Uncovering the clinical impact of kallikrein-related peptidase 5 (KLK5) mRNA expression in the colorectal adenoma-carcinoma sequence

Background: Kallikrein-related peptidases (KLKs) are a subgroup of serine proteases located on chromosome 19q13.3. Most KLKs have been extensively studied as potential biomarkers for several carcinomas and other diseases. KLK5 was originally identified from a keratinocyte library, and its enzyme was purified from the stratum corneum of human skin. KLK5 was shown to be differentially expressed in a variety of endocrine tumors, although it is not as yet examined widely in colorectal cancer (CRC). Methods: In this study, we quantitatively assessed the mRNA expression status of KLK5 in 197 colorectal tissues from 133 patients (70 cancerous and their paired normal colonic mucosa for 64 of them, as well as 63 colorectal adenomas) by quantitative real-time PCR (qPCR) using TaqMan probes. Statistical analysis evaluated the results. Results: It was shown that KLK5 expression is reduced following the histologically non-cancerous-adenoma sequence (p < 0.001), whereas it is increased during the sequence adenoma-carcinoma (p < 0.001). Furthermore, KLK5 positive expression is associated with positive nodal status (p = 0.022), advanced tumor stage (p = 0.038) and high histological grade (p = 0.033). Cox univariate analysis revealed that KLK5 positive expression is associated with disease-free survival (DFS) (p = 0.028) and overall survival (OS) of patients (p = 0.048). Kaplan-Meyer survival models showed that patients with positive KLK5 expression have lower DFS (p = 0.009) and OS (p = 0.019). Receiver operating characteristic (ROC) analysis demonstrated for first time that KLK5 expression had significant discriminatory values between cancer and adenoma tissues (area under the curve [AUC] 0.77; 95% confidence interval [CI] = 0.69-0.85, p = 0.03). Conclusions: KLK5 mRNA expression may be useful for the differentiation of CRC from colorectal adenoma and represents a potential unfavorable prognostic biomarker for CRC.