IDENTIFICATION OF GENES MODULATED BY PROBIOTICS IN COLORECTAL CANCER

CARRIERE P; FEIJÓO N; NOVOA DÍAZ MB; GIGOLA G; CALVO N; GENTILI C

Modalidad virtual

Jornada; XXIII JORNADAS ANUALES DE LA SOCIEDAD ARGENTINA DE BIOLOGÍA ?Evolución, desarrollo y cambio tecnológico: impacto sobre el crecimiento de los individuos y la sociedad?.; 2021

Sociedad Argentina de Biología (SAB)

Probiotics are recognized for their beneficial effect in intestinal pathologies, but their use in therapeutic schemes is still under study due to the complexity of the molecular mechanisms involved in their action. We previously observed that Lactobacillus casei (L. casei) andBifidobacterium breve (B. breve) orally administered in a mixture of probiotic strains to rats with colorectal cancer (CRC) and treated with capecitabine delayed tumor development, improved clinical manifestations and overall survival of animals. The aim of this work was to identify genes and molecular functions associated with the observed effect of both probiotic strains on CRC through an analysis of gene expression profiles and their integration into protein–protein interaction (PPI) networks. The Gene Expression Omnibus (GEO) database and GEO2R analysis software were used to analyze differentially expressed genes (DEG) in microarray expression profiles of CRC patient samples, including GSE41258, GSE37364, GSE68468, and GSE44076. The DEGs (log2FC > 1 and p adj < 0.05) were incorporated into the FunRich software, and 174 overexpressed genes (Up) and 218 common negatively regulated genes (Do) were identified in the tumor samples from the four CRC datasets. Furthermore, the expression profiles of the Caco-2 cell line derived from CRC co-cultured with L. casei (DN-114001) or with B. breve (DN-156007) (GSE37369) were evaluated. The expression profile analyzed in the Caco-2 cell line resulted in 129 genes Up and 57 genes Do under the effect of L. casei, and 379 genes Up and 310 genes Do under the effect of B. breve. The functional enrichment by Enrichr showed that the genes Up by the effects of both strains are involved in cancer signaling pathways (p adj < 8.37e-05) and the Do genes in the FOXO signaling pathway (p adj < 2.76e-04), among others. The overlap between the DEG in CRC and the DEG in the cell model co-cultured with probiotics resulted in 2 Up genes and 12Do genes in CRC that reverted their expression due to the effect of both strains, finding the major change in the growth/differentiation factor-15 (GDF-15) gene. This factor is also known as the macrophage inhibitory cytokine-1 (MIC-1). In addition, using Cytoscape software, the integration of DEG expression in the PPI network showed that GDF-15 is associated with the epithelial membrane protein 1 (EMP1), a tumor suppressor in CRC, and with the activating transcription factor 3 (ATF3) involved in the regulation of immune responses. This bioinformatic analysis indicates that these probiotics could have an immunomodulatory effect through the regulation of GDF-15 in CRC. Experimental studies are necessary to validate this data.