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

The cover for issue 58 of Oncotarget features Figure 5, "Representative images of KLK6 and HMGA2 IHC staining in the surgical material of a colon cancer patient," by Chen, et al.

In the CRC patients, KLK6 protein levels were elevated in the non-cancerous distant and adjacent tissues, compared to their paired tumor tissues.

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.

Dr. Natalia A. Ignatenko from the University of Arizona Cancer Center, Tucson, AZ, USA and the Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA said, "Human 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"

As a proteolytic enzyme, 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.

Figure 5: Representative images of KLK6 and HMGA2 IHC staining in the surgical material of a colon cancer patient. Staining was done in a morphologically normal tissue collected 10 cm away of a tumor, tissue collected 1 cm away from a tumor site and in a tumor sample.

The researchers previously reported that introduction of the mutated K-RAS oncogenic driver gene into Caco-2 colon cell line, which express wild type K-RAS, induced KLK6 expression.

Knocking down endogenously overexpressed KLK6 in highly invasive HCT116 cells, which carries K-RAS mutation, was sufficient to decrease the invasive and metastatic properties of this cell line.

In the present study, the authors investigated the consequences of KLK6 overexpression and its enzymatic activity in colon cancer cells.

They found that KLK6 overexpression in colon cancer cells, regardless of its enzymatic activity, induces the expression of transcription associated protein HMGA2, which has been identified as a driver of the CRC progression and metastasis.

The Ignatenko Research Team concluded, "Moreover, disease recurrence was noted in patients with high KLK6 scores and positive HMGA2 staining. Although more robust analysis of the clinical cases is required, our current observations suggest that KLK6 may contribute to the LIN28B-let7-HMGA2 axis and may serve as an early marker of disease recurrence."

Full text - https://doi.org/10.18632/oncotarget.27153

Correspondence to - Natalia A. Ignatenko - nai@email.arizona.edu

Keywords - colorectal cancer, kallikrein-related peptidase 6 or KLK6, SMAD2/3, epithelial-mesenchymal transition, HMGA2