expression (mean, 49.9 months) than for patients with low <i>KLK8</i> expression (mean, 22.9 months). Collectively, these findings show that <i>KLK8</i> expression confers a favorable clinical outcome in non–small cell lung cancer by suppressing tumor cell invasiveness. (Cancer Res 2006; 66(24): 11763-70)</p></div>