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Human Kallikrein (human + kallikrein)
Selected AbstractsAssociation of kallikrein expression in nipple aspirate fluid with breast cancer riskINTERNATIONAL JOURNAL OF CANCER, Issue 4 2004Edward R. Sauter Abstract Human kallikreins (hK) 2, 3, 6 and 10 are expressed in breast and prostate tissue. hK2 and hK3 (prostate-specific antigen, PSA) are used to screen for prostate cancer. hK6 and hK10 are downregulated in breast cancer compared to normal breast tissue. We demonstrated that levels of PSA in nipple aspirate fluid (NAF) are lower in women with breast cancer than in normal women. We hypothesize that the expression of hK2, 3, 6 and 10 are related and important in detecting breast cancer. The goals of this study are to determine the level of expression of kallikreins in NAF and serum, the association of hK2, 3, 6 and 10 in NAF, and the association of each of the kallikreins with breast cancer. In NAF from 275 women, hK3, 6 and 10 were detectable in , 90% and hK2 in 74% of samples analyzed. NAF levels were highest for hK6 and lowest for hK2, regardless of cancer and menopausal status. hK3 was detectable in 15/29 (52%) and hK2 in 0/29 serum samples collected from 6 women. hK2 and hK3 were concentrated in NAF vs. matched serum. The 4 kallikreins were associated with the exception of hK2 with hK6 or hK10. PSA levels were higher in normal pre- than postmenopausal subjects (but not women with breast cancer), whereas levels of hK2, 6 and 10 did not differ by menopausal status. hK2 and PSA were associated with both pre- and postmenopausal breast cancer; hK6 and 10 were not. hK2 and PSA were more associated with pre- than postmenopausal breast cancer. Using logistic regression, PSA and menopausal status provided the best model of breast cancer prediction, with a sensitivity of 91% and specificity of 39%. In conclusion, 4 kallikreins are expressed in NAF. hK2 and PSA, and hK6 and hK10 are highly associated. Higher premenopausal PSA levels suggest the influence of ovarian steroids. PSA shows the most promise in aiding in the early detection of breast cancer. © 2003 Wiley-Liss, Inc. [source] An experimental strategy for quantitative analysis of the humoral immune response to prostate cancer antigens using natural protein microarraysPROTEOMICS - CLINICAL APPLICATIONS, Issue 5 2007Sara Forrester Abstract The identification of human tumor antigens has potential utility in the diagnosis and treatment of cancers. We demonstrate here a complete strategy to profile immunoreactivity and identify tumor antigens from proteins derived from tumor cell lines. Microarrays of proteins produced from 2-D LC fractionation of prostate tumor cell-line lysates were used to profile immunoreactivity in the sera of prostate cancer patients and control subjects. Cancer-associated immunoreactivity to distinct groups of chromatography fractions was present in about 50% of the patients, with greater immunoreactivity present in patients with non-organ-confined cancer than in patients with organ-confined cancer. We grouped the immunoreactive fractions by similarities in elution order and patterns of immunoreactivity to guide and interpret the MS analysis of selected fractions, which was used to identify the proteins that may be responsible for the immunoreactivity. As a complementary method to further characterize and validate the immunoreactivity of the proteins identified by mass spectrometry, we demonstrate the use of focused microarrays of recombinant proteins. Disease-associated immunoreactivity was confirmed for one of the identified proteins, human Kallikrein 11. These results demonstrate a practical approach to screening, identifying, and validating immunoreactive proteins that could be applied to diverse studies on humoral immune responses. [source] Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidasesFEBS JOURNAL, Issue 5 2008Shoichiro Mukai Hepatocyte growth factor activator (HGFA) is a serine protease and a potent activator of prohepatocyte growth factor/scatter factor (pro-HGF/SF), a multifunctional growth factor that is critically involved in tissue morphogenesis, regeneration, and tumor progression. HGFA circulates as a zymogen (pro-HGFA) and is activated in response to tissue injury. Although thrombin is considered to be an activator of pro-HGFA, alternative pro-HGFA activation pathways in tumor microenvironments remain to be identified. In this study, we examined the effects of kallikrein 1-related peptidases (KLKs), a family of extracellular serine proteases, on the activation of pro-HGFA. Among the KLKs examined (KLK2, KLK3, KLK4 and KLK5), we identified KLK4 and KLK5 as novel activators of pro-HGFA. Using N-terminal sequencing, the cleavage site was identified as the normal processing site, Arg407,Ile408. The activation of pro-HGFA by KLK5 required a negatively charged substance such as dextran sulfate, whereas KLK4 could process pro-HGFA without dextran sulfate. KLK5 showed more efficient pro-HGFA processing than KLK4, and was expressed in 50% (13/25) of the tumor cell lines examined. HGFA processed by these KLKs efficiently activated pro-HGF/SF, and led to cellular scattering and invasion in vitro. The activities of both KLK4 and KLK5 were strongly inhibited by HGFA inhibitor type 1, an integral membrane Kunitz-type serine protease inhibitor that inhibits HGFA and other pro-HGF/SF-activating proteases. These data suggest that KLK4 and KLK5 mediate HGFA-induced activation of pro-HGF/SF within tumor tissue, which may thereafter trigger a series of events leading to tumor progression via the MET receptor. [source] Development of recombinant inhibitors specific to human kallikrein 2 using phage-display selected substratesFEBS JOURNAL, Issue 3 2004Sylvain M. Cloutier The reactive site loop of serpins undoubtedly defines in part their ability to inhibit a particular enzyme. Exchanges in the reactive loop of serpins might reassign the targets and modify the serpin,protease interaction kinetics. Based on this concept, we have developed a procedure to change the specificity of known serpins. First, reactive loops are very good substrates for the target enzymes. Therefore, we have used the phage-display technology to select from a pentapeptide phage library the best substrates for the human prostate kallikrein hK2 [Cloutier, S.M., Chagas, J.R., Mach, J.P., Gygi, C.M., Leisinger, H.J. & Deperthes, D. (2002) Eur. J. Biochem. 269, 2747,2754]. Selected substrates were then transplanted into the reactive site loop of ,1-antichymotrypsin to generate new variants of this serpin, able to inhibit the serine protease. Thus, we have developed some highly specific ,1-antichymotrypsin variants toward human kallikrein 2 which also show high reactivity. These inhibitors might be useful to help elucidate the importance of hK2 in prostate cancer progression. [source] Evaluation of molecular forms of prostate-specific antigen and human kallikrein 2 in predicting biochemical failure after radical prostatectomyINTERNATIONAL JOURNAL OF CANCER, Issue 3 2009Sven Wenske Abstract Most pretreatment risk-assessment models to predict biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer rely on total prostate-specific antigen (PSA), clinical stage, and biopsy Gleason grade. We investigated whether free PSA (fPSA) and human glandular kallikrein-2 (hK2) would enhance the predictive accuracy of this standard model. Preoperative serum samples and complete clinical data were available for 1,356 patients who underwent RP for localized prostate cancer from 1993 to 2005. A case-control design was used, and conditional logistic regression models were used to evaluate the association between preoperative predictors and BCR after RP. We constructed multivariable models with fPSA and hK2 as additional preoperative predictors to the base model. Predictive accuracy was assessed with the area under the ROC curve (AUC). There were 146 BCR cases; the median follow up for patients without BCR was 3.2 years. Overall, 436 controls were matched to 146 BCR cases. The AUC of the base model was 0.786 in the entire cohort; adding fPSA and hK2 to this model enhanced the AUC to 0.798 (p = 0.053), an effect largely driven by fPSA. In the subgroup of men with total PSA ,10 ng/ml (48% of cases), adding fPSA and hK2 enhanced the AUC of the base model to a similar degree (from 0.720 to 0.726, p = 0.2). fPSA is routinely measured during prostate cancer detection. We suggest that the role of fPSA in aiding preoperative prediction should be investigated in further cohorts. © 2008 Wiley-Liss, Inc. [source] Relative concentrations of hK2/PSA mRNA in benign and malignant prostatic tissueTHE PROSTATE, Issue 4 2005Susanna Lintula Abstract BACKGROUND Prostate-specific antigen (PSA/KLK3) and human kallikrein 2 (hK2/KLK2) belong to the human kallikrein gene family. These two highly homologous genes are specifically expressed in the prostate under androgen control. Expression of these is regulated by similar mechanisms but changes in their relative expression have been observed in prostate cancer. METHODS We determined the relative levels of PSA and hK2 mRNA in benign and malignant prostate tissue using a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. The mRNA of PSA and hK2 are reverse transcribed and amplified in one reaction with the same primers. RESULTS The variation in the ratio of hK2/PSA mRNA was remarkably small, the difference between the highest and lowest values being three-fold. The ratio was significantly higher in WHO grade 2 compared to normal or benign prostatic hyperplasia tissue (P,=,0.032 and P,=,0.035, respectively) and in grade 3 compared to normal or benign prostatic hyperplasia tissue (P,=,0.006 in both). CONCLUSIONS The new quantitative RT-PCR technique facilitates very accurate quantitation of the relative mRNA levels of homologous genes. Using this method we have shown that the ratio of hK2/PSA mRNA is higher in cancerous than in benign prostatic tissue. © 2004 Wiley-Liss, Inc. [source] Expression of prostate-specific antigen and androgen receptor in extramammary Paget's disease and carcinomaCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 1 2007N. Inoguchi Summary Prostate-specific antigen (PSA) is a kallikrein-like serine proteinase (human kallikrein 3) produced by epithelial cells of both benign and malignant prostate tissue. In this study, PSA expression was histologically examined in tissue specimens from 34 patients with extramammary Paget's disease (EPD; 31 cases) and extramammary Paget's carcinoma (EPC; three cases), but no associated prostate carcinoma. Tumour cells positive for PSA were found in 17 of the 34 cases. Based on this finding, we examined serum PSA level in the three EPC cases. A high level of serum PSA was observed in one case of EPC, which was correlated with disease progression. Because some reports suggest that 50,80% cases of EPD/EPC express androgen receptor (AR), we also examined expression of AR. Immunohistological staining showed correlation of PSA and AR in expression. These results suggest that PSA and the androgen signalling pathway may be involved in the pathogenesis of EPD. [source] | ||||||||||