MYC and gastric adenocarcinoma carcinogenesis

Abstract

MYC is an oncogene involved in cell cycle regulation, cell growth arrest, cell adhesion, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function. It has been described as a key element of several carcinogenesis processes in humans. Many studies have shown an association between MYC deregulation and gastric cancer. MYC deregulation is also seen in gastric preneoplastic lesions and thus it may have a role in early gastric carcinogenesis. Several studies have suggested that amplification is the main mechanism of MYC deregulation in gastric cancer.In the present review, we focus on the deregulation of the MYC oncogene in gastric adenocarcinoma c a r c i n o g e n e s i s , i n c l u d i n g i t s a s s o c i a t i o n w i t h Helicobacter pylori (H pylori ) MYC AND CANCERMYC gene was found to be the cellular homolog of retroviral v-myc oncogene about 30 years ago [12][13][14] . It is located on chromosomal region 8q24.1, has 3 exons [15,16] and encodes a nuclear phosphoprotein [17] . MYC has to heteromerize with MAX, a protein expressed constitutively, to acquire DNA-binding activity. MYC/MAX dimmers are made viable by a basic region helix-loop-helix leucine-zipper motif (bHLHZip), conserved sequences in the carboxyl terminus of both proteins. MYC/MAX dimmers bind to E-box sequence CACGTG in the promoters of specific target genes and stimulate their transcription [18] . MYC has an effect on up to about 15% of genes in genomes of many organisms, from flies to humans [19] . Groups of genes involved in cell cycle regulation, metabolism, ribosome biogenesis, protein synthesis, and mitochondrial function are over-represented in the Myc target gene network.MYC also consistently represses genes involved in cell growth arrest and cell adhesion [20] . Dominguez-Sola et al [21] recently showed that Myc interacts with the prereplicative complex and localizes to early sites of DNA synthesis. Thus, it also has a direct role in the control of DNA replication.MYC regulates transcription from its targets through several mechanisms, including recruitment of histone acetylases, chromatin modulating proteins, basal transcription factors and DNA methyltransferase [22][23][24][25][26] . Protein products of MYC target genes g o on to mediate the downstream effects of MYC on cell biology. MYC is then rapidly degraded, and the pathway switches to a transcriptionally repressive state when MAX dimerizes with a group of related bHLH-Zip proteins, the MAD family, that act as MYC antagonists [27] ( Figure 1).MYC expression might be regulated transcriptionally (initiation and elongation), post-transcriptionally (mRNA stability and translation) or post-translationally (protein stability) [28] . MYC is generally recognized as an important regulator of proliferation, growth, differentiation and apoptosis [29,30] . Therefore, it is also accepted that the deregulation of MYC expression is a major event in cancer pathogenesis or progression. Deregulated expression of a wild-type MYC protein is suff...

Case study of stomach adenocarcinoma conducted at a cancer referral hospital in northern Brazil

“…In addition, the intestinal type of adenocarcinoma was more frequent than the diffuse type, a finding also demonstrated in other studies conducted in Brazil (19,22) . These data support the proposal that the intestinal type predominates in geographic areas that show a high incidence of gastric cancer, such as the State of Pará (6,19,29) . In patients in whom only one region of the stomach was affected by the disease, the antrum was the most frequent tumor location, followed by the gastric body.…”

MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors

“…41 c-MYC overexpression has frequently been observed in gastric cancer and is associated with therapeutic resistance of certain tumor entities. [16][17][18][19]42 A highaffinity c-MYC binding site in the MCL1 promoter has also been found in U937 histiocytoma cells. 43 Consistent with the downregulation of MCL1 protein and mRNA after the knockdown of c-MYC, we detected binding of c-MYC to the MCL1 promoter in gastric cancer cell lines, demonstrating direct transcriptional regulation.…”

Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells

“…However, we tested the hypothesis that HDAC4 overexpression is essential for gastric tumor cell viability using the gastric cancer cell line SNU-16, which was specifically suited for this study because (i) the originating patient had limited prior therapy (no 5-fluorouracil/adriamycin/mitomycin-C treatment) [27], (ii) c-myc is amplified, which is a common event in gastric cancer (for review, see [28]) and which appears to repress the efficacy of the class I HDAC inhibitor vorinostat [29], and (iii) it has physiologic tumor levels of HDAC4 (Fig. 3A).…”