Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells

Abstract

The human tissue kallikrein family of serine proteases (hK1-hK15 encoded by the genes KLK1-KLK15) is involved in several cancer-related processes. Accumulating evidence suggests that certain tissue kallikreins are part of an enzymatic cascade pathway that is activated in ovarian cancer and other malignant diseases. In the present study, OV-MZ-6 ovarian cancer cells were stably co-transfected with plasmids expressing hK4, hK5, hK6, and hK7. These cells displayed similar proliferative capacity as the vector-transfected control cells (which do not express any of the four tissue kallikreins), but showed significantly increased invasive behavior in an in vitro Matrigel invasion assay (p<0.01; Mann-Whitney U-test). For in vivo analysis, the cancer cells were inoculated into the peritoneum of nude mice. Simultaneous expression of hK4, hK5, hK6, and hK7 resulted in a remarkable 92% mean increase in tumor burden compared to the vector-control cell line. Five out of 14 mice in the 'tissue kallikrein overexpressing' group displayed a tumor/situs ratio greater than 0.198, while this weight limit was not exceeded at all in the vector control group consisting of 13 mice (p=0.017; chi2 test). Our results strongly support the view that tumor-associated overexpression of tissue kallikreins contributes to ovarian cancer progression.

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…More precisely, the transfection of OV-MZ-6 ovarian cancer cells to stably express KLK4, KLK5, KLK6, and KLK7 resulted in their increased invasiveness in vitro . Additionally, infusion of the transfected ovarian cancer cells increases tumor burden in vivo , highlighting their signifi cance in ovarian cancer progression (Prezas et al , 2006 ). This effect could partially be explained by the ability of KLK5 (Michael et al , 2005 ), KLK6 (Bernett et al , 2002 ;Magklara et al , 2003 ), and KLK7 to degrade ECM proteins, whereas KLK4 promotes this degradation indirectly by the activation of the uPA-uPAR-MMPs axis (Takayama et al , 2001 ).…”

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

“…Assessment of KLK protein dysregulation in ovarian cancer was compiled from the results of 17 studies (Dong et al, 2001;Luo et al, 2001Luo et al, , 2003Tanimoto et al, 2001;Hoffman et al, 2002;Yousef et al, , 2003bBorgono et al, 2003;Diamandis et al, 2003;Ni et al, 2004;Scorilas et al, 2004;Xi et al, 2004;Prezas et al, 2006;Shan et al, 2007;Bayani et al, 2008;Shaw and Diamandis, 2008). Chromosomal aberration in ovarian cancer was extracted from the Progenetix comparative genomic hybridisation database available as of January 2009 (Baudis and Cleary, 2001).…”

“…At least seven kallikrein proteins are up-regulated in ovarian cancer compared with normal ovarian tissues (Yousef et al, 2003b). The prognostic value of at least 11 out of 15 members of the human kallikrein family in ovarian cancer has been also published (Clements et al, 2004;Yousef et al, 2005;Prezas et al, 2006;Dorn et al, 2007). Six kallikreins, KLK4, KLK5, KLK6, KLK7, KLK10, and KLK15 (Kim et al, 2001;Kyriakopoulou et al, 2003;Shvartsman et al, 2003;Yousef et al, 2003c;Kountourakis et al, 2008), are markers of poor prognosis in ovarian cancer.…”

Kallikrein 6 is a mediator of K-RAS-dependent migration of colon carcinoma cells

“…Substrates for KLK6 include collagen I and IV, fibrinogen, fibronectin and laminin Blaber et al, 2002;Borgono and Diamandis, 2004). Prezas et al (2006) demonstrated that ovarian cells stably transfected to express KLK4, 5, 6 and 7 were significantly more invasive in vitro and formed larger tumors in mice. KLK6 overexpression has also recently be shown to increase skin cell migration and invasion (Klucky et al, 2007).…”