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

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.

L1CAM, CA9, KLK6, HPN, and ALDH1A1 as Potential Serum Markers in Primary and Metastatic Colorectal Cancer Screening

“…The latter was undoubtedly in parallel with other previously published studies. For instance, overexpression of KLK6 was related to epithelial–mesenchymal transition during CRC progression [ 45 , 99 ]. In 2019, Chen et al discovered critical functions of KLK6 enzymes in CRC advancement to late stages via activation of the high mobility group A2 protein [ 99 ].…”

“…For instance, overexpression of KLK6 was related to epithelial–mesenchymal transition during CRC progression [ 45 , 99 ]. In 2019, Chen et al discovered critical functions of KLK6 enzymes in CRC advancement to late stages via activation of the high mobility group A2 protein [ 99 ]. Furthermore, KLK6 expression in CRC correlated significantly with increasing tumor stage and histological grade [ 100 ] and was connected with a more advanced Dukes’ stage, liver metastasis, and poor prognosis [ 37 , 38 , 39 , 40 ].…”

HMGA Genes and Proteins in Development and Evolution

“…HMGA2 involvement in EMT is very well documented in a variety of tumors, and we have discussed some of its involvement in tumor EMT and migration in connection with NCCs [146,147,[150][151][152][153][154][211][212][213][214][215][216][217][218][219]. HMGA2 is also involved in EMT of crystalline epithelial cells in lens fibrosis; this process apparently uses the same pathway of TGFβ-regulated EMT, recruiting SMAD3, HMGA2, and SNAI [220][221][222].…”

Emerging roles for HMGA2 in colorectal cancer

“…In addition, different upstream factors accounted for dysregulation of HMGA2 in CRC. For instance, KLK6 enhanced cell invasion via promoting the expression of HMGA2 in CRC [ 78 ]. High glucose could facilitate EMT of CRC cells by increasing HMGA2 protein [ 79 ].…”