Oncogenic role of a long-term high-fat diet-induced DNM1 in hepatocellular carcinoma

Abstract

Background:Dietary patterns play important roles in the occurrence and development of numerous human cancers including hepatocellular carcinoma (HCC). In this study, we explored and investigated the potential tumor-promoting genes in mice received high-fat diet (HFD).Methods:We initiated the process by analyzing liver gene expression profile of mice received HFD downloaded from Gene Expression Omnibus (GEO No. GSE108169). Differentially overexpressed genes were assembled and analyzed for the clinical prognosis and biological functions in human cancer databases. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) were screened by The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), Human Protein Atlas (HPA), LinkedOmics analysis, TIMER2.0, and Q-omics analysis. Survival analyses were performed to examine the significance for the newly identified biomarkers for HCC.Results: Among the top 10 overexpressing genes in HFD-fed mice liver, a neuron-specific protein, dynamin 1 (DNM1) was identified as a significant prognostic predictor for poor HCC survival examined by UALCAN. Using HPA, we discovered that normal liver tissue does not express DNM1 protein whereas it was found in 30% HCC, and abundant DNM1 protein was detected in HCC cell cytoplasm and membrane. DNM1 gene expression is positively correlated some genes enhanced epithelial-mesenchymal transition (EMT), proliferation, and neural transduction signaling, and its negatively correlated genes enhanced certain metabolism and host-defense ability. Furthermore, positive correlations between DNM1 and CD8 T cells, regulatory T cells (Treg), B cells, macrophages, and natural killer (NK) cells were observed, indicating possible associations between DNM1 and infiltrating immune cells. We then identified a common gene, TAR (HIV-1) RNA Binding Protein 1 (TARBP1) by overlapping the differentially downregulated genes of HCC cells with single-guide DNM1 (sgDNM1), short-hairpin DNM1 (shDNM1), and the TCGA DNM1 correlated genes that also correlated significantly with poor overall survival and disease-free survival of HCC. ConclusionsThis is the first study proposing a role of the HFD-induced hepatic DNM1 over-expression might affect tumor development and immune microenvironment in human HCC. The discovery of this novel marker can add insights into the link of high fat diet and HCC, and provide potential therapeutic target pathways for treating HCC. We suggest DNM1 be a potential prognostic biomarker and therapeutic target for HCV-positive human HCC.