Identification and Verification of KEAP1-related genes and targets regulated by potential ingredients in KRAS mutant colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most common tumors with complex pathogenesis, and the recurrence leads to poor prognosis in patients with CRC. In the present study, we explored computational simulations through bioinformatics analysis and identified Differentially Expressed Genes (DEGs) in the crosstalk among KEAP1 oncogenic signatures of KRAS mutant that were associated with progression, metastasis, and poor clinical outcomes in CRC. The most recent TCGA data shows that the KRAS mutation is found in 44% of CRC patients. In total, 28 genes were identified as DEGs, and the hub genes such as CDKN2A, SPP1, FOS, BCL2L11 and HPSE were Verified. We further investigated the correlation between the clinical characteristics with prognostic gene expression levels among the KRAS and KEAP1-related key hub genes in COAD, which as predicted targets and demonstrated the anticancer activities of potential drugs in HERB database. Results indicated that SOX9, SPP1 significant correlation with the target predicition of the active herbal ingredients and molecular docking analysis of Key Genes. Furthermore, KEAP1, NFE2L2, SOX9 expression were decreased significantly with the treatment of potential ingredients. Furthermore, cyclopamine could enhance the sensitivity of HCT116 cells, up-regulated the expression of SPP1, and induced activation of KEAP1-NFE2L2 pathway, which cell death are characteristic features of apoptosis, and enhanced anticancer effect. Therefore, KEAP1-related genes might be important oncogenic signatures in KRAS mutant CRC cells and cyclopamine was identified as a potential ingredient and regulated the predict targets of SOX9 and SPP1, may be expand the efficacy and range of novel and effective therapeutics.