Human kallikrein 8 protease confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.
The human kallikrein 8 (KLK8) gene, a member of the human tissue kallikrein gene family, encodes a serine protease. The KLK8 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 KLK8 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 KLK8 expression with a specific short hairpin RNA reduced cancer cell invasiveness. In situ degradation and cell adhesion assays showed that proteins produced from KLK8 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 Alu sequence showed that KLK8 suppresses tumor growth and invasion in vivo. 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 KLK8 expression (mean, 49.9 months) than for patients with low KLK8 expression (mean, 22.9 months). Collectively, these findings show that KLK8 expression confers a favorable clinical outcome in non-small cell lung cancer by suppressing tumor cell invasiveness.
Sher
Yuh-Pyng
YP
Institute of Biomedical Sciences and Statistical Science, Academia Sinica, Taipei, Taiwan.
Chou
Cheng-Chung
CC
Chou
Ruey-Hwang
RH
Wu
Han-Ming
HM
Wayne Chang
Wun-Shaing
WS
Chen
Chun-Houh
CH
Yang
Pan-Chyr
PC
Wu
Cheng-Wen
CW
Yu
Chia-Li
CL
Peck
Konan
K
D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology*; D002448:Cell Adhesion; D017931:DNA Primers; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000235:genetics* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D017931:DNA Primers; D005353:Fibronectins; C094799:KLK8 protein, human; D007610:Kallikreins