Kallikrein gene downregulation in breast cancer

Gm, Yousef; Gm, Yacoub; Me, Polymeris; Popalis, Cynthia; Soosaipillai, Antoninus; Diamandis, Eleftherios P.

doi:10.1038/sj.bjc.6601451

Cited by 87 publications

(68 citation statements)

References 38 publications

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“…KLK8 is no exception, and it has been reported to be differentially expressed in breast, cervical, and ovary cancer tissues compared with their normal tissue counterparts (7,46,47). Our experimental data showed that KLK8 is also expressed in weakly invasive non-hormone-dependent tumor cells, including lung (CL1-0) and bladder (HT1197) cancer cells.…”

Section: Discussionmentioning

confidence: 62%

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

Sher

Chou

et al. 2006

Cancer Research

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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 nonsmall cell lung cancer by suppressing tumor cell invasiveness.

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Section: Discussionmentioning

confidence: 62%

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

Sher

Chou

et al. 2006

Cancer Research

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“…KLK8 is downregulated in breast cancer tissues and cell lines [22]. On the other hand, KLK8, along with several other kallikrein genes, could be primarily up-regulated by 17b-estradiol and, to a lesser degree, by other steroid hormones in hormone receptor-positive breast cancer cell lines MCF-7 and T-47D, suggesting a coordinated kallikrein expression as part of a complex regulatory mechanism that controls the expression of these genes and also their downstream physiological function [23].…”

Section: Discussionmentioning

confidence: 99%

Human Kallikrein 8 Expression in Salivary Gland Tumors

Darling

Tsai

Jackson-Boeters

et al. 2008

Head and Neck Pathol

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The human kallikrein 8 protein (KLK8) is expressed in many normal tissues including esophagus, skin, testis, tonsil, kidney, breast, and salivary gland, and is found in biological fluids including breast milk, amniotic fluid, seminal fluid and serum. It has also been shown to be a biomarker and prognostic factor for breast cancer. The aim of this study was to determine whether KLK8 is expressed in salivary gland tissues and salivary gland tumors (both benign and malignant), in order to compare normal with tumor tissues. Pleomorphic adenomas, adenoid cystic carcinomas, polymorphous low grade adenocarcinomas, acinic cell carcinomas, mucoepidermoid carcinomas, and adenocarcinomas NOS of both minor and major salivary glands were examined. The results of this study indicate that most salivary gland tumors show high levels of expression of KLK8.

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“…In the skin, uncontrolled kallikrein action can lead to desquamation (69), a setting in which PARs may be inappropriately activated. Another situation in which kallikrein-mediated PAR activation may be important is in tumorigenesis, because there is now an extensive literature dealing with changes in both the PARs (7) and the kallikreins in the setting of cancer, including cancers of the ovary, breast, colon, pancreas, and prostate (21,70). These changes in the kallikreins can be correlated with either a favorable or unfavorable prognosis (20,21).…”

Section: Discussionmentioning

confidence: 99%

Proteinase-activated Receptors, Targets for Kallikrein Signaling

Οικονομοπούλου

Hansen

Saifeddine

et al. 2006

Journal of Biological Chemistry

228

206

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Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs).Although thrombin is a recognized physiological activator of PAR 1 and PAR 4 , the endogenous enzymes responsible for activating PAR 2 in settings other than the gastrointestinal system, where trypsin can activate PAR 2 , are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR 1 , PAR 2 , and PAR 4 ; 2) PAR-dependent calcium signaling responses in cells expressing PAR 1 , PAR 2 , and PAR 4 and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR 4 -dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR 1 , PAR 2 , and PAR 4 and to disarm/inhibit PAR 1 . Although hK5 and -6 were also able to activate PAR 2 , they failed to cause PAR 4 -dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR 2 -mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR 1 , PAR 2 , and PAR 4 . Proteinase-activated receptors (PAR 1-4 )3 compose a unique family of four G-protein-coupled cell surface receptors for certain proteinases (1-9). Proteolytic cleavage within the extracellular N terminus reveals a tethered ligand that binds to the extracellular receptor domains to initiate cell signaling (5, 6, 9, 10). Proteinases that activate PARs include coagulation factors, enzymes from inflammatory cells, and proteinases from epithelial cells and neurons. These enzymes, generated and released during injury and inflammation, can cleave and activate PARs on many cell types from a variety of species (humans, rats, and mice) to regulate the critically important processes of hemostasis, inflammation, pain, and tissue repair. Other proteinases that cleave PARs downstream of the N-terminal tethered ligand sequence disable the receptors for further proteolytic activation, thus abrogating PAR signaling. It is of considerable interest to identify the proteinases that activate and/or disable PARs, in view of the emerging role that these receptors can play in diseases such as asthma, arthritis, inflammatory bowel disease, and cancer (5-7).In some systems, the proteinases that activate PARs have been established. For example, in the circulatory system, PAR 1 , PAR 3 , and PAR 4 are recognized physiological targets for thrombin (4), which does not efficiently acti...

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Kallikrein gene downregulation in breast cancer

Cited by 87 publications

References 38 publications

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

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

Human Kallikrein 8 Expression in Salivary Gland Tumors

Proteinase-activated Receptors, Targets for Kallikrein Signaling

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