Dysregulation of pathways involved in the processing of cancer and microenvironment information in MCA plus TPA transformed C3H/10T1/2 cells

The two-stage cell transformation assay is an in vitro model cell culture system to identify the ability of chemicals to act as initiators or promoters of cell transformation and also to study the cellular and molecular mechanisms of chemically induced morphological and neoplastic cell transformation. The global gene expression profiles of 3-methylcholanthrene (MCA) + 12-O-tetradecanoylphorbol-13-acetate (TPA)-transformed C3H/10T1/2 cells are not known. Therefore, we have investigated the global transcriptional profile of MCA + TPA-transformed C3H10T1/2 cells using an 8 x 60 k probe microarray. The study revealed a differential regulation of pathways and gene expressions. Multifold dysregulation was seen in pathways of cancer, phagosomal activity, and tumor cell microenvironment information processing systems, notably the neuroactive ligand-receptor interaction, actin cytoskeleton regulation, tight junction, axon guidance, and cell adhesion molecules. The genes FGF1, EIF4E1B, MAGI1, and GRIA3 showed upregulation; these encoded the pluripotent fibroblast growth factor, the translation initiation factor, the tight junction scaffolding protein, and the antiapoptotic as well as the enhancer of proliferation and migration, respectively. The genes CXCL7/CXCL5/CXCL12, H2DMB1, and HSPA1A showed downregulation; these encoded the chemotactic agent protein, the protein involved in MHC class II antigen processing/presentation or participating in cell adhesion/phagosomal activity/autoimmune disorder, and the chaperone protein stabilizing the existing as well as newly translated cytosolic/organelle proteins against aggregation, respectively. By loss or gain of function, these dysregulated genes apparently seem to reprogram cells for apoptosis or proliferation and support their transformation into the tumor cell phenotype. The observed molecular changes can be seen as molecular signatures of transformed cells and can be of use as objective evidences to C3H/10T1/2 cell transformation assay in investigations on the carcinogenic potential of chemicals and their mechanism of actions using in vitro carcinogenesis method.