Up‐regulation and clinical significance of serine protease kallikrein 6 in colon cancer

Abstract

BACKGROUND: Kallikrein-related peptidase 6 (KLK6) encodes a trypsin-like serine protease that is up-regulated in several cancers, although the putative functions of KLK6 in cancer have not been elucidated. In the current study, overexpression of KLK6 was identified in colon cancer, and the possibility that KLK6 may be a suitable candidate as a tumor marker was examined. METHODS: Messenger RNA (mRNA) transcript levels and protein up-regulation of KLK6 in colon cancer tissues was examined using reverse transcriptase-polymerase chain reaction, immunohistochemistry, and clinicopathologic analyses. Cell proliferation, invasiveness, and antiapoptotic activity were determined in colon cancer cells that were transfected with small-interfering RNA (siRNA) of KLK6. RESULTS: KLK6 mRNA was up-regulated significantly in tumor tissues compared with nontumor regions. KLK6 protein was strongly expressed in adenocarcinomas but was not expressed in normal mucosa or in premalignant dysplastic lesions. Sera from patients with colon cancer revealed an increase in KLK6 secretion (0.25 lg/mL; P ¼ .031) compared with noncancer cells (0.19 lg/mL). Clinicopathologic and immunohistochemical studies of 143 patients with colon cancer revealed a significant correlation between KLK6 expression and Dukes disease stage (P ¼ .005). High KLK6 expression was associated significantly with shorter overall (P ¼ .001) and recurrence-free survival (P ¼ .001). The rates of proliferation and invasiveness were decreased by 50% in cells that were transfected with KLK6 siRNA. The overexpression of KLK6 led to decreased activity of the E-cadherin promoter. CONCLUSIONS: KLK6 was up-regulated significantly in tissues and sera from patients with colon cancer and was associated closely with a poor prognosis, suggesting that KLK6 may be used as a potential biomarker and a therapeutic target for colon cancer.

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

“…In ovarian cancer, for example, accumulating data suggest that KLK6 is responsible for increased E-cadherin shedding, which, in turn, increases metastasis and ascites in epithelial ovarian cancer (7,19,20). Similarly, in colon cancer, in which KLK6 can be used for both prognosis and diagnosis, it induces the invasiveness and proliferation of cancer cells by down-regulating E-cadherin, thereby interrupting E-cadherin-mediated cell-cell adhesion -a prerequisite for tumor invasiveness and metastasis (14,16,21). Moreover, KLK6 appears to be relevant for breast cancer, as high KLK6 expression levels were recently shown to promote the invasiveness of breast cancer cells; KLK6 serum levels were found to be significantly higher in patients with invasive breast cancer, and patients with high KLK6 expression showed poorer survival rates (22)(23)(24).…”

“…Several studies have investigated how KLK6 is involved in the pathogenesis and metastasis of various types of cancer (21,24,25). For instance, KLK6 has been shown to be involved in the progression of melanoma, where it triggers tumor cells and tumor-associated parenchymal cells in the microenvironment of the tumor through the proteolysis and activation of the proteinase-activated receptor PAR1, which leads to the acquisition of a malignant phenotype by facilitating tumor cell invasion and metastasis (8,26,27).…”

“…In addition, in a non-small cell lung cancer model system, KLK6 has been shown to promote the proliferation of lung tumor cells, and this effect was facilitated by KLK6 cleavage and activation of PAR2 (28). By degrading various proteins in the extracellular matrix (29), KLK6 has also been shown, in vitro, to increase the metastatic potential of tumor cells (29,30); concomitantly, both in vitro (6)(7)(8) and in vivo (7,31) studies have established a correlation between the ectopic expression of KLK6 and an increase in tumor proliferation and migration, while an RNA interference-induced KLK6 suppression reduces the cell growth, proliferation, and invasive potential of tumors (14,21). These data underlie KLK6 as an attractive target for novel molecules that could inhibit its proteolytic activity as a treatment for various cancers (32)(33)(34).…”

Development of a survival prediction model for gastric cancer using serine proteases and their inhibitors

“…The urokinase plasminogen activator, one of the SPs, promotes tumor cell invasion (7) and the kallikrein prostate-specific antigen predicts prognosis of prostate cancer (8). KLK6 was found to be significantly up-regulated in tissues and sera from patients with colon cancer and was closely associated with a poor prognosis, suggesting that KLK6 may be used as a potential biomarker and a therapeutic target for colon cancer (9). SP inhibitors (serpins) are the largest family of protease inhibitors identified to date.…”

10 Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients

“…Consistent with most reports, we found high KLK6 expression in primary tumor samples of 42.6 % HNSCC patients. However, while induced KLK6 expression alone or in combination with other KLK family members was associated with poor progression-free and overall survival in colorectal cancer [31,32], gastric cancer [33,34], pancreatic ductal adenocarcinoma [35], ovarian cancer [36,37], lung cancer [38], and intracranial tumors [39,40], a high KLK6 expression pattern served as favorable prognostic biomarker in our OPSCC and LSCC patient cohorts. These data suggest a contextspecific role of KLK6 in regulating the malignant progression and response to therapy, with both tumor promoting and tumor protective functions depending on the cellular origin of the tumor tissue.…”