ABSTRACT
BACKGROUND: Metabolic disturbance is closely correlated with intrahepatic cholangiocarcinoma (IHCC), and we aimed to identify metabolic gene marker for the prognosis of IHCC. METHODS: We obtained expression and clinical data from 141 patients with IHCC from public databases. Prognostic metabolic genes were selected using univariate Cox regression analysis. Unsupervised cluster analysis was applied to identify IHCC subtypes, and CIBERSORT was used for immune infiltration analysis of different subtypes. Then, the metabolic gene signature was screened using multivariate Cox regression analysis and the LASSO algorithm. The prognostic potential and regulatory network of the metabolic gene signature were further investigated. RESULTS: We screened 228 prognosis-related metabolic genes. Based on their expression levels, IHCC samples were divided into two subtypes, which showed significant differences in survival and immune cell infiltration. After LASSO analysis, eight metabolic genes including CYP19A1, SCD5, ACOT8, SRD5A3, MOGAT2, PFKFB3, PPARGC1B, and RPL17 were identified as the optimal genes for the prognosis signature. The prognostic model had excellent predictive abilities, with areas under the receiver-operating characteristic curves over 0.8. A nomogram model was also established based on two independent prognostic clinical factors (pathologic stage and prognostic model), and the generated calibration curves and c-indexes determined its excellent accuracy and discriminative ability to predict 1- and 5-year survival status (c-indexes>0.7). Finally, we found that miR-26a-5p, miR-27a-3p, and miR-27b-3p were the upstream regulators that mediate the involvement of gene signatures in metabolic pathways. CONCLUSION: We developed eight metabolic gene signatures to predict IHCC prognosis and proposed potential upstream regulatory axes of gene signatures.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Gene Regulatory Networks/genetics , MicroRNAs , Transcriptome/genetics , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolism , Female , Humans , Male , MicroRNAs/genetics , MicroRNAs/metabolism , Middle Aged , Nomograms , PrognosisABSTRACT
Histone deacetylase inhibitors (HDACIs) have been shown to have antiproliferative activity through cell-cycle arrest, differentiation, and apoptosis in colorectal cancer (CRC) cells. Our present study revealed that one HDAC inhibitor, valproic acid (VPA), can obviously promote in vitro motility of HCT-116 and SW480 cells. VPA treatment significantly down regulates the expression of epithelial markers E-Cadherin (E-Cad) and Zona occludin-1(ZO-1) while up regulates the mesenchymal markers Vimentin (Vim) and N-cadherin (N-Cad), suggesting that VPA can trigger the epithelial-mesenchymal transition (EMT) of CRC cells. VPA treatment significantly increases the expression and nuclear localization of Snail, the key transcription factors of EMT. Snail knockdown by siRNAs obviously reverses VPA induced EMT of HCT-116 and SW480 cells. Further, VPA can decrease the ubiquitination, increase the acetylation, and then elevate the stabilization of Snail. VPA also increases the phosphorylation of Akt/GSK-3ß. The inhibitor of PI3K/Akt, LY2994002, significantly attenuates VPA induced phosphorylation of Akt and GSK-3ß and up regulation of Snail and Vim. Collectively, our data reveal that VPA can trigger the EMT of CRC cells via up regulation of Snail through AKT/GSK-3ß signals and post-transcriptional modification. It suggests that more attention should be paid when VPA used as a new anticancer drug for CRC patients.
