Gene expression profile in BALB/c-3T3 cells transformed with beryllium sulfate

Differential gene expression was studied to understand the potential molecu lar mechanism responsible for cell transformation and tumorigenesis induced by beryllium. Cell lines were derived from tumors developed in nude mice i njected subcutaneously with BALB/c-3T3 cells morphologically transformed wi th beryllium sulfate. Using the Atlas mouse 1.2 cDNA expression microarray, the expression profiles of 1176 genes, belonging to several different func tional categories, were studied in the tumor cells as well as in the nontra nsformed control cells. Expression of 18 genes belonging to two functional groups was found to be consistently and reproducibly different (at least tw ofold) in the tumor cells compared with the control cells. The functional g roups and the differentially expressed genes are as follows: The cancer-rel ated genes (nine genes) were the ets-related transcription factor activated by ras, colony-stimulating factor, A-myb, sky, cot1, c-fos, c-jun, c-myc, and R-ras proto-oncogenes. The DNA synthesis, repair, and recombination gen es (nine genes) were the DNA replication licensing factor MCM4, the DNA rep lication licensing factor MCM5, the DNA mismatch repair gene PMS2, the DNA excision repair gene, the DNA mismatch repair gene MSH2, the ultraviolet ex cision repair gene Rad23, DNA ligase 1, Rad51, and Rad52. The differential gene expression profile was confirmed with reverse transcription - polymera se chain reaction using primers specific for the differentially expressed g enes. In general, expression of the cancer-related genes was upregulated, w hile expression of genes involved in DNA synthesis, repair, and recombinati on was downregulated in the tumor cells compared with the control cells. Us ing c-fos and c-jun, two of the differentially expressed genes, as model ge nes, we have found that in the nontransformed BALB/c-3T3 cells, the berylli um-induced transcriptional activation of these genes was dependent on pathw ays of protein kinase C and mitogen-activated protein kinase and independen t of reactive oxygen species. These results indicate that beryllium-induced cell transformation and tumorigenesis are accompanied by and are possibly a product of alterations in expression of genes related to cancer and to DN A synthesis, repair, and recombination. (C) 2001 Wiley-Liss, Inc.