1.
Ranking candidate genes of esophageal squamous cell carcinomas based on differentially expressed genes and the topological properties of the co-expression network.
Shen, Y, Tantai, J, Zhao, H
European journal of medical research. 2014;(1):52
Abstract
BACKGROUND The aim of this study was to identify the candidate genes of esophageal squamous cell carcinoma (ESCC). METHODS Gene expression profiling of 17 ESCC samples and 17 adjacent normal samples, GSE20347, was downloaded from Gene Expression Omnibus database. The raw data were preprocessed, and the differentially expressed genes (DEGs) between ESCC and normal samples were identified by using SAM software (false discovery rate <0.001). Then, the co-expression network of DEGs was constructed based on Pearson's correlation test (r-value ≥0.8). Furthermore, the topological properties of the co-expression network were analyzed through NetworkAnalyzer (default settings) of Cytoscape. The expression fold changes of DEGs and topological properties were utilized to identify the candidate genes of ESCC (Crin score >4), which were further analyzed based on DAVID functional enrichment analysis (P-value <0.05). RESULTS A total of 1,063 DEGs were identified, including 490 up-regulated and 573 down-regulated DEGs. Then, the co-expression network of DEGs was constructed, containing 999 nodes and 46,323 edges. Based on the expression fold changes of DEGs and the topological properties of the co-expression network, DEGs were ranked, and the top 24 genes were candidate genes of ESCC, such as CRISP3, EREG, CXCR2, and CRNN. Furthermore, the 24 genes were significantly enriched in bio-functions regarding cell differentiation, glucan biosynthetic process and immune response. CONCLUSION The present study suggested that CRISP3, EREG, CXCR2, and CRNN might be causative genes of ESCC, and play vital roles in the development of ESCC. However, further experimental studies are needed to confirm our results.
2.
Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation.
Dasmahapatra, G, Yerram, N, Dai, Y, Dent, P, Grant, S
Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;(14):4280-90
Abstract
PURPOSE Interactions between the multikinase inhibitor sorafenib (Bay 43-9006) and the histone deacetylase inhibitor vorinostat were examined in chronic myelogenous leukemia (CML) cells sensitive and resistant to imatinib mesylate. EXPERIMENTAL DESIGN K562, LAMA 84, and primary CML patient-derived CD34(+) mononuclear cells were exposed to vorinostat followed by sorafenib, after which effects on cell viability and various survival signaling pathways were monitored by flow cytometry, clonogenic assays, and Western blotting. Real-time reverse transcription-PCR was used to monitor gene expression, and the functional contribution of p21(CIP1) and Mcl-1 down-regulation were determined in cells transfected with corresponding constructs. RESULTS Pretreatment (24 h) with vorinostat followed by sorafenib optimally induced mitochondrial injury and cell death in Bcr/Abl(+) cells (e.g., K562 and LAMA 84). Similar results were obtained in imatinib mesylate-resistant cells expressing activated Lyn as well as in primary CD34(+) bone marrow cells obtained from CML patients. This regimen also markedly inhibited CML cell colony formation. Combined but not individual treatment of CML cells with vorinostat and sorafenib triggered pronounced mitochondrial dysfunction (i.e., cytochrome c, Smac, and AIF release), caspase activation, poly(ADP-ribose) polymerase cleavage, and down-regulation of Mcl-1. Sorafenib also blocked vorinostat-mediated induction of p21(CIP1). Down-regulation of Mcl-1 was caspase and transcription independent, whereas p21(CIP1) down-regulation was partially caspase and transcription dependent. Enforced expression of p21(CIP1) and particularly Mcl-1 significantly attenuated vorinostat/sorafenib-mediated lethality. CONCLUSIONS These findings suggest that combined treatment with vorinostat and sorafenib synergistically induces apoptosis in CML cells through a process that involves Mcl-1 down-regulation and inhibition of p21(CIP1) induction.