ABSTRACT
Numerous mechanisms are believed to contribute to the role of dietary fiber-derived butyrate in the protection against the development of colorectal cancers (CRCs). To identify the most crucial butyrate-regulated genes, we exploited whole genome microarray of HT-29 cells differentiated in vitro by butyrate treatment. Butyrate differentiates HT-29 cells by relaxing the perturbation, caused by mutations of Adenomatous polyposis coli (APC) and TP53 genes, the most frequent mutations observed in CRC. We constructed protein-protein interaction network (PPIN) with the differentially expressed genes after butyrate treatment and extracted the hub genes from the PPIN, which also participated in the APC-TP53 network. The idea behind this approach was that the expression of these hub genes also regulated cell differentiation, and subsequently CRC prognosis by evading the APC-TP53 mutational effect. We used mRNA expression profile of these critical hub genes from seven large CRC cohorts. Logistic Regression showed strong evidence for association of these common hubs with CRC recurrence. In this study, we exploited PPIN to reduce the dimension of microarray biologically and identified five prognostic markers for the CRC recurrence, which were validated across different datasets. Moreover, these five biomarkers we identified increase the predictive value of the TNM staging for CRC recurrence.
Subject(s)
Biomarkers, Tumor/metabolism , Butyrates/pharmacology , Colon/cytology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Cell Differentiation/drug effects , Chromatin Assembly Factor-1/metabolism , Colon/drug effects , Colon/metabolism , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Computational Biology/methods , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression Profiling , Humans , Integrin beta1/metabolism , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Neoplasm Recurrence, Local/drug therapy , Prognosis , Protein Interaction Maps/drug effects , Syk Kinase/metabolismABSTRACT
Caveolin-1(CAV1) is a tyrosine-phosphorylated scaffold protein of caveolae with multiple interacting partners. It functions both as an oncogene and a tumour suppressor depending upon the cellular contexts. In the early stage of colorectal cancers (CRC), CAV1 suppresses tumour progression, while over-expression of CAV1 reduced the tumourigenicity of colon carcinoma cells. In contrast, elevated level of CAV1 was reported in stage III CRC. To address this ambiguity, we studied the functional role and the regulation of CAV1 expression during colonocyte differentiation and apoptosis. Here, we reported for the first time that CAV1 expression was increased during colonocyte differentiation and mediated butyrate-induced differentiation and apoptosis of HT29 cells. CAV1 expression was silenced by promoter hypermethylation in HT-29 cells and reactivated by prolonged histone hyperacetylation of the promoter upon treatment of the cells with butyrate. However, the methylation status was unaltered by butyrate. We for the first time showed that HDAC inhibitor-mediated transactivation of CAV1 was regulated by methylation density of the promoter. Our study further explains the underlying mechanisms of the anti-cancer property of butyrate in CRC.
Subject(s)
Apoptosis , Caveolin 1/genetics , Cell Differentiation , Colon/cytology , DNA Methylation , Promoter Regions, Genetic/genetics , Apoptosis/genetics , Caco-2 Cells , Caveolin 1/biosynthesis , Cell Differentiation/genetics , Cells, Cultured , Colon/metabolism , HT29 Cells , HumansABSTRACT
We report here a 3.2-Mb draft assembled genome of Lactobacillus casei Lbs2. The bacterium shows probiotic and immunomodulatory activities. The genome assembly and annotation will help to identify molecules and pathways responsible for interaction between the host immune system and the microbe.
