TY - JOUR
T1 - Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein
AU - Chen, Hwudaurw
AU - Sells, Earlphia
AU - Pandey, Ritu
AU - Abril, Edward R.
AU - Hsu, Chiu Hsieh
AU - Krouse, Robert S.
AU - Nagle, Raymond B.
AU - Pampalakis, Georgios
AU - Sotiropoulou, Georgia
AU - Ignatenko, Natalia A.
N1 - Funding Information:
The presented work was supported by the National Cancer Institute of the National Institutes of Health under award numbers R01CA157595 (to N.A. Ignatenko), Research in this manuscript was directly supported by the Experimental Mouse, Tissue Acquisition and Molecular Analysis, and Biostatistics Shared Resources funded by the National Cancer Institute Award P30CA023074 (to A.E. Kraft, Cancer Center Support Grant). The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/ tcga.
Funding Information:
The presented work was supported by the National Cancer Institute of the National Institutes of Health under award numbers R01CA157595 (to N.A. Ignatenko), Research in this manuscript was directly supported by the Experimental Mouse, Tissue Acquisition and Molecular Analysis, and Biostatistics Shared Resources funded by the National Cancer Institute Award P30CA023074 (to A.E. Kraft, Cancer Center Support Grant). The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
Publisher Copyright:
© 2019 Impact Journals LLC. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Colorectal cancer
KW - Epithelial-mesenchymal transition
KW - HMGA2
KW - Kallikrein-related peptidase 6 or KLK6
KW - SMAD2/3
UR - http://www.scopus.com/inward/record.url?scp=85075733646&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075733646&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.27153
DO - 10.18632/oncotarget.27153
M3 - Article
AN - SCOPUS:85075733646
SN - 1949-2553
VL - 10
SP - 6062
EP - 6078
JO - Oncotarget
JF - Oncotarget
IS - 58
ER -