Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein
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Hwudaurw Chen1, Earlphia Sells2, Ritu Pandey1,3, Edward R. Abril1, Chiu-Hsieh Hsu4, Robert S. Krouse5,6, Raymond B. Nagle7, Georgios Pampalakis8, Georgia Sotiropoulou8 and Natalia A. Ignatenko1,3
1 University of Arizona Cancer Center, Tucson, AZ, USA
2 Biochemistry and Molecular and Cellular Biology Graduate Program, Department of Molecular and Cellular Biology, College of Science, University of Arizona, Tucson, AZ, USA
3 Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA
4 Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ, USA
5 University of Arizona College of Medicine, Tucson, AZ, USA
6 Southern Arizona Veterans Affairs Health Care System, Tucson, AZ, USA
7 Department of Pathology, College of Medicine, University of Arizona, Tucson, AZ, USA
8 Department of Pharmacy, University of Patras, Patras, Greece
|Natalia A. Ignatenko,||email:||firstname.lastname@example.org|
Keywords: colorectal cancer; kallikrein-related peptidase 6 or KLK6; SMAD2/3; epithelial-mesenchymal transition; HMGA2
Received: February 15, 2018 Accepted: July 30, 2019 Published: October 22, 2019
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.
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