Adams et al. and Leder et al. demonstrated that MYC mRNA expression deregulation can promote the development of cancer in transgenic mouse models. The increase in MYC mRNA level in human cancers may result from both direct and indirect mechanisms, which could till have several explanations. First, MYC amplification is the most common mechanism of MYC deregulation Inhibitors,Modulators,Libraries in GC. This mechanism leads to increased production of oncogenic products in quan Inhibitors,Modulators,Libraries tities that exceed the transcriptional capacity Cilengitide of a normal double copy gene. Here, we observed three or more MYC gene copies in 51. 5% of gastric tumors specimens. Previous studies from our group also showed that MYC amplification or trisomy of chromosome 8, on which MYC is located, was present in all GC samples examined from individuals in Northern Brazil, as well as in GC cell lines established by our group from tumors of Brazilian patients.
The presence of MYC amplification has also been reported in plasma samples Inhibitors,Modulators,Libraries from individ uals with GC. However, no direct association between MYC copy number variation and mRNA expres sion was detected in the present study. Second, the increase in MYC mRNA expression may result from consistent recombination between the immunoglobulin locus and the MYC oncogene. This phenomenon is frequently described in Burkitts lymph oma and is associated with a longer half life of MYC mRNA in affected cells. Previously, our research group observed MYC insertions in diffuse type GC mainly into chromosomes that are mapped to genes of immunoglobulins.
Thus, chromosomal translocations involving the MYC locus in diffuse type CG in individuals from Northern Brazil might also reflect an increase in MYC mRNA level. Immunohistochemistry analysis revealed that MYC expression is more frequently found in intestinal Inhibitors,Modulators,Libraries type GC than diffuse type GC specimens. These alter ations could KPT-185 lead to an abnormal MYC protein that is not recognized by either of the antibodies used in the present study. Moreover, we observed an association between MYC mRNA expression level and MYC staining. Furthermore, posttranscriptional mechanisms control MYC stability. MYC deregulation has been associ ated with loss of FBXW7, a haploinsufficient tumor suppressor gene. In general, FBXW7 loss may be caused by loss of heterozygosity and mutation. The loss at 4q, the FBXW7 locus, is a recurring chromosomal alterations in GC, and FBXW7 mutations have been found in 3. 7 6% of gastric tumors. In the present study, we observed only one copy of the FBXW7 gene in 45. 16% of the gastric tumors studied. Interestingly, FBXW7 mRNA expression in GC samples is markedly decreased in comparison with corresponding non neoplastic tissue.