Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin (TTN), APC, K-RAS, and MUC16 genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-β, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.
Highlights
One of the key hallmarks of cancer is an ability of transformed cells to invade surrounding tissues, which occurs through induction of cell- and tissue-specific signaling pathways [1]
Sixteen samples were identified as high Kallikrein 6 (KLK6) expressers, and seven samples were selected as low KLK6 expressers
We noted that KLK10 transcript levels were significantly higher than KLK6, KLK7, and KLK8 in normal tissues (Figure 1A), and KLK10 was elevated in tumor samples in KLK6-low group but to a lesser degree than in KLK6-high samples (Figure 1B2)
Summary
One of the key hallmarks of cancer is an ability of transformed cells to invade surrounding tissues, which occurs through induction of cell- and tissue-specific signaling pathways [1]. Proteases, which catalyze the hydrolysis of peptide bonds, have long been associated with colon cancer progression because of their ability to degrade extracellular matrices. Tissue kallikrein-related peptidases (KLK) are a subgroup of serine proteases, known to serve a variety of functions, ranging from the normal physiological processes to different disease conditions, including cancer [2]. Several members of kallikrein family are overexpressed in colon cancer patients, i.e., KLK4, KLK6, KLK7, KLK10, and KLK14 [3,4,5,6]. KLK6 mRNA levels correlated with serosal invasion, liver metastasis, advanced Duke’s stage, and overall poor patient prognosis [8]. Presence of KLK6 transcripts in lymph nodes of colorectal cancer (CRC) patients was associated with the shorter average survival time after surgery and was more sensitive indicator of poor prognosis than carcinoembryonic antigen (CEA) [9]. KLK6 expression in colon cancer can be induced by the major colon cancer driver gene, oncogenic K-RAS, while the knockdown of KLK6 in colon cancer cells leads to suppression of their invasive and metastatic properties [10,11,12]
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