Kallikrein-related peptidase-6 (KLK6) mRNA expression is an independent prognostic tissue biomarker of poor disease-free and overall survival in colorectal adenocarcinoma.

Members of the family of tissue kallikrein and kallikrein-related peptidases possess important prognostic value in cancer. Moreover, the oncogenic role of kallikrein-related peptidase-6 (KLK6) in colorectal cancer has been well documented so far. This study investigated the prognostic value of KLK6 mRNA expression as a molecular tissue biomarker in colorectal adenocarcinoma. For this purpose, KLK6 mRNA expression was studied in 110 primary colorectal adenocarcinomas and 39 paired noncancerous colorectal specimens. A dramatic upregulation of KLK6 mRNA expression was observed in colorectal tumors. KLK6 mRNA overexpression was associated with high depth of tumor invasion, presence of distant metastases, and tumor-node-metastasis (TNM) stage of patients. Furthermore, KLK6 mRNA expression was shown to predict poor disease-free and overall survival independently of patient gender, age, tumor size, location, histological subtype, grade, venous invasion, lymphatic invasion, TNM stage, radiotherapy, and chemotherapy treatment. Moreover, Kaplan-Meier survival analysis revealed that colorectal adenocarcinoma patients with negative regional lymph nodes (N0) and those without distant metastases (M0) harboring KLK6 mRNA-positive colorectal tumors tended to relapse and die earlier than N0 and M0 patients with KLK6 mRNA-negative colorectal adenocarcinoma. Thus, KLK6 mRNA expression could be considered as an independent, unfavorable molecular prognostic biomarker in colorectal adenocarcinoma, with additional prognostic value in patients without regional or distant metastases.

Expression analysis and clinical evaluation of kallikrein-related peptidase 10 (KLK10) in colorectal cancer.

Kallikrein-related peptidases (KLKs) represent a serine protease family having 15 members. KLK10 is a secreted protease with a trypsin-like activity. The function of KLK10 is poorly understood, although it has been suggested that KLK10 may function as a tumor suppressor gene. In human cancer, KLK10 gene shows organ-specific up- or down-regulation. Since KLKs are promising tumor biomarkers, the examination of KLK10 mRNA expression and its association with colorectal cancer (CRC) progression was studied using semi-quantitative PCR. One hundred and nineteen primary CRC specimens were examined for which follow-up information was available for a median period of 29 months (range, 1-104 months). KLK10 expression was found to be significantly associated with TNM stage (p=0.028). Cox proportional hazard regression model using univariate analysis revealed for the first time that high status KLK10 expression is a significant factor for disease-free survival (DFS; p=0.002) and overall survival (OS; p=0.026) of patients. Kaplan-Meier survival curves demonstrated that KLK10 expression of low status is significantly associated with longer DFS (p=0.001) as well as OS (p=0.021), suggesting that KLK10 gene expression may be used as a marker of unfavorable prognosis for CRC. As the epigenetics of cancer are unraveled, KLK10 may represent not only a novel biomarker, but also a promising future therapeutic target for the disease.

Clinical significance of kallikrein-related peptidase 7 (KLK7) in colorectal cancer.

Human tissue kallikrein-related peptidases are a family of 15 secreted serine proteases, located at chromosome 19q13.4. Most of them have been reported to be potential biomarkers for several carcinomas and other diseases. Human tissue kallikrein-related peptidase 7 (KLK7) has been purified from human stratum corneum and resembles a chymotryptic endopeptidase originally called stratum corneum chymotryptic enzyme (SCCE). In this study, we examined for the first time, the prognostic value of KLK7 mRNA expression, using a semi-quantitative RT-PCR method, in 105 colorectal cancer tissues for 54 of which, paired normal colonic mucosa were available. Furthermore, we analysed the expression of KLK7 in 10 adenomas, in 18 biopsies of inflamed colon mucosa, as well as in 22 human cancer cell lines of various origin, four of them being of colon. A defined number of colon cancer samples were also examined by immunohistochemistry. KLK7 expression was higher in cancerous than in normal tissues. Less differentiated tumors of more advanced stage showed higher KLK7 expression. Follow-up analysis revealed that KLK7 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). In addition, selected colon cancer samples highly expressing KLK7 gene, showed intense immunohistochemical staining for KLK7, enhancing RT-PCR results. Present data suggest that KLK7 gene is up-regulated in colon cancer and its expression predicts poor prognosis for colon cancer patients.

KLK11 mRNA expression predicts poor disease-free and overall survival in colorectal adenocarcinoma patients.

BACKGROUND: Dysregulated expression of several KLK family members has been observed in colorectal adenocarcinoma. In the present study, the prognostic value of KLK11 mRNA expression as a molecular tissue biomarker in colorectal adenocarcinoma was examined. MATERIALS & METHODS: Using quantitative real-time PCR, KLK11 mRNA expression was studied in 120 cancerous and 41 paired noncancerous colorectal specimens obtained from 120 patients with primary colorectal adenocarcinoma. RESULTS: A significant upregulation of KLK11 transcripts in colorectal tumors was observed. KLK11 mRNA expression was associated with the depth of tumor invasion and the histological grade. Furthermore, KLK11 mRNA expression predicted poor disease-free and overall survival, independently of patient gender, age, tumor size, location, histological subtype, grade, venous invasion, lymphatic invasion, TNM stage, radiotherapy and chemotherapy treatment. CONCLUSION: KLK11 mRNA expression could be considered as a new molecular prognostic biomarker in colorectal adenocarcinoma, with additional prognostic value in patients with highly invasive tumors and/or positive lymph nodes.

Clinical significance of kallikrein-related peptidase (KLK10) mRNA expression in colorectal cancer.

OBJECTIVES: Colorectal cancer (CRC) is one of the three most common cancers in both genders. Even though several biomarkers are in use in diagnosis and prognosis of the disease, they are marred by limited specificity and sensitivity. The human kallikrein-related peptidase 10 (KLK10) gene is a member of the human tissue kallikrein family. Because prostate specific antigen (PSA), the best biomarker for detecting and monitoring prostate cancer, is a member of this family, many other members, including KLK10, have been widely examined as novel biomarkers for different cancer types. In previous studies, KLK10 has been proposed as a diagnostic biomarker for ovarian carcinoma, while its methylation on exon 3 has been proposed as a prognostic marker for early-stage breast cancer patients. The purpose of this study was to analyse KLK10 mRNA expression and examine its prognostic value and potential clinical application as a novel molecular tissue biomarker in CRC. DESIGN AND METHODS: The study group consisted of 190 colorectal samples. Total RNA was extracted from pulverised tissues and cDNA was prepared by reverse transcription. KLK10 was amplified by real-time PCR. B2M was used as a reference gene and HT-29 cells as positive control. RESULTS: KLK10 expression was significantly higher in cancer tissues (P<0.001). Tumours of advanced TNM and Dukes' stage showed high KLK10 expression status (P=0.036; P=0.025). Patients with high KLK10 expression had a shorter disease-free and overall survival rates (P=0.014; P=0.020). CONCLUSION: Our results suggest that KLK10 may serve as a new marker of unfavourable prognosis of colorectal cancer.