Molecular pathways associated with kallikrein 6 overexpression in colorectal cancer

Ritu Pandey, Muhan Zhou, Yuliang Chen, Dalila Darmoul, Conner C. Kisiel, Valentine N. Nfonsam, Natalia A. Ignatenko

Research output: Contribution to journalArticlepeer-review

Abstract

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death world-wide. 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.

Original languageEnglish (US)
Article number749
JournalGenes
Volume12
Issue number5
DOIs
StatePublished - May 2021

Keywords

  • Colorectal cancer
  • Gene set enrichment analysis
  • K-RAS-oncogene
  • Kallikrein 6
  • Organoid culture
  • Regulatory pathways
  • TCGA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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