Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer

• Main Authors: Ritu Pandey, Muhan Zhou, Yuliang Chen, Dalila Darmoul, Conner C. Kisiel, Valentine N. Nfonsam, Natalia A. Ignatenko
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: Genes
• Subjects: colorectal cancer; kallikrein 6; TCGA; gene set enrichment analysis; K-RAS-oncogene; regulatory pathways
• Online Access: https://www.mdpi.com/2073-4425/12/5/749

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 <i>KLK6</i> 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 (<i>TTN</i>), <i>APC</i>, <i>K-RAS</i>, and <i>MUC16</i> 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.