Abstract
Kallikrein-related peptidase 6 (KLK6) overexpression is commonly observed in primary tumors of colorectal cancer (CRC) patients and has been associated with tumor aggressiveness, metastasis, and poor prognosis. We previously established a unique contribution of KLK6 in colon cancer metastasis via a specific network of microRNAs and mRNAs. Here we evaluated the cellular functions of KLK6 protease in Caco-2 colon adenocarcinoma cell line after introduction of the enzymatically active or inactive form of the enzyme. We found that proteolytically active KLK6 increased Caco-2 cells invasiveness in vitro and decreased the animal survival in the orthotopic colon cancer model. The active KLK6 induced phosphorylation of SMAD 2/3 proteins leading to the altered expression of the epithelial-mesenchymal transition (EMT) markers. KLK6 overexpression also induced the RNA-binding protein LIN28B and high-mobility group AT-hook 2 (HMGA2) transcription factor, two essential regulators of cell invasion and metastasis. In the CRC patients, KLK6 protein levels were elevated in the non-cancerous distant and adjacent tissues, compared to their paired tumor tissues (p < 0.0001 and p = 0.0157, respectively). Patients with mutant K-RAS tumors had significantly higher level of KLK6 protein in the luminal surface of non-cancerous distant tissue, compared to the corresponding tissues of the patients with K-RAS wild type tumors (p ≤ 0.05). Furthermore, KLK6 and HMGA2 immunohistochemistry (IHC) scores in patients’ tumors and paired adjacent tissues positively correlated (Spearman correlation P < 0.01 and p = 0.03, respectively). These findings demonstrate the critical function of the KLK6 enzyme in colon cancer progression and its contribution to the signaling network in colon cancer.
Highlights
Human Kallikrein 6 (KLK6), is a member of the kallikrein-related peptidase family of proteins, originally identified and cloned based on its aberrant expression in human breast and ovarian cancer [1]
We found that KLK6 overexpression in colon cancer cells, regardless of its enzymatic activity, induces the expression of transcription associated protein high-mobility group AT-hook 2 (HMGA2), which has been identified as a driver of the colorectal cancer (CRC) progression and metastasis [21, 22]
50% of CRC patients with tumor detected in the lymph nodes and 25% of patients without lymph node involvement will undergo recurrence [27]
Summary
Human KLK6 (initially named protease M/zyme/ neurosin), is a member of the kallikrein-related peptidase family of proteins, originally identified and cloned based on its aberrant expression in human breast and ovarian cancer [1]. KLK6 can contribute to the invasive phenotype of cancer cells via degradation of extracellular matrix proteins, such as collagen, fibronectin, laminin, fibrinogen and activation of matrix metalloproteinases [6, 10]. KLK6 has been reported to facilitate cell migration and invasion via its effects on the epithelial-mesenchymal transition (EMT). When KLK6 was overexpressed in mouse keratinocytes and HEK293 cells, an upregulation of the EMT marker vimentin and loss of E-cadherin was observed [10]. Re-expression of KLK6 in non-expressing breast cancer cell lines resulted in suppression of their malignant phenotypes through inhibition of vimentin, upregulation of calreticulin and epithelial markers cytokeratin 8 and 19 [11]. Similar inhibitory function of KLK6 on the EMT markers was reported in head and neck squamous cell carcinoma [15]
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