Identification of Hub Genes and Biological Mechanisms Associated with Non-Alcoholic Fatty Liver Disease and Triple-Negative Breast Cancer.

Abstract

The relationship between non-alcoholic fatty liver disease (NAFLD) and triple-negative breast cancer (TNBC) has been widely recognized, but the underlying mechanisms are still unknown. The objective of this study was to identify the hub genes associated with NAFLD and TNBC, and to explore the potential co-pathogenesis and prognostic linkage of these two diseases. We used GEO, TCGA, STRING, ssGSEA, and Rstudio to investigate the common differentially expressed genes (DEGs), conduct functional and signaling pathway enrichment analyses, and determine prognostic value between TNBC and NAFLD. GO and KEGG enrichment analyses of the common DEGs showed that they were enriched in leukocyte aggregation, migration and adhesion, apoptosis regulation, and the PPAR signaling pathway. Fourteen candidate hub genes most likely to mediate NAFLD and TNBC occurrence were identified and validation results in a new cohort showed that ITGB2, RAC2, ITGAM, and CYBA were upregulated in both diseases. A univariate Cox analysis suggested that high expression levels of ITGB2, RAC2, ITGAM, and CXCL10 were associated with a good prognosis in TNBC. Immune infiltration analysis of TNBC samples showed that NCF2, ICAM1, and CXCL10 were significantly associated with activated CD8 T cells and activated CD4 T cells. NCF2, CXCL10, and CYBB were correlated with regulatory T cells and myeloid-derived suppressor cells. This study demonstrated that the redox reactions regulated by the NADPH oxidase (NOX) subunit genes and the transport and activation of immune cells regulated by integrins may play a central role in the co-occurrence trend of NAFLD and TNBC. Additionally, ITGB2, RAC2, and ITGAM were upregulated in both diseases and were prognostic protective factors of TNBC; they may be potential therapeutic targets for treatment of TNBC patients with NAFLD, but further experimental studies are still needed.