Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein

Hwudaurw Chen, Earlphia Sells, Ritu Pandey, Edward R. Abril, Chiu Hsieh Hsu, Robert S. Krouse, Raymond B. Nagle, Georgios Pampalakis, Georgia Sotiropoulou, Natalia A. Ignatenko

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6062-6078
Number of pages17
JournalOncotarget
Volume10
Issue number58
StatePublished - Jan 1 2019

Fingerprint

High Mobility Group Proteins
Kallikreins
varespladib methyl
Colon
Carcinogenesis
Peptide Hydrolases
Colonic Neoplasms
AT-Hook Motifs
Neoplasms
Neoplasm Metastasis
Colorectal Neoplasms
Proteins
Epithelial-Mesenchymal Transition
RNA-Binding Proteins
Caco-2 Cells
Enzymes
MicroRNAs
Adenocarcinoma
Transcription Factors

Keywords

  • Colorectal cancer
  • Epithelial-mesenchymal transition
  • HMGA2
  • Kallikrein-related peptidase 6 or KLK6
  • SMAD2/3

ASJC Scopus subject areas

  • Oncology

Cite this

Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein. / Chen, Hwudaurw; Sells, Earlphia; Pandey, Ritu; Abril, Edward R.; Hsu, Chiu Hsieh; Krouse, Robert S.; Nagle, Raymond B.; Pampalakis, Georgios; Sotiropoulou, Georgia; Ignatenko, Natalia A.

In: Oncotarget, Vol. 10, No. 58, 01.01.2019, p. 6062-6078.

Research output: Contribution to journalArticle

Chen, H, Sells, E, Pandey, R, Abril, ER, Hsu, CH, Krouse, RS, Nagle, RB, Pampalakis, G, Sotiropoulou, G & Ignatenko, NA 2019, 'Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein', Oncotarget, vol. 10, no. 58, pp. 6062-6078.
Chen H, Sells E, Pandey R, Abril ER, Hsu CH, Krouse RS et al. Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein. Oncotarget. 2019 Jan 1;10(58):6062-6078.
Chen, Hwudaurw ; Sells, Earlphia ; Pandey, Ritu ; Abril, Edward R. ; Hsu, Chiu Hsieh ; Krouse, Robert S. ; Nagle, Raymond B. ; Pampalakis, Georgios ; Sotiropoulou, Georgia ; Ignatenko, Natalia A. / Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein. In: Oncotarget. 2019 ; Vol. 10, No. 58. pp. 6062-6078.
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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.",
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AU - Hsu, Chiu Hsieh

AU - Krouse, Robert S.

AU - Nagle, Raymond B.

AU - Pampalakis, Georgios

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AU - Ignatenko, Natalia A.

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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.

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