Parallel overexpression and clinical significance of kallikrein-related peptidases 7 and 14 (KLK7 & KLK14) in colon cancer

Abstract

Currently available colon cancer (CC) markers lack sensitivity and specificity. Kallikrein-related peptidases (KLKs) present a new class of biomarkers under investigation for diverse diseases, including cancer. KLKs are co-expressed in various tissues participating in proteolytic cascades. KLK7 in human tumours facilitates metastasis by degrading components of the extracellular matrix. KLK14 promotes tumourigenesis by activating proteinase-activated receptors. In the present study we examined the concomitant expression of KLK7 and KLK14 in245 colonic tissue specimens from 175 patients; 70 were pairs of cancerous-normal tissues, 31 were cancerous tissues and 74 were colonic adenomas. We used quantitative real-time PCR and proved that both genes are up-regulated in CC at the mRNA level. Receiver-operating characteristic (ROC) analysis of our results showed that both genes have discriminatory value between CC and adenoma tissues, with KLK14 obtaining greater distinguishing power (area under the curve [AUC]=0.708 for KLK14; AUC=0.669 for KLK7). Current work showed that the two genes are fairly co-expressed in all three types of colon tissues examined (normal rs=0.667, p<0.001, adenomas rs=0.373, p=0.001, carcinomas rs=0.478, p<0.001). KLK14 is associated with shorter disease-free survival (DFS) and overall survival (OS) of patients (p=0.003, p=0.016 respectively), whereas KLK7only with shorter DFS (p=0.004). KLK7 and KLK14 gene expression can be regarded as markers of poor prognosis for CC patients with discriminating power between CC and adenoma patients.

mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients

“…Therefore, high mRNA expression of the KLK14 gene is most likely an independent predictor of poor prognosis in CLL. A similar prognostic role has been suggested for KLK14 expression in breast cancer [45] and colon cancer [20]. On the contrary, KLK14 has been suggested as a molecular biomarker of favorable prognosis in ovarian cancer [24].…”

“…In addition, low levels of KLK14 expression have been observed in many other human tissues, including breast, thyroid, kidney, colon, spleen, bone marrow, uterus, small intestine, and placenta [19]. Remarkable alterations in KLK14 mRNA expression have been noticed in several malignancies, including breast, ovarian, prostate, testicular, and colorectal cancer [19][20][21]. For instance, KLK14 mRNA expression is significantly upregulated in cancerous prostate specimens, especially in malignant tumors presenting high aggressiveness.…”

Inhibitors of kallikrein‐related peptidases: An overview

“…Kallikrein peptidases are a family of serine proteases that are implicated in many complex proteolytic networks. Even if the exact physiopathological roles of KLKs in the development or in the progression of several diseases are still not completely elucidated, it is now well‐established that dysregulation of their activities could be associated with several pathophysiological disorders such as Netherton syndrome and cancers . Consequently, inhibition of this excessive proteolytic activity by small synthetic compounds as well as by polypeptidic inhibitors based on natural protein inhibitors might constitute a promising therapeutic strategy.…”

“…Due to these mutations, the LEKTI could not effectively control the proteolytic activity of KLK5, KLK7, and KLK14, inducing inflammation and atopic‐like lesions in the skin . On the other hand, overexpression and activity of mostly all the KLKs were reported to be associated with pro‐cancer determinants . Implications of KLKs in several other pathologies, such as neurodegeneration, neuropsychological disorders, abnormal enamel formation of teeth ( amelogenesis imperfecta ), and so on were also reported.…”

Aberrant expression of kallikrein‐related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion

“…Thus, KLK7 may be an aberrantly expressed melanoma‐produced proteinase with tumorigenic functions and may represent a potential key element in melanoma progression. Although KLK7 has been described as a biomarker in many types of cancers (Devetzi et al ., ; Kryza et al ., ; Walker et al ., ), to our knowledge, this is the first report demonstrating a role for KLK7 in the metastatic process of melanoma. Our study showed that only 69% of the analyzed melanoma cell lines ectopically express KLK7 , whereas KLK14 and KLK6 are expressed by almost all of the cell lines.…”