― 241 ―A) PanNETs may experience two-hit inactivation of PHLDA3 through LOH and methylation at its loci. B) Tumorigenesis in PanNETs requires the loss of both PHLDA3 and MEN1 function, as these genes normally restrain cell proliferation in islet cells. C) The progressive development of PanNETs involves the functional loss of PHLDA3 alongside MEN1, leading to islet abnormalities and eventual tumorigenesis.chromosomal region, where the PHLDA3 gene resides, with PanNETs aggressiveness 10). Loss of PHLDA3 leads to increased AKT activation and subsequently increased signaling through the PI3K/AKT/mTOR pathway, which is commonly upregulated in PanNETs 11). Recently, hyper-methylation of p53 and its downstream target PHLDA3 promoter regions has been reported, suggesting epigenetic and genetic regulation of p53 signaling in PanNETs development. We found that the loss of PHLDA3 expression in PanNETs is caused by a combination of LOH and promoter methylation (Fig. 3A) 12). Analysis utilizing a microsatellite marker in close proximity to the PHLDA3 gene revealed LOH in a significant 72% of human PanNETs samples. Furthermore, PanNETs specimens that exhibited LOH showed substantially reduced expression of PHLDA3 compared to specimens without LOH. Interestingly, PanNETs consistently exhibited methylation in the remaining PHLDA3 allele transcriptional regulatory region. The PHLDA3 gene in PanNETs is efficiently silenced through a two-hit inactivation mechanism, including LOH and methylation. The mechanism of downregulation by promoter methylation involves the addition of methyl groups to CpG islands within the promoter region of the PHLDA3 gene. This modification represses transcription by preventing the binding of transcription factors and recruiting methyl-binding proteins that form a repressive chromatin structure. In PanNETs, a CpG island overlapping the promoter region and first exon of PHLDA3 has been identified as a site of frequent methylation. Methylation at this site is tightly linked to transcriptional silencing, as demonstrated by significantly reduced PHLDA3 mRNA expression in PanNETs with promoter methylation.Treatment with the demethylating agent 5-aza-C led toFig 3. Defects in the PHLDA3 gene are observed in PanNETs.
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